Multiple therapeutic effects of human neural stem cells derived from induced pluripotent stem cells in a rat model of post-traumatic syringomyelia

Xu, Tingting; Li, Xiaofei; Guo, Yu-xi; Uhlin, Elias; Holmberg, Lena; Mitra, Sumonto; Winn, Dania; Falk, Anna; Sundström, Erik

doi:10.1016/j.ebiom.2022.103882

Cited by 9 publications

(11 citation statements)

References 47 publications

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“…Interestingly, although in vitro almost all of the sNPCs expressed markers of neuronal lineage, the transplanted sNPC population were demonstrated to be multi-potent and retained the ability to differentiate into astrocytes, oligodendrocytes, and neurons when transplanted into chronically injured rats. Similar observations have been made by various authors, including ourselves, with different cells types and treatment paradigms [ 13 , 18 , 47 – 49 ] including using different rat strains that requires injections of cyclosporine to prevent rejection of human neural cell grafts which could drive the transplanted cells toward glial fate. We further observed that the expression of NF200 was significantly higher without glial scar ablation as compared with glial scar ablation at both 8 and 16 weeks after transplantation.…”

Section: Discussionsupporting

confidence: 85%

Electrical stimulation affects the differentiation of transplanted regionally specific human spinal neural progenitor cells (sNPCs) after chronic spinal cord injury

Patil,

Korenfeld,

Scalf

et al. 2023

Stem Cell Res Ther

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Background There are currently no effective clinical therapies to ameliorate the loss of function that occurs after spinal cord injury. Electrical stimulation of the rat spinal cord through the rat tail has previously been described by our laboratory. We propose combinatorial treatment with human induced pluripotent stem cell-derived spinal neural progenitor cells (sNPCs) along with tail nerve electrical stimulation (TANES). The purpose of this study was to examine the influence of TANES on the differentiation of sNPCs with the hypothesis that the addition of TANES would affect incorporation of sNPCs into the injured spinal cord, which is our ultimate goal. Methods Chronically injured athymic nude rats were allocated to one of three treatment groups: injury only, sNPC only, or sNPC + TANES. Rats were sacrificed at 16 weeks post-transplantation, and tissue was processed and analyzed utilizing standard histological and tissue clearing techniques. Functional testing was performed. All quantitative data were presented as mean ± standard error of the mean. Statistics were conducted using GraphPad Prism. Results We found that sNPCs were multi-potent and retained the ability to differentiate into mainly neurons or oligodendrocytes after this transplantation paradigm. The addition of TANES resulted in more transplanted cells differentiating into oligodendrocytes compared with no TANES treatment, and more myelin was found. TANES not only promoted significantly higher numbers of sNPCs migrating away from the site of injection but also influenced long-distance axonal/dendritic projections especially in the rostral direction. Further, we observed localization of synaptophysin on SC121-positive cells, suggesting integration with host or surrounding neurons, and this finding was enhanced when TANES was applied. Also, rats that were transplanted with sNPCs in combination with TANES resulted in an increase in serotonergic fibers in the lumbar region. This suggests that TANES contributes to integration of sNPCs, as well as activity-dependent oligodendrocyte and myelin remodeling of the chronically injured spinal cord. Conclusions Together, the data suggest that the added electrical stimulation promoted cellular integration and influenced the fate of human induced pluripotent stem cell-derived sNPCs transplanted into the injured spinal cord.

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Section: Discussionsupporting

confidence: 85%

Electrical stimulation affects the differentiation of transplanted regionally specific human spinal neural progenitor cells (sNPCs) after chronic spinal cord injury

Patil,

Korenfeld,

Scalf

et al. 2023

Stem Cell Res Ther

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“…Cell therapy can be considered an alternative therapy to treat syringomyelia. Animal experiments have shown good therapeutic effects of MSCs and NESCs (neuroepithelial-like stem cells) injection on syringomyelia [ 16 , 44 , 45 ]. Previous case reports have indicated that cell transplantation facilitates a reduction in syrinx and alleviation of disease [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Suppression of TGFβR-Smad3 pathway alleviates the syrinx induced by syringomyelia

Liu

et al. 2023

Cell Biosci

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Background Syringomyelia is a cerebrospinal fluid (CSF) disorder resulted in separation of pain and temperature, dilation of central canal and formation of syrinx in central canal. It is unclear about mechanisms of the dilation and syrinx formation. We aimed to investigate roles of ependymal cells lining central canal on the dilation, trying to reduce syrinx formation in central canal. Methods We employed 78 Sprague–Dawley (SD) rats totally with syringomyelia to detect the contribution of ependymal cells to the dilation of central canal. Immunofluorescence was used to examine the activation of ependymal cells in 54 syringomyelia rat models. BrdU was used to indicate the proliferation of ependymal cells through intraperitoneal administration in 6 syringomyelia rat models. 18 rats with syringomyelia were injected with SIS3, an inhibitor of TGFβR-Smad3, and rats injected with DMSO were used as control. Among the 18 rats, 12 rats were used for observation of syrinx following SIS3 or DMSO administration by using magnetic resonance imaging (MRI) on day 14 and day 30 under syringomyelia without decompression. All the data were expressed as mean ± standard deviation (mean ± SD). Differences between groups were compared using the two-tailed Student’s t-test or ANOVA. Differences were considered significant when *p < 0.05. Results Our study showed the dilation and protrusions of central canal on day 5 and enlargement from day 14 after syringomyelia induction in rats with activation of ependymal cells lining central canal. Moreover, the ependymal cells contributed to protrusion formation possibly through migration along with central canal. Furthermore, suppression of TGFβR-Smad3 which was crucial for migration reversed the size of syrnix in central canal without treatment of decompression, suggesting TGFβR-Smad3 signal might be key for dilation of central canal and formation of syrinx. Conclusions The size of syrinx was decreased after SIS3 administration without decompression. Our study depicted the mechanisms of syrinx formation and suggested TGFβR-Smad3 signal might be key for dilation of central canal and formation of syrinx.

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“…Preclinical studies have indicated that the grafting of NES cells into SCI models results in functional recovery ( Fujimoto et al, 2012 ; Xu et al, 2021 ; 2022 ) supporting several mechanisms of actions of grafted NES cells, including integration and differentiation combined with promotion of host neuron survival ( Dell’Anno et al, 2018 ; Fujimoto et al, 2012 ). However, most studies have focused on the sub-acute phase and only a limited number of studies have focused on the chronic phase ( Shibata et al, 2023 ).…”

Section: Introductionmentioning

confidence: 91%

Pre-clinical evaluation of clinically relevant iPS cell derived neuroepithelial stem cells as an off-the-shelf cell therapy for spinal cord injury

Winn,

Uhlin,

Kele

et al. 2024

Front. Pharmacol.

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Preclinical transplantations using human neuroepithelial stem (NES) cells in spinal cord injury models have exhibited promising results and demonstrated cell integration and functional improvement in transplanted animals. Previous studies have relied on the generation of research grade cell lines in continuous culture. Using fresh cells presents logistic hurdles for clinical transition regarding time and resources for maintaining high quality standards. In this study, we generated a good manufacturing practice (GMP) compliant human iPS cell line in GMP clean rooms alongside a research grade iPS cell line which was produced using standardized protocols with GMP compliant chemicals. These two iPS cell lines were differentiated into human NES cells, from which six batches of cell therapy doses were produced. The doses were cryopreserved, thawed on demand and grafted in a rat spinal cord injury model. Our findings demonstrate that NES cells can be directly grafted post-thaw with high cell viability, maintaining their cell identity and differentiation capacity. This opens the possibility of manufacturing off-the-shelf cell therapy products. Moreover, our manufacturing process yields stable cell doses with minimal batch-to-batch variability, characterized by consistent expression of identity markers as well as similar viability of cells across the two iPS cell lines. These cryopreserved cell doses exhibit sustained viability, functionality, and quality for at least 2 years. Our results provide proof of concept that cryopreserved NES cells present a viable alternative to transplanting freshly cultured cells in future cell therapies and exemplify a platform from which cell formulation can be optimized and facilitate the transition to clinical trials.

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Multiple therapeutic effects of human neural stem cells derived from induced pluripotent stem cells in a rat model of post-traumatic syringomyelia

Cited by 9 publications

References 47 publications

Electrical stimulation affects the differentiation of transplanted regionally specific human spinal neural progenitor cells (sNPCs) after chronic spinal cord injury

Electrical stimulation affects the differentiation of transplanted regionally specific human spinal neural progenitor cells (sNPCs) after chronic spinal cord injury

Suppression of TGFβR-Smad3 pathway alleviates the syrinx induced by syringomyelia

Pre-clinical evaluation of clinically relevant iPS cell derived neuroepithelial stem cells as an off-the-shelf cell therapy for spinal cord injury

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