Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells

Kajikawa, Keita; Imaizumi, Kent; Shinozaki, Munehisa; Shibata, Shinsuke; Shindo, Tomoko; Kitagawa, Takahiro; Shibata, Reo; Kamata, Yasuhiro; Kojima, Kosuke; Nagoshi, Narihito; Matsumoto, Morio; Nakamura, Masaya

doi:10.1186/s13041-020-00662-w

Cited by 58 publications

(51 citation statements)

References 46 publications

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“…Following the primary injury, which causes immediate structural damage, a series of secondary injuries, including haemorrhage, enema, demyelination, and axonal and neuronal necrosis, occur [ 31 ]. Cell transplantation is a promising treatment, including NSCs/NPCs [ 32 ], MSCs [ 33 ], and Schwann cell-like cells [ 34 ]. To date, three main sources of NSCs have been described: direct isolation from the primary CNS tissue (either from the foetal or adult brain), differentiation from pluripotent stem cells, and transdifferentiation from somatic cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…In our study, ChR2-NPCs displayed increased proliferation following short BL stimulation for three consecutive days compared to unstimulated ChR2-NPCs. The discrete but significant proliferative effect in stimulated ChR2-NPCs could contribute to improve cell survival rates rather than tumorigenic complications, despite the already large number of studies employing NPCs [ 4 , 7 , 9 , 11 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Optogenetic Modulation of Neural Progenitor Cells Improves Neuroregenerative Potential

Giraldo

Palmero-Canton

Martínez-Rojas

et al. 2020

IJMS

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Neural progenitor cell (NPC) transplantation possesses enormous potential for the treatment of disorders and injuries of the central nervous system, including the replacement of lost cells or the repair of host neural circuity after spinal cord injury (SCI). Importantly, cell-based therapies in this context still require improvements such as increased cell survival and host circuit integration, and we propose the implementation of optogenetics as a solution. Blue-light stimulation of NPCs engineered to ectopically express the excitatory light-sensitive protein channelrhodopsin-2 (ChR2-NPCs) prompted an influx of cations and a subsequent increase in proliferation and differentiation into oligodendrocytes and neurons and the polarization of astrocytes from a pro-inflammatory phenotype to a pro-regenerative/anti-inflammatory phenotype. Moreover, neurons derived from blue-light-stimulated ChR2-NPCs exhibited both increased branching and axon length and improved axon growth in the presence of axonal inhibitory drugs such as lysophosphatidic acid or chondroitin sulfate proteoglycan. Our results highlight the enormous potential of optogenetically stimulated NPCs as a means to increase neuroregeneration and improve cell therapy outcomes for enhancing better engraftments and cell identity upon transplantation in conditions such as SCI.

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“…Given that in our procedure to generate ffiPSC-gNS/PCs required RA, well-known for caudalizing activity on neural tissues during development, 39 we examined difference in the regional identity. As shown in Figure S2, we examined expression of regional specific neural markers [52][53][54] and observed ffiPSC-gNS/PCs hold regional properties as caudalized neural tissues compared to ffiPSC-nNS/PCs, indicating regional identity in addition to differentiation capacity was altered. To characterize difference between these NS/PCs, we classified them based on transcriptome, and identified three clusters (C1-C3) ( Figure 3D).…”

Section: Transcriptome Signature Of Ffipsc-gns/pcsmentioning

confidence: 99%

A robust culture system to generate neural progenitors with gliogenic competence from clinically relevant induced pluripotent stem cells for treatment of spinal cord injury

Kamata

Isoda

Sanosaka

et al. 2020

Stem Cells Translational Medicine

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Cell-based therapy targeting spinal cord injury (SCI) is an attractive approach to promote functional recovery by replacing damaged tissue. We and other groups have reported the effectiveness of transplanting neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) in SCI animal models for neuronal replacement. Glial replacement is an additional approach for tissue repair; however, the lack of robust procedures to drive iPSCs into NS/PCs which can produce glial cells has hindered the development of glial cell transplantation for the restoration of neuronal functions after SCI. Here, we established a method to generate NS/PCs with gliogenic competence (gNS/PCs) optimized for clinical relevance and utilized them as a source of therapeutic NS/PCs for SCI. We could successfully generate gNS/PCs from clinically relevant hiPSCs, which efficiently produced astrocytes and oligodendrocytes in vitro. We also performed comparison between gNS/PCs and neurogenic NS/PCs based on single cell RNA-seq analysis and found that gNS/PCs were distinguished by expression of several transcription factors including HEY2 and NFIB. After gNS/PC transplantation, the graft did not exhibit tumor-like tissue formation, indicating the safety of them as a source of cell therapy. Importantly, the gNS/PCs triggered functional recovery in an SCI animal model, with remyelination of demyelinated axons and improved motor function. Given the inherent safety of gNS/PCs and favorable outcomes observed after their transplantation, cell-based medicine using the gNS/PCs-induction procedure described here together with clinically relevant iPSCs is realistic and would be beneficial for SCI patients.

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Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells

Cited by 58 publications

References 46 publications

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

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

Optogenetic Modulation of Neural Progenitor Cells Improves Neuroregenerative Potential

A robust culture system to generate neural progenitors with gliogenic competence from clinically relevant induced pluripotent stem cells for treatment of spinal cord injury

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