research article on stem cell therapy

Neurology and Neurosurgery

Study finds stem cell therapy is safe and may benefit people with spinal cord injuries

May 23, 2024

Mayo Clinic researchers have demonstrated the safety and potential benefit of stem cell regenerative medicine therapy for patients with subacute and chronic spinal cord injury.

The results of the phase 1 Clinical Trial of Autologous Adipose-Derived Mesenchymal Stem Cells in the Treatment of Paralysis Due to Traumatic Spinal Cord Injury, known as CELLTOP, were published in Nature Communications.

Illustration shows the process of fat harvest via biopsy, adipose-derived mesenchymal stem cells (AD-MSC) preparation and administration of treatment.

All trial participants had experienced traumatic spinal injury classified as grade A or B on the American Spinal Injury Association Impairment Scale (AIS). Stem cell treatment was initiated on average 11 months after injury. Participants were evaluated over a two-year period.

Key findings:

Stem cells were successfully manufactured, and products were delivered to all 10 enrolled participants.
No serious adverse effects occurred among any participants. The most commonly reported side effects were headache and musculoskeletal pain, which resolved with over-the-counter treatment.
Seven participants demonstrated improvement, with each moving up at least one AIS grade.

As reported earlier in Mayo Clinic Proceedings, the first participant in the phase 1 trial was a superresponder who, after stem cell therapy, saw significant improvements in the function of his upper and lower extremities.

"Future research may show whether stem cells in combination with other therapies could be part of a new paradigm of treatment to improve outcomes for patients," says Mohamad Bydon, M.D. , a neurosurgeon at Mayo Clinic in Rochester, Minnesota, and the first author of both studies. "Not every patient who receives stem cell treatment is going to be a superresponder. One objective in our future studies is to delineate the optimal treatment protocols and understand why patients respond differently."

Dr. Bydon notes that stem cells' mechanism of action isn't fully understood. The researchers are analyzing changes in participants' MRI and cerebrospinal fluid to identify avenues for potential regeneration. Work is also underway on a larger, controlled trial of stem cell regenerative therapy.

"For years, treatment of spinal cord injury has been limited to stabilization surgery and physical therapy," Dr. Bydon says. "Many historical textbooks state that this condition does not improve. We have seen findings in recent years that challenge prior assumptions. This research is a step forward toward the ultimate goal of improving treatments for patients."

For more information

Bydon M, et al. Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial . Nature Communications. 2024;15:2201.

Bydon M, et al. CELLTOP clinical trial: First report from a phase I trial of autologous adipose tissue-derived mesenchymal stem cells in the treatment of paralysis due to traumatic spinal cord injury . Mayo Clinic Proceedings. 2020;95:406.

Refer a patient to Mayo Clinic.

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Stem cells: past, present, and future

Affiliations.

1 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland. [email protected].
2 Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocław, 50-425, Poland.
3 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland.
PMID: 30808416
PMCID: PMC6390367
DOI: 10.1186/s13287-019-1165-5

In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Keywords: Differentiation; Growth media; Induced pluripotent stem cell (iPSC); Pluripotency; Stem cell derivation; Stem cells; Teratoma formation assay; Tissue banks; Tissue transplantation.

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New way to extend ‘shelf life’ of blood stem cells will improve gene therapy

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Researchers have discovered a way to extend the shelf life of blood stem cells outside the body for use in gene therapy, providing patients with better options and improving their outcomes.

We were able to identify a key molecular pathway...that can be targeted by a drug which is already in use and is safe to use. Elisa Laurenti

Researchers have identified a drug already used for cancer patients, that, when applied to current gene therapy protocols can improve blood stem cell function threefold.

One trillion blood cells are produced every day in humans, and blood stem cells are the only cell types in our body capable of producing all blood cell types over our lifespan, giving them immense regenerative potential.

Blood stem cell gene therapy is a ground-breaking treatment that currently provides the only cure to more than ten life-debilitating genetic diseases and has already saved the lives of more than two million people with blood cancers and other diseases.

These therapies take blood stem cell samples from patients, where their genetic defect is corrected in a dish before being delivered back to the patient. However, limitations persist in blood stem cell therapies because of the shelf life of the cells outside the body. When removed from their environment in the human body and cultured in a dish, most blood stem cells lose their function. The exact timing and cause of this function loss has not previously been well understood.

Now, scientists in the Laurenti Group and others at the University of Cambridge’s Cambridge Stem Cell Institute (CSCI) and Department of Haematology have pinpointed a timeline for the blood stem cells under the current gene therapy protocols, which typically take place over three days. After the first 24 hours in a dish, more than 50% of the blood stem cells can no longer sustain life-long blood production, which is before therapy would even begin in a clinical setting.

During those first 24 hours, the cells activate a complex molecular stress response in order to adapt to the dish. By studying this stress response, the team identified a solution. Through repurposing a cancer growth blocker drug (Ruxolitinib), already in use for cancer treatments, they were able to improve stem cell function in a dish by three times its former capabilities.

The group is now aiming to modify current gene therapy protocols to include this drug, providing patients with the highest number of high-quality blood stem cells and improving their outcomes.

The study is published today in the journal Blood .

Professor Elisa Laurenti at the University of Cambridge Stem Cell Institute, and senior author of the study, said: “This is really exciting because we are now in a position where we can begin to understand the huge stress that these stem cells sense when they are manipulated outside of our body. Biologically it is really fascinating because it affects every aspect of their biology. Luckily, we were able to identify a key molecular pathway which governs many of these responses, and that can be targeted by a drug which is already in use and is safe to use.

“I hope our findings will enable safer treatments for gene therapy patients. Our discovery also opens up many possibilities to better expand blood stem cells ex vivo and expand the set of disease where we can use blood stem cells to improve patients’ lives.”

Dr Carys Johnson at the University of Cambridge Stem Cell Institute, and first author of the study, said: “Although we expected that removing these cells from the body and culturing them on a plastic surface would alter gene expression, the extent of change we found was surprising, with over 10,000 genes altered and a significant stress response detected. It was also striking to discover that the majority of blood stem cells are functionally lost during gene therapy protocols, before transplantation back to the patient.

“We have identified a key bottleneck where function is lost and clinical culture could be improved. I hope that our work will drive advancements in culture protocols to better harness the power of blood stem cells and improve the safety and efficacy of clinical approaches.”

C.S. Johnson, M.J. Williams, K. Sham, et al. ‘ Adaptation to ex vivo culture reduces human hematopoietic stem cell activity independently of cell cycle .’ Blood 2024; DOI: 10.1182/blood.2023021426

Story written by Laura Puhl, Cambridge Stem Cell Institute.

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Carys Johnson
Cambridge Stem Cell Institute
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Published: 28 July 2022

Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review

Ria Margiana 1 , 2 , 3 ,
Alexander Markov 4 , 5 ,
Angelina O. Zekiy 6 ,
Mohammed Ubaid Hamza 7 ,
Khalid A. Al-Dabbagh 8 ,
Sura Hasan Al-Zubaidi 9 ,
Noora M. Hameed 10 ,
Irshad Ahmad 11 ,
R. Sivaraman 12 ,
Hamzah H. Kzar 13 ,
Moaed E. Al-Gazally 14 ,
Yasser Fakri Mustafa 15 &
Homayoon Siahmansouri 16

Stem Cell Research & Therapy volume 13 , Article number: 366 ( 2022 ) Cite this article

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The multipotency property of mesenchymal stem cells (MSCs) has attained worldwide consideration because of their immense potential for immunomodulation and their therapeutic function in tissue regeneration. MSCs can migrate to tissue injury areas to contribute to immune modulation, secrete anti-inflammatory cytokines and hide themselves from the immune system. Certainly, various investigations have revealed anti-inflammatory, anti-aging, reconstruction, and wound healing potentials of MSCs in many in vitro and in vivo models. Moreover, current progresses in the field of MSCs biology have facilitated the progress of particular guidelines and quality control approaches, which eventually lead to clinical application of MSCs. In this literature, we provided a brief overview of immunoregulatory characteristics and immunosuppressive activities of MSCs. In addition, we discussed the enhancement, utilization, and therapeutic responses of MSCs in neural, liver, kidney, bone, heart diseases, and wound healing.

Introduction

In the last decade, stem cells are increasingly applied as a therapeutic method for numerous disorders. Stem cell therapy, traditionally applied for hematopoietic disorders, nonetheless, is now established for the treatment of non-hematologic disorders [ 1 , 2 ].

Accumulating evidence has shown that mesenchymal stem cells (MSCs) offer an encouraging option for cell treatment and reconstruction of human tissues because of their differentiation multipotency, self‐renewal capacity, long‐term ex vivo proliferation, paracrine potentials, and immunoregulatory effect [ 3 ]. Furthermore, MSCs have the capability to support the progression and differentiation of other stem cells. They can release bioactive molecules, which is a key benefit in tissue regeneration [ 4 , 5 ]. These properties result in progression of treatments for a wide range of diseases, such as diseases affecting the bone, neuron, lung, liver, heart, kidney, etc. [ 4 ]. Due to these features, it is obvious that MSCs will hold a major therapeutic role in clinical trials. Because of these properties, we provided a general overview of the latest trials that studied the effectiveness of MSCs in several diseases such as neural, liver, kidney, bone, heart diseases, and wound healing.

Stem cells in regenerative medicine

In the last years, numerous studies have demonstrated that cellular therapy has exhibited great development in both in vitro and in vivo researches. Stem cells have the capability to self-renew, and also to differentiate into all cell types and are involved in physiological regeneration [ 6 ]. There are multiple stem cell sources of adult and pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) for tissue regeneration. PSCs have a high potential for pluripotency and self-renewal, which makes these cells an important option for treatment of diseases. However, there are ethical issues when using these cells, in which ESCs are separated from blastocyst-stage embryos, requiring destruction of the embryo [ 7 , 8 , 9 ]. The results of studies have revealed the regenerative ability of iPSCs in preclinical setting and conducted the first clinical study for treatment of age-associated with macular deterioration [ 10 , 11 ]. Nonetheless, the tumorigenicity risk remains unsolved. Because of these limitations, researchers began to investigate adult stem cells, the multipotent stem cells found in tissues and organs of adults. Various investigations have reported that stem cell therapy can regenerate and repair injured organs in vivo, including bone repair, cutaneous wound, pulpitis, and ischemic cardiac tissue through stem cell differentiation and production of new particular cells [ 12 , 13 , 14 , 15 ]. Moreover, some investigations have demonstrated that cultured adult stem cells release many molecular factors with anti-apoptotic, immunoregulatory, angiogenic, and chemoattractant features that stimulate regeneration [ 16 , 17 , 18 ]. Hematopoietic stem cells (HSCs) and MSCs are part of adult stem cells, which are the most widely used, generally because they can be isolated from individuals in diseased conditions.

Mesenchymal stem cell

In the late 1960s, Friedenstein and colleagues discovered MSCs as multipotent stem cells for the first time [ 19 ]. MSCs are non-hematopoietic cells and have the capability to differentiate into various lineage including mesodermal (adipocytes, osteocytes, and chondrocytes), ectodermal (neurocytes), and endodermal lineage (hepatocytes) [ 20 , 21 ]. At the beginning, it was thought that MSCs are “stromal” cells instead of stem cells [ 22 ]. Several investigators tried to alter the name of MSCs to medicinal signaling cells due to their function in secretion of some metabolites molecules in the sites of diseases, injuries, and inflammations [ 23 , 24 ]. After that, some studies have stated that MSCs can release prostaglandin E2 (PGE2), which plays a major role in the self-renewal ability, immunomodulation of MSCs, and generating a cascade of events, that demonstrates the stemness of MSCs [ 25 ]. Therefore, the term mesenchymal stem cells is justified.

MSCs chiefly found in the bone marrow (BM) possess the ability of self-renewal and also display multilineage differentiation [ 8 , 26 , 27 ]. They were obtained from various tissues and organs including BM, adipose tissue, Wharton’s jelly, peripheral blood, umbilical cord, placenta, amniotic fluid, and dental pulp [ 3 , 28 , 29 , 30 ]. MSCs can express a wide range of surface markers and cytokine profiles according to the origin of isolation [ 31 ]. Nevertheless, the common characterization markers of MSCs are CD73, CD105, CD90 and lacking expression of CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA-DR [ 32 , 33 , 34 ]. During the last decades, MSCs have shown various biological roles such as multilineage differentiation, immunomodulation, angiogenesis, anti-apoptotic and anti-fibrotic activity, chemo-attraction, and tissue repair development [ 35 , 36 , 37 ]. The MSCs have broad properties that make them a suitable source for cell therapy, such as stemness potency, easily isolation from different sources, they can be rapidly expanded in a large scale for clinical use, have less ethical issues as compared to ESCs, unlike iPSCs, MSCs transport a lower risk of teratoma formation, and they are beneficial for a wide scale of therapeutic applications due to their capability to migrate to injured tissue through chemo-attraction [ 38 , 39 , 40 ]. In addition, MSCs can release a variety of bioactive components including proteins, growth factors chemokines, microRNAs (miRNAs), and cytokines which can suggest their acceptable application [ 41 ].

The biological roles of MSCs

MSCs have the ability to inhibit the immune response in inflammatory cytokine-rich situations, including infections, wounds, or immune-mediated disorders. These immunomodulatory properties were discovered in preclinical and clinical trials, where MSCs effectively suppressed T cell activation and proliferation along with stimulation of macrophages shift from M1 to M2 [ 42 , 43 , 44 ]. This specific performance of MSCs in the presence and absence of inflammatory mediators is termed MSC polarization. MSCs have the ability to migrate to damaged areas after systemic infusion and consequently exert a beneficial effect by various mechanisms, chiefly immunoregulation, and angiogenesis [ 45 , 46 ]. Although the related mechanism-mediated MSC immunosuppression has not been entirely clear, it appears that cellular interaction, accompanied by many factors, performs the principal function in this process. In the presence of high levels of inflammatory cytokines, e.g., TNF-α and IFN-γ, MSCs release several cytokines including TGF-β and hepatocyte growth factor (HGF) and produce soluble factors including indoleamine 2,3-dioxygenase (IDO), PGE2, and nitric oxide (NO). These mediators suppress T effector cells and enhance the expression of FOXP3, CTLA4, and GITR in regulatory T cells (Tregs) to increase their immunomodulation effects [ 47 , 48 , 49 ]. Moreover, cell-to-cell communication facilitates the stimulation of Tregs by cytokine-primed MSCs [ 50 ]. Overexpression of inducible co-stimulator ligands (ICOSL) induces the stimulation of efficient Tregs [ 51 ].

In addition, MSCs can enhance the generation of Treg cells indirectly. According to the literature, MSCs stimulate M2 macrophage and alter the phenotype through secretion of extracellular vesicles in an in vitro study [ 52 ]. Also, M2 cells that are activated by MSCs express CCL-18 and induce Treg cells [ 53 ]. Moreover, MSCs increase the expression of cyclooxygenase 2 (COX2) and IDO, resulting in expression of CD206 and CD163 in M2 cells, as well as enhance the expression of IL-6 and IL-10 in the microenvironment [ 54 ]. The overexpression of IL-10 that is produced by dendritic cells (DCs) and M2 cells upon MSCs co-culture leads to further immunomodulation via inhibition of effector T cells [ 55 , 56 ]. Furthermore, the secretion of IDO from MSCs can induce the proliferation, activation, and IgG releasing of B cells, thereby suppressing T effector cells [ 57 , 58 ].

One of the typical properties of MSCs is their multipotency capacity in which these stem cells are able to differentiate into a number of tissues in vitro [ 59 ]. Chondrogenic differentiation of MSCs in vitro occurs commonly via culturing them in the existence of TGF-β1 or TGF-β3, IGF-1, FGF-2, or BMP-2 [ 60 , 61 , 62 , 63 ]. MSC differentiation into chondroblasts is characterized by the increasing of various genes such as collagen type II, IX, aggrecan, and proliferation of chondroblast cell morphology. During the process of chondrogenesis, FGF-2 promotes the MSCs induced with TGF-β1 or TGF-β3 and/ or IGF-1 [ 64 ]. According to the literature works, several molecular pathways such as hedgehog, Wnt/β-catenin, TGF-βs, BMPs, and FGFs can regulate chondrogenesis [ 65 ]. In addition, MSCs can exert the osteogenesis function by inducing MSCs with ascorbic acid, β-glycerophosphate, vitamin D3, and/or BMP-2, BMP-4, BMP-6, and BMP-7 [ 66 ].

One of the major abilities of MSCs is anti-fibrotic activity. These cells can differentiate into various cell lineages such as hepatocytes, both in vivo and in vitro [ 67 ]. MSCs contain multiple trophic factors which induce cells and matrix remodeling to stimulate progenitor cells and the recovery of damaged cells. MSCs can decrease myofibroblasts and reverse the fibrotic activity of injured tissues [ 68 ]. Furthermore, these cells release pro-angiogenic factors including VEGF, IGF-1, and anti-inflammatory factors that participate in the recovery of tissue function. For instance, MSCs can increase neovascularization of ischemic myocardium through VEGF in a mice model of heart disease [ 69 ]; also, IGF-1 exerts an advantageous effect on the survival and proliferation of cardiomyocytes [ 70 ].

Bone marrow mesenchymal stem cell-based regenerative medicine

So far, increasing data have lately studied the effects of MSCs in the treatment or regeneration of various disorders (Table 1 ). In this section, we reviewed the latest clinical studies that investigate the potential contribution of MSCs in the regenerative medicine, as shown in Fig. 1 .

Effect of bone marrow mesenchymal stem cell-based regenerative medicine

Neural regeneration

The application of BMSCs has demonstrated promising therapeutic results in the treatment of neurological diseases. Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a neurodegenerative disorder that leads to degeneration of the motor neurons that causes paralysis and muscle weakness [ 138 , 139 ]. Syková et al. [ 71 ] carried out a study that intrathecally injected 15 ± 4.5 × 10 6 autologous BMSCs into 26 patients with ALS. After mesenchymal stem cells transplantation (MSCT), ALS functional rating scale (ALSFRS) significantly reduced, forced vital capacity (FVC) remained stable or above 70%, and weakness scales (WSs) were stable in 75% of patients. They have shown that the intrathecal BMSCs intervention in ALS patients is a safe method and it can slow down the development of the disease. There were no significant adverse events related to the trial during and after transplantation of BMSCs. Barczewska and colleagues indicated that three intrathecal injections of 30 × 10 6 Wharton’s jelly-MSCs (WJ-MSCs) improved ALSFRS [ 77 ]. They showed that WJ-MSCs are safe and effective in individuals that suffer from ALS. However, one other group found that intrathecal injection of autologous adipose MSCs does not improve clinical symptoms of ALS patients [ 76 ]. Their results indicated that the levels of CSF protein and nucleated cells were increased and ALSFRS-R showed development of disease in all treated patients. In the trial by OH et al., autologous BMSCs were injected to treat seven participants that suffer from ALS [ 75 ]. The participants were injected twice with autologous BMSCs (one million cells per kg) and followed up for 12 months. No serious adverse events were reported during the follow-up period. Furthermore, during the 12-month follow-up, there was no acceleration in the decrease in the ALSFRS-Revised (ALSFRS-R) score, Appel ALS score, and FVC. Moreover, CSF analysis showed that the levels of TGF-β and IL-10 were evaluated, while MCP-1, which is chemokine-related and exacerbates the motor neuron damage in ALS, was decreased. Their results exhibited that two repeated MSC infusions have safety and feasibility for at least 1 year in seven individuals; nevertheless, the study has some limitations such as low number of participants and short-time follow-up. In another study [ 73 ], 15 ALS patients were transplanted with autologous BMSCs. These 15 patients were divided into two groups (group 1: patients who had ALS with an inherently slow course, group 2: individuals who had ALS with an inherently rapid course) and received three intrathecal infusions of MSCs. There were no significant adverse events in the course of multiple intrathecal injections of MSCs. In group 1, there were no major changes in the rate of disease development and in group 2 ameliorating of the disease was indicated following MSCs therapy. According to their observation, the response of patients with ALS to treatment with MSCs was variable. Also, the authors indicated that due to the small number of patients, less subgroups were available for statistical analysis, limiting their ability to draw conclusions from the data.

Spinal cord injury (SCI) is usually related to devastating results. The damage to the spinal cord leads to injury to the motor, sensory, and autonomic roles of the spinal cord that affects patients’ well-being such as their physical and psychological state [ 140 , 141 ]. In a phase I, nonrandomized, uncontrolled study by Mendonça et al. [ 84 ], 15 SCI patients were administered 1 × 10 7 cells/ml MSCs. The results of the investigation revealed that SCI symptoms were meaningfully decreased by MSCT, all participants showed variable improvements in tactile sensitivity, and eight participants improved lower limb motor functional gains, chiefly in the hip flexors. Seven patients revealed sacral sparing and developed American Spinal Injury Association impairment scale (AIS) grades B or C – partial damage. Nine participants had developments in urologic function and one patient showed alterations in somatosensory evoked potentials (SSEP) 3 and 6 months after MSCT. These results stated that treatment with MSCs ameliorated the organ malfunction in people with SCI and has clinical safety, because no serious adverse effects were reported. The authors indicated that their results should be confirmed in larger and controlled clinical trials. Albu and colleagues have been demonstrated that intrathecal administration of WJ-MSCs considerably improved the pinprick sensation in the dermatomes below the level of damage [ 88 ]. Further results showed that bladder maximum capacity was elevated and bladder neurogenic hyperactivity and external sphincter dyssynergy were reduced. In another study [ 85 ], ten SCI subjects received four subarachnoid injections of 30 × 10 6 autologous BMSCs, maintained in autologous plasma, at weeks 1, 16, 28, and 40 of the trial and followed up for 12 months. There were no adverse events and all participants tolerated the therapy. Vaquero et al. [ 86 ] demonstrated that MSCT is safe and improves sensitivity, motor power, spasms, spasticity, neuropathic pain, sexual function, or sphincter dysfunction in the SCI patients. The results of their study have shown that 55.5% of patients improved in SSEP and 44.4% of patients ameliorated in voluntary muscle contraction together with intralesional active muscle reinnervation. Hur et al. carried out a study in which 14 patients with SCI were administered intrathecally 9 × 10 7 adipose MSCs [ 87 ]. Their observations showed mild progresses in neurological function. No serious adverse events were observed. In a phase 2 study, 13 patients with SCI were intravenously administered a single dose of autologous MSCs cultured in auto-serum [ 82 ]. The results of this trial revealed that SCI symptoms were considerably declined by MSC therapy, ASI, International Standards for Neurological and Functional Classification of Spinal Cord (ISCSCI-92), and Spinal Cord Independence Measure (SCIM-III) demonstrated functional improvements after MSC injection. No severe adverse effects were related to MSC administration.

Parkinson’s disease (PD) is a neurological disorder principally characterized by the deterioration of motor activities due to the impairment of the dopaminergic nigrostriatal system [ 142 , 143 ]. It has been indicated that MSCs improved the symptoms of PD. In a phase I controlled, randomized clinical study, patients that suffer from progressive supranuclear palsy were administered autologous BMSCs via intra-arterial injection [ 78 ]. The results of the study exhibited that autologous BMSCs are safe and reduce disease progression. Canesi et al. [ 79 ] have demonstrated that injection of MSCs into cerebral arteries of PD patients led to positive results in 17 PD participants: all treated participants were alive and motor function rating scales remained stable for at least 6 months during the 12-month follow-up period. One patient died 9 months after the injection for reasons not associated with cell infusion or to disease development.

In a study conducted by Jaillard and colleagues in 2019 [ 89 ], 31 individuals with subacute stroke were administered the intravenous injections of autologous BMSCs. The results of the trial exhibited significant improvements in motor-National Institute of the Health Stroke Scale (NIHSS) score, motor-Fugl-Meyer scores, and task-related functional MRI activity in motor cortex-4a. However, there was no remarkable progress in Barthel Index, NIHSS, and modified Rankin scores. In general, their results suggested that BMSCs improved motor recovery via sensorimotor neuroplasticity. In another study, 17 patients with subacute middle cerebral artery infarct received two million cells/kg autologous BMSCs [ 92 ]. During the follow-up process, NIHSS score, modified Rankin Scale or Barthel Index did not improve after the transplantation. Nonetheless, there was a significant improvement in absolute change in median infarct volume, but no treatment-related adverse effects were observed.

In sum, these outcomes suppose that BMSCs can safely and efficiently treat neural diseases, inhibit disease development, and considerably ameliorate the quality of life and clinical manifestations of patients. Consequently, BMSCs can become a new option for the clinical treatment of neural diseases.

Liver regeneration

The potential of BMSCs to differentiate into the endodermal lineage, such as hepatocyte‐like cells, makes them an attractive alternative for the treatment of liver diseases [ 144 ]. Some clinical studies have demonstrated the efficacy and feasibility of BMSC therapy in patients with liver diseases. The effect of BMSCs has been studied in individuals suffering from liver cirrhosis by Suk et al. [ 98 ]. Seventy-two patients were enrolled in this trial and randomly classified into three groups: one control group and two autologous BMSC groups that received one-time or two-time hepatic arterial administrations of fifty million autologous BMSCs 30 days after BM aspiration. Fibrosis quantification exhibited that in one-time and two-time BMSC groups there are a reduction of 25% and 37% in the proportion of collagen, respectively. In addition, the Child–Pugh (CP) scores of both test groups were meaningfully improved following BMSC administration in comparison with the control group. No serious adverse events were associated with MSC injection during the 12-month follow-up. Wang and coworkers have found that intravenous injection of UC-MSCs (0.5 × 10 6 cells/kg) is feasible and well tolerated in patients with primary biliary cirrhosis (PBC) [ 93 ]. They exhibited that MSCs significantly decreased the level of ALP and GGT; however, there were no considerable changes in serum AST, ALT, total bilirubin, albumin, prothrombin time activity, or immunoglobulin M levels. Similarly, Zhang et al. [ 94 ] have demonstrated that intravenous administration of 1.0 × 10 6 cells/kg UC-MSCs is safe and efficient for patients with ischemic-type biliary lesions after liver transplantation. According to their results, MSCs therapy reduced the serum ALP, GGT, and total bilirubin. In a randomized placebo-controlled phase I–II single-center study, nine patients that suffer from acute-on-chronic liver failure (ACLF) grades 2 and 3 were enrolled [ 95 ]. The experiment group (n = 4) received standard medical therapy along with five injections of 1 × 10 6 cells/kg of BMSC for 3 weeks. There were no transplant-related adverse events; however, one patient in the experiment group showed hypernatremia and a gastric ulcer, after the third and fifth administrations, respectively. Furthermore, MSCT revealed a considerable improvement in CP, model for end-stage liver disease (MELD), and ACLF (grade 3 to 0). Thus, MSCT is safe and viable in individuals with ACLF. In an open-label non-blinded randomized controlled study conducted by Lin et al. [ 96 ], 110 patients with hepatitis B virus (HBV)-related ACLF were enrolled in this trial. These patients were divided into two groups: control group (N = 54) was treated with standard medical therapy only and the intervention group (N = 56) was injected four times with 1.0–10 × 10 5 cells/kg allogeneic BMSCs, and then followed up for 6 months. There were no serious adverse events associated with transplantation. The results of that study demonstrated that MSCT significantly improved clinical laboratory measurements, such as serum total bilirubin, and MELD scores in comparison with control group. In addition, mortality from multiple organ failure and prevalence rate of serious infection in the intervention group was lower than that in the control group. Their results clearly established the safety and feasibility of the clinical use of peripheral administration of allogeneic BMSCs for subjects with HBV-associated ACLF, and markedly enhanced the survival rate through enhancing liver function and reducing the prevalence of severe infections.

In summary, MSCT can meaningfully ameliorate the clinical manifestations of these patients, reduce the liver fibrosis, and inhibit the development of disease.

Kidney regeneration

Hurt to renal cells can occur because of a wide range of ischemic and toxic insults and results in inflammation and cell death, which can lead to kidney damage. Inflammation has a significant role in the damage of renal cells, as well as following cellular regeneration processes [ 3 , 145 ]. Various investigations have consistently demonstrated a supportive effect of MSC on acute and chronic renal injury [ 146 ]. Makhlough et al. declared that intravenous administration of 1–2 × 10 6 cells/kg into seven patients with chronic kidney disease failed to induce remission [ 101 ]. They indicated that variations in estimated glomerular filtration rate (eGFR) and serum creatinine during the 18-month follow-up were not statistically significant. Nonetheless, no severe adverse events were reported, and they could not assess the efficacy because of their study design. Authors postulated that limited sample size and lack of a control group led to the lack of success. A study conducted by Swaminathan et al. in 2021, has displayed the effect of allogeneic BMSCs in acute kidney injury patients. They have shown that treatment of MSCs with SBI-101 stimulated an immunotherapeutic response that initiated an enhanced phenotypic alteration from tissue injury to tissue repair [ 102 ]. In a single-arm phase I clinical trial carried out by Makhlough et al. [ 100 ], six patients with autosomal dominant polycystic kidney disease (ADPKD) were intravenously injected 2 × 10 6 cells/kg autologous BMSCs. The results of the study showed that the mean eGFR value declined and the level of serum creatinine enhanced during the 1-year follow-up. Moreover, no remarkable modifications in renal function parameters and blood pressure were observed during the year after intervention. However, there were no severe adverse events after 1-year follow-up. In addition, the authors indicated that there are some reasons for the lack of success, including small number of patients, absence of a comparison group, limited follow-up period, single dose administration, and they did not utilize htTKV as a surrogate endpoint. Abumoawad and colleagues have established that adipose MSCs enhanced blood flow, GFR and reduced inflammatory injury in poststenotic kidneys of individuals that suffer from atherosclerotic renovascular disease (ARVD) [ 99 ]. Their results illustrated that mean renal blood flow was considerably enhanced, and hypoxia, renal vein inflammatory cytokines, and angiogenic factors were considerably attenuated.

Heart regeneration

Heart disease is the first and most frequently diagnosed disease and the leading cause of disease death [ 147 ]. When cardiomyocytes are damaged via ischemic and other factors, the remaining viable cardiomyocytes have a restricted ability to proliferate and dead cardiomyocytes are changed by non-contractile fibrous tissue, leading to functional impairment that elicits the progression of heart failure. According to the developing number of patients with heart disease, there is a vital need to expand an innovative remedy to rescue deteriorating hearts. Regenerative medicine and cell therapy are the upcoming therapeutic opportunities for heart diseases. According to the literature, the transplantation of BM-derived cells and cardiac stem cells into deteriorating hearts appeared to provide functional benefits [ 148 , 149 ].

In a study by Yagyu et al. [ 110 ], 8 individuals with symptomatic heart failure were infused with BMSCs. During the follow-up period, no serious adverse events were observed. There were no major differences in B-type natriuretic peptide, left ventricular ejection fraction (LVEF), and peak oxygen uptake at 2 months. The results of this study recommend further research regarding the feasibility and efficacy of MSCs. In a study by Gao et al. [ 107 ], 116 patients with acute myocardial infarction randomly received an intracoronary injection of WJ-MSCs. They indicated that MSCs therapy elevated the myocardial viability and perfusion within the infarcted territory. In addition, the LVEF was elevated and LV end-systolic volumes and end-diastolic volumes were decreased in the WJ-MSCs group.

Chan et al. demonstrated that intramyocardial infusion of autologous BMSCs in conjunction with transmyocardial revascularization or coronary artery bypass graft surgery was technically feasible and could be performed safely. The results showed that regional contractility in the cell-treated regions improved during the 1-year follow-up; also, the quality of life was improved along with a substantial decrease in angina scores at 12 month post-treatment [ 104 ]. In a study by Kaushal et al. [ 113 ], 12 participants with hypoplastic left heart syndrome were transplanted with allogeneic human MSCs (2.5 × 10 5 cells/kg). This study determined the safety, feasibility, and usefulness of MSC administration into the left ventricular myocardium. No serious adverse effects were reported during the trial. Mathiasen et al. observed that after BM-MSCT, left ventricular end-systolic volume was significantly reduced, also LVEF, stroke volume, and myocardial mass remarkably improved [ 103 ]. In addition, a major decrease in the amount of scar tissue and quality of life score was observed. No side effects were identified. In a randomized, double-blind, placebo-controlled, multicenter, phase II study, 100 patients with anterior ST elevation myocardial infarction received autologous BMSCs and atorvastatin (ATV) treatment. The results of that study represented the absolute change of LEVF within 12 months, improvement in cardiac function, induction of remodeling and regeneration, and improvement in quality of life [ 108 ]. Recently, Celis-Ruiz and coworkers conducted a study in which intravenous administration of adipose MSCs within the first 2 weeks of ischemic stroke onset is safe at 24 months of follow-up [ 106 ]. In a study conducted by Hare et al. [ 112 ], 37 non-ischemic dilated cardiomyopathy patients were divided into two groups and received 10 × 10 7 allogeneic and autologous BMSCs. Minnesota Living with Heart Failure Questionnaire score decreased in both groups. The major adverse cardiac event rate was lower in allo vs. auto. Also, TNF-α decreased, to a greater extent in allo vs. auto at 6 months. These results suggested the clinically meaningful efficacy of allogeneic vs. autologous BMSCs in non-ischemic dilated cardiomyopathy patients. Qayyum et al. have found that intra‑myocardial injections of autologous adipose MSCs ameliorated cardiac functions and unchanged exercise capacity, in contrast to deterioration in the placebo group [ 115 ].

Levy et al. indicated that after allogeneic BMSCs in patients with chronic stroke, Barthel Index scores increased. Moreover, electrocardiograms, laboratory tests, and computed tomography scans of chest/abdomen/pelvis suggest that BMSCs could alleviate the clinical symptoms in patients with stroke [ 90 ].

In sum, BMSC therapy can be an effective, achievable, and safe process that remarkably improves cardiac function and promotes patients’ quality of life.

Bone regeneration

Bone regeneration is a hot topic of research in clinical studies. Bone regeneration is a crucial problem in numerous cases, including bone fracture, defect, osteoarthritis, and osteoporosis, which should be resolved [ 150 , 151 , 152 ]. Autogenous bone grafts are considered the standard approach for bone formation by means of the participants’ own cells that stimulate osteoinductive, bone conductivity, and histocompatibility in bone diseases [ 153 ]. Nevertheless, there are some shortcomings of this procedure such as unpredictable absorption, extended recovery time, and patients commonly experience pain and nerve injury at the harvest area [ 154 , 155 , 156 ]. With the development of understanding bone tissue biology as well as recent approaches in the improvement in tissue regeneration, the application of MSC has become an attractive subject in augmenting bone tissue forming [ 157 , 158 ].

In a pilot study by Jayankura and coworkers, allogeneic BMSCs were applied to treat 22 participants with bone fractures [ 128 ]. All participants received percutaneous implantation of autologous BMSCs (5 to 10 × 10 7 cells) into the fracture area. After intervention, Tomographic Union Score (TUS) and Global Disease Evaluation (GDE) score were improved, and pain at palpation at the fracture site was reduced. In addition, the ratio of blood samples comprising donor-specific anti-HLA antibodies enhanced at 6 months post-intervention. Three serious cell-related adverse events were reported. In another study by Shim and coworkers [ 129 ], intramedullary (4 × 10 7 cells) and intravenous (2 × 10 8 cells) infusion of WJ-MSCs in combination with teriparatide showed beneficial results in individuals with osteoporotic vertebral compression fractures. Their observation displayed that the mean visual analog scale, Oswestry Disability Index, and Short Form-36 scores meaningfully improved. They stated that WJ-MSCs in combination with teriparatide are viable and have a clinical profit for fracture healing by stimulating bone architecture.

Several studies investigated the effect of BMSCs in osteoarthritis (OA) patients. Chahal et al. carried out a clinical phase I/IIa trial that involved 12 individuals with late-stage Kellgren–Lawrence knee OA. These 12 patients were injected with a single intra-articular of 1 × 10 6 , 10 × 10 6 , and 50 × 10 6 BMSCs. The results showed that patients had improved Knee Injury and Osteoarthritis Outcome Score (KOOS) pain, symptoms, quality of life, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) stiffness relative to baseline. Moreover, cartilage catabolic biomarkers and MRI synovitis were meaningfully lower at higher doses and the levels of pro-inflammatory monocytes/macrophages and IL-2 reduced in the synovial fluid after intervention. No serious events had occurred [ 116 ]. Dilogo et al. have reported that UC-MSCs (10 × 10 6 cells) significantly decreased the WOMAC and could be a potentially new regenerative treatment for patients with knee OA [ 127 ]. In a study conducted by Hernigou et al. [ 117 ], 140 patients with OA received a subchondral infusion of BMSCs on one side and received total knee arthroplasty (TKA) on the contralateral knee. They demonstrated that subchondral MSCs had a significant effect on pain to postpone or avoid the TKA in the contralateral joint of patients with OA. In a phase II multicenter randomized controlled clinical trial, 60 OA patients received 10 × 10 7 cells of autologous BMSCs along with platelet-rich plasma and followed up for 12 months [ 119 ]. No serious adverse effects were observed after MSCs injection or during follow‑up. According to the observations, treatment with BMSC related to platelet-rich plasma was demonstrated to be a feasible alternative treatment for individuals with OA, along with clinical development at the end of follow-up. Similarly, Bastos et al. have reported that MSCs alone or in combination with platelet-rich plasma are safe and have an advantageous effect on symptoms in OA individuals [ 121 ]. They found that MSCs group and MSCs + platelet-rich plasma group can improve the pain, function and daily living activities, and quality of life subscales. Ten adverse events were reported in three participants in the MSCs group and in two of the MSCs + platelet-rich plasma group. PERS and colleagues reported another clinical phase Ia study that involved 19 individuals suffering from knee OA [ 123 ]. These 18 individuals were classified into three groups and received a single intra-articular administration of 2 × 10 6 , 10 × 10 6 , and 50 × 10 6 adipose MSCs. According to their results, individuals had experienced significant improvement in pain levels and function. There were no severe adverse events; however, 4 individuals experienced transient knee joint pain and swelling after local administration. In a long-term follow-up of a multicenter randomized controlled clinical trial by Espinosa et al. [ 120 ], 30 OA patients were administered the intra-articular infusion of two diverse doses of autologous BMSCs cells (10 × 10 6 or 10 × 10 7 ) versus hyaluronic acid in the treatment of OA. No adverse effects occurred after MSCT or during the 4-year follow‑up. Their results showed that intra-articular infusion of BMSCs together with hyaluronic acid is a safe and viable process that leads to a clinical and functional improvement in knee OA.

Overall, these data display that BMSCs can be a promising, safe and effective alternative for bone regeneration, significantly improve the clinical manifestation of patients, and inhibit development of diseases.

Wound regeneration

The skin has several layers along with different compounds and roles that work together to support internal organs and serve various biological roles. It has three main layers, the epidermis, the dermis, and the subcutaneous layer [ 159 ]. Generally, skin wound healing, triggered by tissue injury, includes four stages: hemostasis, inflammation, proliferation, and maturation. MSCs can assist in all stages of the wound healing process. The use of MSCs for the treatment of skin can improve the regeneration of skin and reduce scarring. MSCs exert their functions through migration into the skin damage site, suppressing inflammation, and increasing the growth and differentiation ability of fibroblasts, epidermal cells, and endothelial cells [ 160 , 161 ]. As MSCs have exhibited wound healing in many preclinical studies, the application of MSCs for chronic wounds contributes to progress toward clinical trials. Falanga et al. have demonstrated that autologous BMSCs are an impressive and safe treatment method for wound healing [ 131 ]. The results of the study indicated a trend toward a reduction in ulcer size or complete wound closure by 4–5 months. No adverse events were noted. In a study by Zhou et al., 346 patients with skin wounds were administered adipose MSCs [ 132 ]. There were no adverse events during the trial. They reported that the granulation tissue coverage rate and thickness of granulation tissue were considerably ameliorated. In an open-label phase I/II study, sixteen participants with vocal fold scarring were administered a single dose of 0.5–2 × 10 6 cells autologous MSCs [ 137 ]. Video ratings of vocal fold vibrations and digitized analysis of high-speed laryngoscopy and phonation pressure threshold were considerably enhanced for 62–75% of the participants. Voice Handicap Index was meaningfully enhanced in eight participants, with the remaining experiencing no remarkable alteration. No serious adverse events or minor side effects were reported. Lonardi et al. observed that micro-fragmented adipose tissue improved skin tropism in patients with diabetic foot ulcer [ 135 ]. Furthermore, the results of studies have shown that adipose-derived stem cells had a beneficial effect on the full-thickness foot dorsal skin wound in diabetic mice with a considerably decreased ulcer area [ 162 ]. Recently, Huang et al. carried out a clinical study in which six subjects with intrauterine adhesion and four with cesarean scar diverticulum enrolled in this trial [ 136 ]. They found that intrauterine injection of UC-MSCs improved the endometrial thickness, cesarean scar diverticulum, and the volume of the uterus.

In the last decades, optimizations of isolation, culture, and differentiation procedures have permitted MSCs to improve closer to clinical uses for improving disorders and various tissue regeneration. MSCs have some important characteristics that make them preferred candidates to use for regenerative medicine: immunomodulatory capability valuable to improve immune system abnormalities, paracrine or autocrine roles that produce growth factors, and the vital potential to differentiate into various cells. Several clinical trials have reported that both autologous and allogeneic MSCs are valuable sources for tissue forming. Particularly, autologous MSCs signify the chief sources examined safe for administration and minimization of immunological threat, regardless of the lack of reported grievances concerning allogeneic MSC-based therapy. According to the studies described in this literature, administration of MSCs appear to be more effective and the usefulness of MSC therapy in bone and heart disorders has been broadly established. In terms of safety, no significant relationship was found between the MSC therapy and incidence of cancer and infection. Intravenous injection of MSCs is the most widely used form of administration and the dosage commonly fluctuates between 1 × 10 6 cells/kg and 2 × 10 8 cells/kg. According to the literature works mentioned in this review, the repeated administration of MSCs suggests being more beneficial than a single injection. In addition, the effectiveness of MSCs therapy in osteoarthritis disorder has been widely established. Long-term follow-up studies exhibited that serum tumor markers did not enhance before and 3 years after MSCs therapy. Nevertheless, there is still a lack of reliable scientific data on the mechanisms whereby the MSC therapy improves the numerous disorders that can develop the MSC modification and increase their prospective clinical application.

Availability of data and materials

Not applicable.

Abbreviations

Amyotrophic lateral sclerosis

Association impairment scale

ALS functional rating scale

ALSFRS-revised

Acute-on-chronic liver failure

Autosomal dominant polycystic kidney disease

Atorvastatin

Bone marrow

Bone marrow mesenchymal stem cells

Cyclooxygenase 2

Dendritic cells

Embryonic stem cells

Estimated glomerular filtration rate

Forced vital capacity

Global Disease Evaluation

Hematopoietic stem cells

Hepatitis B virus

Hepatocyte growth factor

Induced pluripotent stem cells

Indoleamine 2,3-dioxygenase

Inducible co-stimulator ligands

International Standards for Neurological and Functional Classification of Spinal Cord

Knee injury and osteoarthritis outcome score

Left ventricular ejection fraction

Mesenchymal stem cells

Mesenchymal stem cells transplantation

Model for end-stage liver disease

Nitric oxide

Osteoarthritis

Pluripotent stem cells

Prostaglandin E2

Spinal cord injury

Somatosensory evoked potentials

Spinal cord independence measure

Regulatory T cells

Tomographic Union Score

Total knee arthroplasty

Weakness scales

Western Ontario and McMaster Universities Osteoarthritis Index

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Acknowledgements

The authors express their gratitude to the Deanship of Scientific Research at King Khalid University for funding this work through the Research Group Program under grant number RGP. 2/122/43.

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Ria Margiana

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Dr. Soetomo General Academic Hospital, Surabaya, Indonesia

Tyumen State Medical University, Tyumen, Russian Federation

Alexander Markov

Tyumen Industrial University, Tyumen, Russian Federation

Department of Prosthetic Dentistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia

Angelina O. Zekiy

Medical Technical College, Al-Farahidi University, Baghdad, Iraq

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Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq

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Margiana, R., Markov, A., Zekiy, A.O. et al. Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review. Stem Cell Res Ther 13 , 366 (2022). https://doi.org/10.1186/s13287-022-03054-0

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Will Stem Cells Help You Live Longer?

By Jennifer Chesak

Medically Reviewed by Natalie Kunsman, M.D.

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On their never-ending quest for the proverbial fountain of youth, biohackers and celebrities alike have latched onto stem cell anti-aging therapies. Do these treatments, reportedly used by longevity influencer Bryan Johnson and actors John Cleese and William Shatner, have any merit? Can they really turn back the hands of time and help you look and feel more youthful?

A harsh, but also beautiful fact of life is that we age. We say goodbye to the emotional angst of our teens and 20s, only for our joints begin to express their angst via aches, pains, and creaks.

Ultimately, aging happens because of various inflammatory processes that fall under the umbrella term inflammaging . Inflammaging affects our stem cells, the body’s innate repair system. Stem cell therapy, although still controversial as the research is in its infancy, may hold promise for reducing the impact of inflammaging, thereby boosting longevity.

“As we age the number of circulating stem cells decreases,” says stem cell scientist Christian Drapeau, M.S.c. By the age of 30, he adds, the decline reaches about 90 percent. “This reduction means that at some point in our 30s, we don’t have enough stem cells to keep up with cellular loss, and that’s when aging begins,” he says.

About the Experts

Christian Drapeau, M.S.c ., is a stem cell scientist and the founder and chief science officer at Stemregen . He is also the bestselling author of Cracking the Stem Cell Code . Drapeau is credited as first proposing and publishing the hypothesis that stem cells are the body’s repair system.

Fouad Ghaly, M.D. , is the founder of the Ghaly Center for Regenerative Medicine in California. He focuses on stem cell research and regenerative medicine therapies in his practice.

What Are Stem Cells, Anyway?

Stem cells are unique cells found in nearly all bodily tissues. They help keep tissue healthy and repair tissue that’s damaged.

Though we still have a long way to go, researchers have made substantial progress in stem cell research in the 21st century. “Historically, stem cells were primarily recognized as precursors to blood cells, including white and red blood cells, as well as platelets.”

But, as Drapeau notes, the early 2000s led to a promising discovery. “Stem cells are remarkable cells with the unique ability to renew and differentiate into any cell type in the body throughout a person’s lifetime,” Drapeau says. Their ability to differentiate means they can convert or morph. This enables them to aid in the repair and regeneration of any bodily organ ( 2 ). No other cells in the body have stem cells’ natural abilities ( 1 ).

“This groundbreaking finding has propelled stem cells into today’s therapeutic limelight and suggested new applications,” Drapeau says.

How stem cells function

Stem cells have two important functions: to make more stem cells and to convert into other types of cells that do different jobs ( 3 ).

Let’s say you seriously tweak your ankle on a trail run. The injured tissue sends signals to your bone marrow to release stem cells, Drapeau explains. Circulating stem cells will increase 3- to 10-fold ( 4 ). “The stem cells move to the site of damage, multiply, and transform into the necessary cells to repair the tissue,” he adds.

Stem cells also replace cells we naturally lose every day in all our organs and tissues ( 5 ). “To stay healthy, we need to constantly replace these lost cells, and that’s the role of stem cells,” Drapeau says.

Current application for stem cell therapies

You’ve likely heard of stem cell therapies to treat diseases. Stem cell therapy is currently approved by the U.S. Food and Drug Administration (FDA) for treating certain cancers and disorders that affect the blood and immune system.

Stem cell treatments have different processes, depending on the condition. Blood cancer treatment, for example, may involve a stem cell transplant. In these cases, healthy stem cells are harvested from either the blood or bone marrow of a donor or the patient, and then transplanted into the patient ( 6 ).

Can Stem Cells Reverse Aging?

The number of circulating stem cells available to help us repair and renew tissue is crucial for our health and vitality ( 7 ). And those stem cells decline with age. Where things get tricky with this type of treatment is who gets to have access to them, as they are extremely expensive.

“Currently, stem cell treatments for anti-aging are mostly accessible to the wealthy,” Drapeau says. However, endogenous stem cell mobilization may be more accessible. “This process involves stimulating the release of one’s own stem cells from the bone marrow, rather than relying on injections to increase circulating stem cells,” he says.

How a stem cell transplant for anti-aging works

Stem cell transplants are not currently available for anti-aging, at least not in the sense that such transplants are available in the United States to treat certain immune system conditions, blood disorders, or cancers.

However, some clinics in the country do offer therapies that harness stem cells from one’s own body. Regenerative medicine specialist Fouad Ghaly, M.D., explains one of the regenerative therapy options he offers at his clinic in California.

“I can take fat from a man or a woman, isolate the stem cells, activate the stem cells, and inject them into the body,” he says. The stem cells go to the damaged areas and create “a field of regeneration,” he adds. (Critics of stem cell research say that stem cells may migrate to areas on the body that don’t need them.)

But not many practitioners in the U.S. offer the treatment. When you read about biohackers and celebrities getting stem cell therapies, they probably traveled elsewhere to get it. Bryan Johnson, for example, said in a post on X that he participated in a clinical trial in the Bahamas in which bone marrow-derived stem cells were injected into his knees, shoulders, and hips.

Live Longer

Age-Related Issues Stem Cell Therapy May Help

Over time, inflammaging and other factors can lead to age-related diseases including type 2 diabetes, cardiovascular disease, neurodegenerative diseases, cancer, musculoskeletal disorders, sexual dysfunction, and more ( 8 ).

Age-related diseases are linked to a reduction in stem cells. “People with conditions affecting the heart, liver, kidneys, pancreas, lungs, and cardiovascular system, as well as those with high blood pressure or erectile dysfunction typically have less than 50 percent of the circulating stem cells found in healthy individuals of the same age,” Drapeau says.

Not everyone develops these diseases as they age. The conditions are simply more prevalent in older populations. Lifestyle, environmental, and genetic factors all play a role in disease development ( 9 ).

“Harnessing the power of endogenous stem cell mobilization—releasing your own stem cells—or utilizing stem cell treatments can significantly impact age-related health issues,” Drapeau says.

Why Stem Cell Treatments Are Controversial

Over the past five years or so, the FDA, the Centers for Disease Control and Prevention (CDC), and the National Institutes of Health (NIH), have repeatedly warned the public about clinics and companies that market stem cell products or therapies ( 10 , 11 , 12 ).

Stem cell products and treatments are not currently approved to treat any orthopedic conditions, neurological disorders, cardiopulmonary disorders, chronic pain, fatigue, macular degeneration, or autism, according to the FDA ( 10 ).

The federal agency also warns of severe health issues that have come about from unapproved therapies. “FDA has received reports of blindness, tumor formation, infections, and more … due to the use of these unapproved products,” the agency states ( 10 ). According to a 2017 report, patients who received stem cell eye injections at a Florida clinic became blind shortly after treatment ( 13 ).

And while the CDC and NIH both remain hopeful about stem cell therapy’s potential to treat various medical conditions and diseases, further research is needed to rule out acute and long-term health complications ( 11 , 12 ).

Where Stem Cell Research Is Heading

Research around stem cell therapy’s capabilities have, in many ways, only just begun ( 14 ). However, Drapeau and Ghaly say the evidence is growing around how stem cell therapies can be used strategically to combat aging and support longevity.

“It will become clear that supporting stem cell function is the first step in addressing any type of tissue damage or degeneration,” Drapeau says. “As research progresses and clinical evidence accumulates, endogenous stem cell mobilization is likely to become standard practice for treating a wide range of conditions, from cardiovascular diseases to musculoskeletal injuries.”

But more than that, stem cells could potentially be used for organ replacement. “Can we induce a regular cell to become a liver? Yes,” Ghaly says. “Can we induce it to become a kidney? Yes. So now there will come a day when they can manufacture organs.”

Researchers have already regenerated fully functional urinary bladder tissue in a nonhuman primate by using stem cells from the animal’s bone marrow ( 15 ). The research serves as a preclinical model for humans.

Ultimately, stem cell research may shape how we treat and prevent age-related diseases, how we repair damaged tissue and organs, and how we recover from illness and injury. Such changes could help us theoretically feel and look better, despite our chronological age .

By using regenerative therapies, such as those related to stem cells, we may even be able to extend our lifespan, which is how long we live, and our healthspan, which is how long we generally feel healthy and have good quality of life.

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Bury M, et al. (2024.) Multipotent bone marrow cell–seeded polymeric composites drive long-term, definitive urinary bladder tissue regeneration.

About the author

Jennifer Chesak is a freelance science and medical journalist and editor who covers the pandemic, chronic health issues, medical rights, healthcare, and the scientific evidence around health and wellness trends. Her work has appeared in Washington Post, Prevention, Healthline, Health, The Daily Beast, Runner's World, Greatist, Real Simple, and more.

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Introduction to Stem Cell Therapy

Jesse k. biehl.

1 Department of Bioengineering, University of Illinois at Chicago

Brenda Russell

2 Department of Physiology and Biophysics and Department of Bioengineering, University of Illinois at Chicago

Stem cells have the ability to differentiate into specific cell types. The two defining characteristics of a stem cell are perpetual self-renewal and the ability to differentiate into a specialized adult cell type. There are two major classes of stem cells: pluripotent that can become any cell in the adult body, and multipotent that are restricted to becoming a more limited population of cells. Cell sources, characteristics, differentiation and therapeutic applications are discussed. Stem cells have great potential in tissue regeneration and repair but much still needs to be learned about their biology, manipulation and safety before their full therapeutic potential can be achieved.

Introduction

Stem cells have the ability to build every tissue in the human body, hence have great potential for future therapeutic uses in tissue regeneration and repair. In order for cells to fall under the definition of “stem cells,” they must display two essential characteristics. First, stem cells must have the ability of unlimited self-renewal to produce progeny exactly the same as the originating cell. This trait is also true of cancer cells that divide in an uncontrolled manner whereas stem cell division is highly regulated. Therefore, it is important to note the additional requirement for stem cells; they must be able to give rise to a specialized cell type that becomes part of the healthy animal. 1

The general designation, “stem cell” encompasses many distinct cell types. Commonly, the modifiers, “embryonic,” and “adult” are used to distinguish stem cells by the developmental stage of the animal from which they come, but these terms are becoming insufficient as new research has discovered how to turn fully differentiated adult cells back into embryonic stem cells and, conversely, adult stem cells, more correctly termed “somatic” stem cells meaning “from the body”, are found in the fetus, placenta, umbilical cord blood and infants. 2 Therefore, this review will sort stem cells into two categories based on their biologic properties - pluripotent stem cells and multipotent stem cells. Their sources, characteristics, differentiation and therapeutic applications are discussed.

Pluripotent stem cells are so named because they have the ability to differentiate into all cell types in the body. In natural development, pluripotent stem cells are only present for a very short period of time in the embryo before differentiating into the more specialized multipotent stem cells that eventually give rise to the specialized tissues of the body ( Figure 1 ). These more limited multipotent stem cells come in several subtypes: some can become only cells of a particular germ line (endoderm, mesoderm, ectoderm) and others, only cells of a particular tissue. In other words, pluripotent cells can eventually become any cell of the body by differentiating into multipotent stem cells that themselves go through a series of divisions into even more restricted specialized cells.

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During natural embryo development, cells undergo proliferation and specialization from the fertilized egg, to the blastocyst, to the gastrula during natural embryo development (left side of panel). Pluripotent, embryonic stem cells are derived from the inner cell mass of the blastoctyst (lightly shaded). Multipotent stem cells (diamond pattern, diagonal lines, and darker shade) are found in the developing gastrula or derived from pluripotent stem cells and are restricted to give rise to only cells of their respective germ layer.

Stem Cell Fates

Based on the two defining characteristics of stem cells (unlimited self-renewal and ability to differentiate), they can be described as having four outcomes or fates 3 ( Figure 2 ). A common fate for multipotent stem cells is to remain quiescent without dividing or differentiating, thus maintaining its place in the stem cell pool. An example of this is stem cells in the bone marrow that await activating signals from the body. A second fate of stem cells is symmetric self-renewal in which two daughter stem cells, exactly like the parent cell, arise from cell division. This does not result in differentiated progeny but does increase the pool of stem cells from which specialized cells can develop in subsequent divisions. The third fate, asymmetric self-renewal, occurs when a stem cell divides into two daughter cells, one a copy of the parent, the other a more specialized cell, named a somatic or progenitor cell. Asymmetric self-renewal results in the generation of differentiated progeny needed for natural tissue development/regeneration while also maintaining the stem cell pool for the future. The fourth fate is that in which a stem cell divides to produce two daughters both different from the parent cell. This results in greater proliferation of differentiated progeny with a net loss in the stem cell pool.

An external file that holds a picture, illustration, etc.
Object name is nihms100185f2.jpg

Four potential outcomes of stem cells. A) Quiescence in which a stem cell does not divide but maintains the stem cell pool. B) Symmetric self-renewal where a stem cell divides into two daughter stem cells increasing the stem cell pool. C) Asymmetric self-renewal in which a stem cell divides into one differentiated daughter cell and one stem cell, maintaining the stem cell pool. D) Symmetric division without self-renewal where there is a loss in the stem cell pool but results in two differentiated daughter cells. (SC- Stem cell, DP-Differentiated progeny)

The factors that determine the fate of stem cells is the focus of intense research. Knowledge of the details could be clinically useful. For example, clinicians and scientists might direct a stem cell population to expand several fold through symmetrical self-renewal before differentiation into multipotent or more specialized progenitor cells. This would ensure a large, homogeneous population of cells at a useful differentiation stage that could be delivered to patients for successful tissue regeneration.

Sources of Stem Cells

Pluripotent.

Pluripotent stem cells being used in research today mainly come from embryos, hence the name, “embryonic stem cells”. Pre-implantation embryos a few days old contain only 10-15% pluripotent cells in the “inner cell mass” ( Figure 1 ). Those pluripotent cells can be isolated, then cultured on a layer of “feeder” cells which provide unknown cues for many rounds of proliferation while sustaining their pluripotency.

Recently, two different groups of scientists induced adult cells back into the pluripotent state by molecular manipulation to yield “induced pluripotent stem cells” (iPS) that share some of the same characteristics as embryonic stem cells such as proliferation, morphology and gene expression (in the form of distinct surface markers and proteins being expressed). 4 - 8 Both groups used retroviruses to carry genes for transcription factors into the adult cells. These genes are transcribed and translated into proteins that regulate the expression of other genes designed to reprogram the adult nucleus back into its embryonic state. Both introduced the embryonic transcription factors known as Sox2 and Oct4. One group also added Klf4 and c-Myc 4 , and the other group added Lin28 and Nanog. 6 Other combinations of factors would probably also work, but, unfortunately, neither the retroviral carrier method nor the use of the oncogenic transcription factor c-Myc are likely to be approved for human therapy. Consequently, a purely chemical approach to deliver genes into the cells, and safer transcription factors are being tried. Results of these experiments look promising. 9

Multipotent

Multipotent stem cells may be a viable option for clinical use. These cells have the plasticity to become all the progenitor cells for a particular germ layer or can be restricted to become only one or two specialized cell types of a particular tissue. The multipotent stem cells with the highest differentiating potential are found in the developing embryo during gastrulation (day 14-15 in humans, day 6.5-7 in mice). These cells give rise to all cells of their particular germ layer, thus, they still have flexibility in their differentiation capacity. They are not pluripotent stem cells because they have lost the ability to become cells of all three germ layers ( Figure 1 ). On the low end of the plasticity spectrum are the unipotent cells that can become only one specialized cell type such as skin stem cells or muscle stem cells. These stem cells are typically found within their organ and although their differentiation capacity is restricted, these limited progenitor cells play a vital role in maintaining tissue integrity by replenishing aging or injured cells. There are many other sub-types of multipotent stem cells occupying a range of differentiation capacities. For example, multipotent cells derived from the mesoderm of the gastrula undergo a differentiation step limiting them to muscle and connective tissue; however, further differentiation results in increased specialization towards only connective tissue and so on until the cells can give rise to only cartilage or only bone.

Multipotent stem cells found in bone marrow are best known, because these have been used therapeutically since the 1960’s 10 (their potential will be discussed in greater detail in a later section). Recent research has found new sources for multipotent stem cells of greater plasticity such as the placenta and umbilical cord blood. 11 Further, the heart, until recently considered void of stem cells, is now known to contain stem cells with the potential to become cardiac myocytes. 12 Similarly, neuro-progenitor cells have been found within the brain. 13

The cardiac stem cells are present in such small numbers, that they are difficult to study and their function has not been fully determined. The second review in this series will discuss their potential in greater detail.

Characteristics that Identify Stem Cells

Since Federal funding for human embryonic stem cells is restricted in the United States, many scientists use the mouse model instead. Besides their ability to self-renew indefinitely and differentiate into cell types of all three germ layers, murine and human pluripotent stem cells have much in common. It should not be surprising that so many pluripotency traits are conserved between species given the shared genomic sequences and intra-cellular structure in mammals. Both mouse and human cells proliferate indefinitely in culture, have a high nucleus to cytoplasm ratio, need the support of growth factors derived from other live cells, and display similar surface antigens, transcription factors and enzymatic activity (i.e. high alkaline phosphatase activity). 14 However, differences between mouse and human pluripotent cells, while subtle, are very important. Although the transcription factors mentioned above to induce pluripotency from adult cells (Oct3/4 and Sox2) are shared, the extracellular signals needed to regulate them differ. Mouse embryonic stem cells need the leukemia inhibitory factor and bone morphogenic proteins while human require the signaling proteins Noggin and Wnt for sustained pluripotency. 15 Surface markers used to identify pluripotent cells also differ slightly between the two species as seen in the variants of the adhesion molecule SSEA (SSEA-1 in mouse, SSEA-3 & 4 in humans). 16 Thus, while pluripotency research in mouse cells is valuable, a direct correlation to the human therapy is not likely.

Last, but certainly not least, a big difference between mouse and human stem cells are the moral and ethical dilemmas that accompany the research. Some people consider working with human embryonic stem cells to be ethically problematic while very few people have reservations on working with the mouse models. However, given the biological differences between human and mouse cells, most scientists believe that data relevant for human therapy will be missed by working only on rodents.

Cell surface markers are typically also used to identify multipotent stem cells. For example, mesenchymal stem cells can be purified from the whole bone marrow aspirate by eliminating cells that express markers of committed cell types, a step referred to as lineage negative enrichment, and then further separating the cells that express the sca-1 and c-Kit surface markers signifying mesenchymal stem cells. Both the lineage negative enrichment step and the sca-1/c-Kit isolation can be achieved by using flow cytometry and is discussed in further detail in the following review. The c-Kit surface marker also is used to distinguish the recently discovered cardiac stem cells from the rest of the myocardium. A great deal of recent work in cardiovascular research has centered on trying to find which markers indicate early multipotent cells that will give rise to pre-cardiac myocytes. Cells with the specific mesodermal marker, Kdr, give rise to the progenitor cells of the cardiovascular system including contracting cardiac myocytes, endothelial cells and vascular smooth muscle cells and are therefore considered to be the earliest cells with specification towards the cardiovascular lineage. 17 Cells at this early stage still proliferate readily and yet are destined to become cells of the cardiovascular system and so may be of great value therapeutically.

Differentiation

Scientists are still struggling to reliably direct differentiation of stem cells into specific cell types. They have used a virtual alphabet soup of incubation factors toward that end (including trying a variety of growth factors, chemicals and complex substrates on which the cells are grown), with, so far, only moderate success. As an example of this complexity, one such approach to achieve differentiation towards cardiac myocytes is to use the chemical activin A and the growth factor BMP-4. When these two factors are administered to pluripotent stem cells in a strictly controlled manner, both in concentration and temporally, increased efficiency is seen in differentiation towards cardiac myocytes, but still, only 30% of cells can be expected to become cardiac. 18

Multipotent cells have also been used as the starting point for cell therapy, again with cocktails of growth factors and/or chemicals to induce differentiation toward a specific, desired lineage. Some recipes are simple, such as the use of retinoic acid to induce mesenchymal stem cells into neuronal cells, 19 or transforming growth factor-β to make bone marrow-derived stem cells express cardiac myocyte markers. 20 Others are complicated or ill-defined such as addition of the unknown factors secreted by cells in culture. Physical as well as chemical cues cause differentiation of stem cells. Simply altering the stiffness of the substrate on which cells are cultured can direct stem cells to neuronal, myogenic or osteogenic lineages. 21 Cells evolve in physical and chemical environments so a combination of both will probably be necessary for optimal differentiation of stem cells. The importance of physical cues in the cell’s environment will be discussed in greater detail in the final review of this series. Ideally, for stem cells to be used therapeutically, efficient, uniform protocols must be established so that cells are a well-controlled and well-defined entity.

Stem Cell Therapy

Pluripotent stem cells.

Pluripotent stem cells have not yet been used therapeutically in humans because many of the early animal studies resulted in the undesirable formation of unusual solid tumors, called teratomas. Teratomas are made of a mix of cell types from all the early germ layers. Later successful animal studies used pluripotent cells modified to a more mature phenotype which limits this proliferative capacity. Cells derived from pluripotent cells have been used to successfully treat animals. For example, animals with diabetes have been treated by the creation of insulin-producing cells responsive to glucose levels. Also, animals with acute spinal cord injury or visual impairment have been treated by creation of new myelinated neurons or retinal epithelial cells, respectively. Commercial companies are currently in negotiations with the FDA regarding the possibility of advancing to human trials. Other animal studies have been conducted to treat several maladies such as Parkinson’s disease, muscular dystrophy and heart failure. 18 , 22 , 23

Scientists hope that stem cell therapy can improve cardiac function by integration of newly formed beating cardiac myocytes into the myocardium to produce greater force. Patches of cardiac myocytes derived from human embryonic stem cells can form viable human myocardium after transplantation into animals, 24 with some showing evidence of electrical integration. 25 , 26 Damaged rodent hearts showed slightly improved cardiac function after injection of cardiac myocytes derived from human embryonic stem cells. 21 The mechanisms for the gain in function are not fully understood but it may be only partially due to direct integration of new beating heart cells. It is more likely due to paracrine effects that benefit other existing heart cells (see next review).

Multipotent stem cells

Multipotent stem cells harvested from bone marrow have been used since the 1960’s to treat leukemia, myeloma and lymphoma. Since cells there give rise to lymphocytes, megakaryocytes and erythrocytes, the value of these cells is easily understood in treating blood cancers. Recently, some progress has been reported in the use of cells derived from bone marrow to treat other diseases. For example, the ability to form whole joints in mouse models 27 has been achieved starting with mesenchymal stem cells that give rise to bone and cartilage. In the near future multipotent stem cells are likely to benefit many other diseases and clinical conditions. Bone marrow-derived stem cells are in clinical trials to remedy heart ailments. This is discussed in detail in the next review of this series.

Pluripotent vs. Multipotent

Pluripotent and multipotent stem cells have their respective advantages and disadvantages. The capacity of pluripotent cells to become any cell type is an obvious therapeutic advantage over their multipotent kin. Theoretically, they could be used to treat diseased or aging tissues in which multipotent stem cells are insufficient. Also, pluripotent stem cells proliferate more rapidly so can yield higher numbers of useful cells. However, use of donor pluripotent stem cells would require immune suppressive drugs for the duration of the graft 28 while use of autologous multipotent stem cells (stem cells from ones’ self) would not. This ability to use one’s own cells is a great advantage of multipotent stem cells. The immune system recognizes specific surface proteins on cells/objects that tell them whether the cell is from the host and is healthy. Autologous, multipotent stem cells have the patient’s specific surface proteins that allow it to be accepted by the host’s immune system and avoid an immunological reaction. Pluripotent stem cells, on the other hand, are not from the host and therefore, lack the proper signals required to stave off rejection from the immune system. Research is ongoing trying to limit the immune response caused by pluripotent cells and is one possible advantage that iPS cells may have.

The promises of cures for human ailments by stem cells have been much touted but many obstacles must still be overcome. First, more human pluripotent and multipotent cell research is needed since stem cell biology differs in mice and men. Second, the common feature of unlimited cell division shared by cancer cells and pluripotent stem cells must be better understood in order to avoid cancer formation. Third, the ability to acquire large numbers of the right cells at the right stage of differentiation must be mastered. Fourth, specific protocols must be developed to enhance production, survival and integration of transplanted cells. Finally, clinical trials must be completed to assure safety and efficacy of the stem cell therapy. When it comes to stem cells, knowing they exist is a long way from using them therapeutically.

Acknowledgments

Supported by NIH (HL 62426 and T32 HL 007692)

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Published: 14 August 2024

Lab & life

Stem cell science starters

Vivien Marx 1

Nature Methods ( 2024 ) Cite this article

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Early-career scientists shared some of their plans, hopes and dreams about being a principal investigator at the 2024 annual meeting of the International Society for Stem Cell Research.

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Introduction to Stem Cell Therapy

Brenda Russell

Introduction

Stem Cell Fates

Sources of Stem Cells

Multipotent

Characteristics that Identify Stem Cells

Differentiation

Stem Cell Therapy

Multipotent stem cells

Pluripotent vs. Multipotent