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

Abstract

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.

Elucidating the Pivotal Neuroimmunomodulation of Stem Cells in Spinal Cord Injury Repair

“…Induced pluripotent stem cells (iPSCs) ( Figure 1 ) show features analogous to those of embryonic stem cells (ESCs) and are capable of generating all three germ layers [ 1 , 73 ]. Thus, iPSCs are capable of improving ectodermal neural-lineage cells with suitable culture stimulation [ 1 ].…”

“…Thus, iPSCs are capable of improving ectodermal neural-lineage cells with suitable culture stimulation [ 1 ]. Human iPSC-NPCs were able to boost axonal regrowth, angiogenesis, and maintenance of the whole spinal cord [ 1 , 73 ]. Thus, iPSC-NPCs were able to influence neurological and electrophysiological recovery [ 1 ].…”

“…Studies has shown that transplanted human NPCs obtained from fetal CNS tissues stimulated regeneration of the host corticospinal tract in the spinal cord with motor functional improvement compared to NPCs with brain characteristics [68][69][70][71]. Nevertheless, the major disadvantage with NPCs is the risk for tumorigenicity due to the contamination of undifferentiated cells prior to transplantation [72,73]. Thus, to prevent tumorigenicity, contaminated cells were eliminated using the γ-secretase inhibitor (GSI), which inhibits Notch signaling (Table 1) [72].…”

“…Stem Cells International angiogenesis, and maintenance of the whole spinal cord [1,73]. Thus, iPSC-NPCs were able to influence neurological and electrophysiological recovery [1].…”

Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment

“…The induced differentiation of human iPSC into NSC (iPSC-NSC) provides a proliferative and broadly expandable in vitro cell source with glial [ 12 ] and neuronal differentiation potential [ 13 , 14 ]. In 2019, Okano et al described the first licensed trial for the clinical evaluation of iPSC-NSC in chronic SCI treatment in Japan [ 15 ].…”