The effect of stem cell therapy and comprehensive physical therapy in motor and non-motor symptoms in patients with multiple sclerosis

Alghwiri, Alia A.; Jamali, Fatima; Aldughmi, Mayis; Khalil, Hanan; Al‐Sharman, Alham; Alhattab, Dana; Al-Radaideh, Ali; Awidi, Abdalla

doi:10.1097/md.0000000000021646

Cited by 14 publications

(6 citation statements)

References 56 publications

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“…In brief, this study demonstrated the potential of NSCs to induce anti-inflammatory responses and provide neuroprotection and promote endogenous neurogenesis resulting in the reversal of EAE clinical symptoms and repair of the damaged CNS. Although there have been a number of clinical trials utilizing autologous bone marrow MSCs and umbilical cord-derived MSCs, the results are not always conclusive [66][67][68]. Furthermore, most of these studies were limited to phase I and II trials due to the limited availability of cells.…”

Section: Discussionmentioning

confidence: 99%

Neural stem cells derived from primitive mesenchymal stem cells reversed disease symptoms and promoted neurogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis

et al. 2021

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Background Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). MS affects millions of people and causes a great economic and societal burden. There is no cure for MS. We used a novel approach to investigate the therapeutic potential of neural stem cells (NSCs) derived from human primitive mesenchymal stem cells (MSCs) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Methods MSCs were differentiated into NSCs, labeled with PKH26, and injected into the tail vein of EAE mice. Neurobehavioral changes in the mice assessed the effect of transplanted cells on the disease process. The animals were sacrificed two weeks following cell transplantation to collect blood, lymphatic, and CNS tissues for analysis. Transplanted cells were tracked in various tissues by flow cytometry. Immune infiltrates were determined and characterized by H&E and immunohistochemical staining, respectively. Levels of immune regulatory cells, Treg and Th17, were analyzed by flow cytometry. Myelination was determined by Luxol fast blue staining and immunostaining. In vivo fate of transplanted cells and expression of inflammation, astrogliosis, myelination, neural, neuroprotection, and neurogenesis markers were investigated by using immunohistochemical and qRT-PCR analysis. Results MSC-derived NSCs expressed specific neural markers, NESTIN, TUJ1, VIMENTIN, and PAX6. NSCs improved EAE symptoms more than MSCs when transplanted in EAE mice. Post-transplantation analyses also showed homing of MSCs and NSCs into the CNS with concomitant induction of an anti-inflammatory response, resulting in reducing immune infiltrates. NSCs also modulated Treg and Th17 cell levels in EAE mice comparable to healthy controls. Luxol fast blue staining showed significant improvement in myelination in treated mice. Further analysis showed that NSCs upregulated genes involved in myelination and neuroprotection but downregulated inflammatory and astrogliosis genes more significantly than MSCs. Importantly, NSCs differentiated into neural derivatives and promoted neurogenesis, possibly by modulating BDNF and FGF signaling pathways. Conclusions NSC transplantation reversed the disease process by inducing an anti-inflammatory response and promoting myelination, neuroprotection, and neurogenesis in EAE disease animals. These promising results provide a basis for clinical studies to treat MS using NSCs derived from primitive MSCs.

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Section: Discussionmentioning

confidence: 99%

Neural stem cells derived from primitive mesenchymal stem cells reversed disease symptoms and promoted neurogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis

et al. 2021

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“…In some cases, there was improvement in the quality of life measures one month following treatment; however, the participants reported similar levels of pain one year after treatment (54,55). Furthermore, most of these studies were limited to phase I and II trials due to limited availability of cells.…”

Section: Resultsmentioning

confidence: 99%

Neural Stem Cells Reversed Disease Symptoms in an Experimental Autoimmune Encephalomyelitis Mouse Model of Multiple Sclerosis

et al. 2021

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Background Multiple sclerosis (MS) is an autoimmune in ammatory disease of the central nervous system (CNS). MS affects millions of people and causes a great economic and societal burden. Currently used treatment drugs have side effects and only address the symptoms but not the causes of MS. In this study, a novel approach of transplanting neural stem cells (NSCs) derived from human primitive mesenchymal stem cells (MSCs) was investigated in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Methods Primitive MSCs were differentiated into NSCs using selective media. The cells were labeled with PKH26 and injected into the tail vein of EAE mice. The animals were evaluated for changes in neurobehavior and weight twice daily. Two weeks following cell transplantation, the animals were sacri ced to collect the blood, lymphatic and CNS tissues for analysis. FACS analysis was used to track labeled cells and in ltrates. Histochemical analysis was performed to determine the levels of myelination. Expression of in ammation, neural, astrogliosis, neuroprotection, and myelination markers was investigated by using immunohistochemical and qRT-PCR analyses. Results Neurobehavioral assays showed that EAE disease process was halted by transplantation of both MSCs and NSCs. However, NSCs showed greater e cacy in reversing the disease symptoms, which resulted in near complete recovery of EAE animals. Post-transplantation analyses also showed homing of transplanted cells into the CNS with concomitant induction of anti-in ammatory response resulting in reduction of immune in ltrates. Luxol fast blue staining intensity of CNS tissues was signi cantly improved in treated mice as compared to EAE animals, suggesting endogenous remyelination. NSC transplantation also modulated Treg and Th17 cells in EAE mice to levels comparable to healthy controls. In addition, several of the markers associated with neuroprotection (i.e. Igf, Bdnf, and Trkb), myelination (i.e. Erk2, Krox-20, Oct-6, Mpz, Mbp, and Mog) and neurogenesis (i.e. Tuj1 and Nestin) were upregulated, suggesting endogenous regeneration in treated animals. Conclusions Cell transplantation was more effective at an earlier point of EAE disease (EAE stage 1) than later (EAE stage 2). These promising results provide basis for large-scale clinical studies to treat MS using NSCs derived from primitive MSCs.

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“…The most encouraging results were for CD/IBD, in which peri‐fistula injections of either autologous or allogenic BMMSCs or allogenic AdMSCs promoted healing of perianal fistulas 83‐86 ; intravenous injection of allogenic WJUCMSCs to CD and ulcerative colitis (UC) patients also reduced mucosal inflammation 87,88 . The six published reports using autologous BMMSCs administered intravenously or intrathecally for MS demonstrated safety and some non‐significant reduction of inflammatory parameters 89‐94 ; two other reports utilized allogeneic WJUCMSCs, with one study still ongoing 95 and one seeing benefit in several clinical parameters 96 . For RA, both autologous BMMSCs and allogenic AdMSCs were well tolerated and trended toward efficacy 97,98 .…”

Section: Current Clinical Trials Of Msct For Immune‐related Diseases: Specific Indicationsmentioning

confidence: 99%

Advances in Mesenchymal Stem Cell Therapy for Immune and Inflammatory Diseases: Use of Cell-Free Products and Human pluripotent Stem Cell-Derived Mesenchymal Stem Cells

Wang

Liu

Sytwu

et al. 2021

Stem Cells Translational Medicine

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Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID-19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off-the-shelf products. In addition, new products such as cell-free exosomes and human pluripotent stem cell (hPSC)-derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications-including graft-vs-host-disease, strongly Th17-mediated autoimmune diseases, and osteoarthritiswhich are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.

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The effect of stem cell therapy and comprehensive physical therapy in motor and non-motor symptoms in patients with multiple sclerosis

Abstract: Supplemental Digital Content is available in the text

Cited by 14 publications

References 56 publications

Neural stem cells derived from primitive mesenchymal stem cells reversed disease symptoms and promoted neurogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis

Neural stem cells derived from primitive mesenchymal stem cells reversed disease symptoms and promoted neurogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis

Neural Stem Cells Reversed Disease Symptoms in an Experimental Autoimmune Encephalomyelitis Mouse Model of Multiple Sclerosis

Advances in Mesenchymal Stem Cell Therapy for Immune and Inflammatory Diseases: Use of Cell-Free Products and Human pluripotent Stem Cell-Derived Mesenchymal Stem Cells

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