HiPSC-Derived NSCs Effectively Promote The Functional Recovery of Acute Spinal Cord Injury in Mice

Abstract Background: Spinal cord injury (SCI) is a common disease that results in motor and sensory disorders and even lifelong paralysis. The transplantation of stem cells, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), or subsequently generated stem/progenitor cells, is predicted to be a promising treatment for SCI. In this study, we aimed to investigate effect of human iPSC-derived neural stem cells (hiPSC-NSCs) and umbilical cord-derived MSCs (huMSCs) in a mouse model of acute SCI. Methods: Acute SCI mice model were established and were randomly treated as PBS (control group), repaired with 1×105 hiPSC-NSCs (NSC group), and 1×105 huMSCs (MSC group), respectively, in a total of 54 mice (n = 18 each). Hind limb motor function was evaluated in open-field tests using the Basso Mouse Scale (BMS) at days post-operation (dpo) 1, 3, 5 and 7 after spinal cord injury, and weekly thereafter. Spinal cord and serum samples were harvested at dpo 7, 14 and 21. HE staining and Masson staining were used to evaluate the morphological changes and fibrosis area. The differentiation of the transplanted cells in vivo was evaluated with immunohistochemical staining. Results: The hiPSC-NSC-treated group presented a significantly smaller GFAP+ area than MSC-treated mice at all time points. Additionally, MSC-transplanted mice had a similar GFAP+ area to mice receiving PBS. At dpo14, the immunostained hiPSC-NSCs were positive for SOX2. Furthermore, the transplanted hiPSC-NSCs differentiated into glial fibrillary acidic protein (GFAP)-positive astrocytes and beta-III tubulin-positive neurons, whereas the transplanted huMSCs differentiated into GFAP-positive astrocytes. In addition, hiPSC-NSC transplantation reduced fibrosis formation and the inflammation level. Compared with the control or huMSC transplanted group, the group with transplantation of hiPSC-NSCs exhibited significantly improved behaviours, particularly limb coordination. Conclusions: HiPSC-NSCs promote functional recovery in mice with acute SCI by replacing missing neurons and attenuating fibrosis, glial scar formation, and inflammation.

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hiPSC-derived NSCs effectively promote the functional recovery of acute spinal cord injury in mice

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02217-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Desheng Kong ◽

Baofeng Feng ◽

Asiamah Ernest Amponsah ◽

Jingjing He ◽

Ruiyun Guo ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Morphological Changes ◽

Embryonic Stem ◽

Control Group ◽

Common Disease ◽

Mice Model ◽

Cord Injury

Abstract Background Spinal cord injury (SCI) is a common disease that results in motor and sensory disorders and even lifelong paralysis. The transplantation of stem cells, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), or subsequently generated stem/progenitor cells, is predicted to be a promising treatment for SCI. In this study, we aimed to investigate effect of human iPSC-derived neural stem cells (hiPSC-NSCs) and umbilical cord-derived MSCs (huMSCs) in a mouse model of acute SCI. Methods Acute SCI mice model were established and were randomly treated as phosphate-buffered saline (PBS) (control group), repaired with 1 × 105 hiPSC-NSCs (NSC group), and 1 × 105 huMSCs (MSC group), respectively, in a total of 54 mice (n = 18 each). Hind limb motor function was evaluated in open-field tests using the Basso Mouse Scale (BMS) at days post-operation (dpo) 1, 3, 5, and 7 after spinal cord injury, and weekly thereafter. Spinal cord and serum samples were harvested at dpo 7, 14, and 21. Haematoxylin-eosin (H&E) staining and Masson staining were used to evaluate the morphological changes and fibrosis area. The differentiation of the transplanted cells in vivo was evaluated with immunohistochemical staining. Results The hiPSC-NSC-treated group presented a significantly smaller glial fibrillary acidic protein (GFAP) positive area than MSC-treated mice at all time points. Additionally, MSC-transplanted mice had a similar GFAP+ area to mice receiving PBS. At dpo 14, the immunostained hiPSC-NSCs were positive for SRY-related high-mobility-group (HMG)-box protein-2 (SOX2). Furthermore, the transplanted hiPSC-NSCs differentiated into GFAP-positive astrocytes and beta-III tubulin-positive neurons, whereas the transplanted huMSCs differentiated into GFAP-positive astrocytes. In addition, hiPSC-NSC transplantation reduced fibrosis formation and the inflammation level. Compared with the control or huMSC transplanted group, the group with transplantation of hiPSC-NSCs exhibited significantly improved behaviours, particularly limb coordination. Conclusions HiPSC-NSCs promote functional recovery in mice with acute SCI by replacing missing neurons and attenuating fibrosis, glial scar formation, and inflammation. Graphical abstract

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Stem Cell Transplantation: A Promising Therapy for Spinal Cord Injury

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190823144424 ◽

2020 ◽

Vol 15 (4) ◽

pp. 321-331 ◽

Cited By ~ 2

Author(s):

Zhe Gong ◽

Kaishun Xia ◽

Ankai Xu ◽

Chao Yu ◽

Chenggui Wang ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Therapeutic Potential ◽

Embryonic Stem ◽

Current Status ◽

Cord Injury

Spinal Cord Injury (SCI) causes irreversible functional loss of the affected population. The incidence of SCI keeps increasing, resulting in huge burden on the society. The pathogenesis of SCI involves neuron death and exotic reaction, which could impede neuron regeneration. In clinic, the limited regenerative capacity of endogenous cells after SCI is a major problem. Recent studies have demonstrated that a variety of stem cells such as induced Pluripotent Stem Cells (iPSCs), Embryonic Stem Cells (ESCs), Mesenchymal Stem Cells (MSCs) and Neural Progenitor Cells (NPCs) /Neural Stem Cells (NSCs) have therapeutic potential for SCI. However, the efficacy and safety of these stem cellbased therapy for SCI remain controversial. In this review, we introduce the pathogenesis of SCI, summarize the current status of the application of these stem cells in SCI repair, and discuss possible mechanisms responsible for functional recovery of SCI after stem cell transplantation. Finally, we highlight several areas for further exploitation of stem cells as a promising regenerative therapy of SCI.

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Exercise Ameliorates Spinal Cord Injury by Changing DNA Methylation

Cells ◽

10.3390/cells10010143 ◽

2021 ◽

Vol 10 (1) ◽

pp. 143

Author(s):

Ganchimeg Davaa ◽

Jin Young Hong ◽

Tae Uk Kim ◽

Seong Jae Lee ◽

Seo Young Kim ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Motor Cortex ◽

Functional Recovery ◽

Treadmill Exercise ◽

Exercise Group ◽

Control Group ◽

Epigenetic Changes ◽

Cord Injury ◽

The Brain

Exercise training is a traditional method to maximize remaining function in patients with spinal cord injury (SCI), but the exact mechanism by which exercise promotes recovery after SCI has not been identified; whether exercise truly has a beneficial effect on SCI also remains unclear. Previously, we showed that epigenetic changes in the brain motor cortex occur after SCI and that a treatment leading to epigenetic modulation effectively promotes functional recovery after SCI. We aimed to determine how exercise induces functional improvement in rats subjected to SCI and whether epigenetic changes are engaged in the effects of exercise. A spinal cord contusion model was established in rats, which were then subjected to treadmill exercise for 12 weeks. We found that the size of the lesion cavity and the number of macrophages were decreased more in the exercise group than in the control group after 12 weeks of injury. Immunofluorescence and DNA dot blot analysis revealed that levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the brain motor cortex were increased after exercise. Accordingly, the expression of ten-eleven translocation (Tet) family members (Tet1, Tet2, and Tet3) in the brain motor cortex also elevated. However, no macrophage polarization was induced by exercise. Locomotor function, including Basso, Beattie, and Bresnahan (BBB) and ladder scores, also improved in the exercise group compared to the control group. We concluded that treadmill exercise facilitates functional recovery in rats with SCI, and mechanistically epigenetic changes in the brain motor cortex may contribute to exercise-induced improvements.

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CD157 in bone marrow mesenchymal stem cells mediates mitochondrial production and transfer to improve neuronal apoptosis and functional recovery after spinal cord injury

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02305-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jing Li ◽

Heyangzi Li ◽

Simin Cai ◽

Shi Bai ◽

Huabo Cai ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Motor Neurons ◽

Functional Recovery ◽

Mitochondrial Transfer ◽

Cord Injury ◽

Marrow Mesenchymal Stem Cells

Abstract Background Recent studies demonstrated that autologous mitochondria derived from bone marrow mesenchymal stem cells (BMSCs) might be valuable in the treatment of spinal cord injury (SCI). However, the mechanisms of mitochondrial transfer from BMSCs to injured neurons are not fully understood. Methods We modified BMSCs by CD157, a cell surface molecule as a potential regulator mitochondria transfer, then transplanted to SCI rats and co-cultured with OGD injured VSC4.1 motor neuron. We detected extracellular mitochondrial particles derived from BMSCs by transmission electron microscope and measured the CD157/cyclic ADP-ribose signaling pathway-related protein expression by immunohistochemistry and Western blotting assay. The CD157 ADPR-cyclase activity and Fluo-4 AM was used to detect the Ca2+ signal. All data were expressed as mean ± SEM. Statistical analysis was analyzed by GraphPad Prism 6 software. Unpaired t-test was used for the analysis of two groups. Multiple comparisons were evaluated by one-way ANOVA or two-way ANOVA. Results CD157 on BMSCs was upregulated when co-cultured with injured VSC4.1 motor neurons. Upregulation of CD157 on BMSCs could raise the transfer extracellular mitochondria particles to VSC4.1 motor neurons, gradually regenerate the axon of VSC4.1 motor neuron and reduce the cell apoptosis. Transplantation of CD157-modified BMSCs at the injured sites could significantly improve the functional recovery, axon regeneration, and neuron apoptosis in SCI rats. The level of Ca2+ in CD157-modified BMSCs dramatically increased when objected to high concentration cADPR, ATP content, and MMP of BMSCs also increased. Conclusion The present results suggested that CD157 can regulate the production and transfer of BMSC-derived extracellular mitochondrial particles, enriching the mechanism of the extracellular mitochondrial transfer in BMSCs transplantation and providing a novel strategy to improve the stem cell treatment on SCI.

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BDNF-Hypersecreting Human Mesenchymal Stem Cells Promote Functional Recovery, Axonal Sprouting, and Protection of Corticospinal Neurons after Spinal Cord Injury

Journal of Neuroscience ◽

10.1523/jneurosci.2769-09.2009 ◽

2009 ◽

Vol 29 (47) ◽

pp. 14932-14941 ◽

Cited By ~ 186

Author(s):

M. Sasaki ◽

C. Radtke ◽

A. M. Tan ◽

P. Zhao ◽

H. Hamada ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Functional Recovery ◽

Human Mesenchymal Stem Cells ◽

Axonal Sprouting ◽

Cord Injury

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Transplantation of Neural Stem/Progenitor Cells at Different Locations in Mice with Spinal Cord Injury

Cell Transplantation ◽

10.3727/096368913x670967 ◽

2014 ◽

Vol 23 (11) ◽

pp. 1451-1464 ◽

Cited By ~ 21

Author(s):

Hiroki Iwai ◽

Satoshi Nori ◽

Soraya Nishimura ◽

Akimasa Yasuda ◽

Morito Takano ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Progenitor Cells ◽

Functional Recovery ◽

Control Group ◽

Cord Injury ◽

Neural Stem Progenitor Cells ◽

Neurotropic Factor ◽

Transplantation Site

Transplantation of neural stem/progenitor cells (NS/PCs) promotes functional recovery after spinal cord injury (SCI); however, few studies have examined the optimal site of NS/PC transplantation in the spinal cord. The purpose of this study was to determine the optimal transplantation site of NS/PCs for the treatment of SCI. Wild-type mice were generated with contusive SCI at the T10 level, and NS/PCs were derived from fetal transgenic mice. These NS/PCs ubiquitously expressed ffLuc-cp156 protein (Venus and luciferase fusion protein) and so could be detected by in vivo bioluminescence imaging 9 days postinjury. NS/PCs (low: 250,000 cells per mouse; high: 1 million cells per mouse) were grafted into the spinal cord at the lesion epicenter (E) or at rostral and caudal (RC) sites. Phosphate-buffered saline was injected into E as a control. Motor functional recovery was better in each of the transplantation groups (E-Low, E-High, RC-Low, and RC-High) than in the control group. The photon counts of the grafted NS/PCs were similar in each of the four transplantation groups, suggesting that the survival of NS/PCs was fairly uniform when more than a certain threshold number of cells were transplanted. Quantitative RT-PCR analyses demonstrated that brain-derived neurotropic factor expression was higher in the RC segment than in the E segment, and this may underlie why NS/PCs more readily differentiated into neurons than into astrocytes in the RC group. The location of the transplantation site did not affect the area of spared fibers, angiogenesis, or the expression of any other mediators. These findings indicated that the microenvironments of the E and RC sites are able to support NS/PCs transplanted during the subacute phase of SCI similarly. Optimally, a certain threshold number of NS/PCs should be grafted into the E segment to avoid damaging sites adjacent to the lesion during the injection procedure.

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