Abstract

Background: Cell-based strategies focusing on replacement or protection of dopaminergic neurons have been considered as a potential approach to treat Parkinson’s disease (PD) for decades. However, despite promising preclinical results, clinical trials on cell-therapy for PD reported mixed outcomes and a thorough synthesis of these findings is lacking. We performed a systematic review and meta-analysis to evaluate cell-therapy for PD patients.

Methods: We systematically identified all clinical trials investigating cell- or tissue-based therapies for PD published before July 2023. Out of those, studies reporting transplantation of homogenous cells (containing one cell type) were included in meta-analysis. The mean difference or standardized mean difference in quantitative neurological scale scores before and after cell-therapy was analyzed to evaluate treatment effects.

Results: The systematic literature search revealed 106 articles. Eleven studies reporting data from 11 independent trials (210 patients) were eligible for meta-analysis. Disease severity and motor function evaluation indicated beneficial effects of homogenous cell-therapy in the ‘of’ state at 3-, 6-, 12-, or 24-month follow-ups, and for motor function even after 36 months. Most of the patients were levodopa responders (61.6–100% in different follow-ups). Cell-therapy was also effective in improving the daily living activities in the ‘of’ state of PD patients. Cells from diverse sources were used and multiple transplantation modes were applied. Autografts did not improve functional outcomes, while allografts exhibited beneficial effects. Encouragingly, both transplantation into basal ganglia and to areas
outside the basal ganglia were effective to reduce disease severity. Some trials reported adverse events potentially related to the surgical procedure. One confirmed and four possible cases of graft-induced dyskinesia were reported in two trials included in this meta-analysis.

Conclusions: This meta-analysis provides preliminary evidence for the beneficial effects of homogenous cell-therapy for PD, potentially to the levodopa responders. Allogeneic cells were superior to autologous cells, and the effective transplantation sites are not limited to the basal ganglia.

PROSPERO registration number: CRD42022369760

Keywords Parkinson’s disease, Cell-therapy, Homogenous cell, Transplantation, Meta-analysis

Abstract

Parkinson’s disease (PD) is the second most predominant neurodegenerative disease worldwide. It is recognized clinically by severe complications in motor function caused by progressive degeneration of dopaminergic neurons (DAn) and dopamine depletion. As the current standard of treatment is focused on alleviating symptoms through Levodopa, developing neuroprotective techniques is critical for adopting a more pathology-oriented therapeutic approach. Regenerative cell therapy has provided us with an unrivaled platform for evaluating potentially effective novel methods for treating neurodegenerative illnesses over the last two decades. Mesenchymal stem cells (MSCs)
are most promising, as they can differentiate into dopaminergic neurons and produce neurotrophic substances. The precise process by which stem cells repair neuronal injury is unknown, and MSC-derived exosomes are suggested to be responsible for a significant portion of such effects. The present review discusses the application of mesenchymal stem cells and MSC-derived exosomes in PD treatment.

Keywords: Mesenchymal stem cell, Exosome, Parkinson’s disease, Therapeutic application

Abstract

Background: We performed a meta-analysis of the efficacy and safety of stem cell therapy as a clinical treatment of knee osteoarthritis. This meta-analysis is expected to provide evidence of the efficacy of stem cell therapy, which is currently controversial, as a conservative treatment for knee osteoarthritis.
Methods: An online search for relevant articles was conducted in the PubMed, EMBASE, and Cochrane Library databases. The search terms were “stem cells” and “osteoarthritis.” We conducted a quality assessment of the included articles and extracted the following indicators: Visual Analogue Scale (VAS) score, Subjective International Knee Documentation Committee (IKDC) score, Western Ontario and McMaster Universities (WOMAC) subscales, and adverse events. The RevMan5.3 software was used for
determining effect sizes.

Results: Nine randomized controlled trials involving 339 patients were included. VAS score and IKDC score from baseline to 24 months were improved in the stem cell therapy group compared to those in the control group. However, no significant difference was observed between the 2 groups in IKDC score changes from baseline to 6 and 12 months, as well as in WOMAC-Pain, WOMACStiffness, and WOMAC-Physical Function score changes at each visit point.

Conclusion: Stem cell therapy is certainly superior to traditional treatments in the conservative treatment of KOA; it considerably reduces pain with no obvious additional side effects.

Abbreviations: AD-MSCs = adipose-derived mesenchymal stem cells, BMAC = bone marrow aspirate concentrate, BM-MSCs = bone marrow mesenchymal stromal cells, Cl = confidence interval, HA = hyaluronic acid, HTO = high tibial osteotomy, IKDC = International Knee Documentation Committee, IL-1RA = IL-1 receptor antagonist, MSCs = mesenchymal stem cells, PBSC = peripheral blood stem cells, PRG = progenza, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analysis, PRP
= platelet-poor plasma, RCTs = randomized controlled trials, SMD = standardized mean difference, VAS = Visual Analogue Scale, WOMAC = Western Ontario and McMaster Universities.

Keywords: knee osteoarthritis, meta-analysis, stem cell therapy

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Abstract

Background: The last decade has seen an explosion in the interest in using biologics for regenerative medicine applications, including umbilical cord-derived Wharton’s Jelly. There is insufficient literature assessing the amount of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes in these products. The present study reports the development of a novel Wharton’s jelly formulation and evaluates the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes.

Methods: Human umbilical cords were obtained from consenting caesarian section donors. The Wharton’s jelly was then isolated from the procured umbilical cord and formulated into an injectable form. Randomly selected samples from different batches were analyzed for sterility testing and to quantify the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles.

Results: All samples passed the sterility test. Growth factors including IGFBP 1, 2, 3, 4, and 6, TGF-α, and PDGF-AA were detected. Several immunomodulatory cytokines, such as RANTES, IL-6R, and IL-16, were also detected. Proinflammatory cytokines MCSFR, MIP-1a; anti-inflammatory cytokines TNF-RI, TNF-RII, and IL-1RA; and homeostatic cytokines TIMP-1 and TIMP-2 were observed. Cytokines associated with wound healing, ICAM-1, G-CSF, GDF-15, and regenerative properties, GH, were also expressed. High concentrations of hyaluronic acid were observed. Particles in the extracellular vesicle size range were also detected and were enclosed by the membrane, indicative of true extracellular vesicles.

Conclusion: There are numerous growth factors, cytokines, hyaluronic acid, and extracellular vesicles present in the Wharton’s jelly formulation analyzed. The amount of these factors in Wharton’s jelly is higher compared with other biologics and may play a role in reducing inflammation and pain and augment healing of musculoskeletal injuries.

Keywords: Regenerative medicine, Musculoskeletal injuries, Osteoarthritis, Biologics, Umbilical cord, Wharton’s jelly, Growth factors, cytokines, Hyaluronic acid, Exosomes

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Abstract

Background: Compromised wound healing has become a global public health challenge which presents a significant psychological, financial, and emotional burden on patients and physicians. We recently reported that acellular gelatinous Wharton’s jelly of the human umbilical cord enhances skin wound healing in vitro and in vivo in a murine model; however, the key player in the jelly which enhances wound healing is still unknown.

Methods: We performed mass spectrometry on acellular gelatinous Wharton’s jelly to elucidate the chemical structures of the molecules. Using an ultracentrifugation protocol, we isolated exosomes and treated fibroblasts with these exosomes to assess their proliferation and migration. Mice were subjected to a full-thickness skin biopsy experiment and treated with either control vehicle or vehicle containing exosomes. Isolated exosomes were subjected to further mass spectrometry analysis to determine their cargo.

Results: Subjecting the acellular gelatinous Wharton’s jelly to proteomics approaches, we detected a large amount of proteins that are characteristic of exosomes. Here, we show that the exosomes isolated from the acellular gelatinous Wharton’s jelly enhance cell viability and cell migration in vitro and enhance skin wound healing in the punch biopsy wound model in mice. Mass spectrometry analysis revealed that exosomes of Wharton’s jelly umbilical cord contain a large amount of alpha-2-macroglobulin, a protein which mimics the effect of acellular gelatinous Wharton’s jelly exosomes on wound healing.

Conclusions: Exosomes are being enriched in the native niche of the umbilical cord and can enhance wound healing in vivo through their cargo. Exosomes from the acellular gelatinous Wharton’s jelly and the cargo protein alpha-2- macroglobulin have tremendous potential as a noncellular, off-the-shelf therapeutic modality for wound healing.

Keywords: Skin, Umbilical cord, Wound healing, Wharton’s jelly, Exosomes, Stem cells