Applications of induced pluripotent stem cell technologies in spinal cord injury

Abstract

Numerous basic research studies have suggested the potential efficacy of neural precursor cell (NPC) transplantation in spinal cord injury (SCI). However, in most such studies, the origin of the cells used was mainly fetal tissue or embryonic stem cells, both of which carry potential ethical concerns with respect to clinical use. The development of induced pluripotent stem cells (iPSCs) opened a new path toward regenerative medicine for SCI. iPSCs can be generated from somatic cells by induction of transcription factors, and induced to differentiate into NPCs with characteristics of cells of the central nervous system. The beneficial effect of iPSC-derived NPC transplantation has been reported from our group and others working in rodent and non-human primate models. These promising results facilitate the application of iPSCs for clinical applications in SCI patients. However, iPSCs also have issues, such as genetic/epigenetic abnormalities and tumorigenesis because of the artificial induction method, that must be addressed prior to clinical use. The selection of somatic cells, generation of integration-free iPSCs, and characterization of differentiated NPCs with thorough quality management are all needed to address these potential risks. To enhance the efficacy of the transplanted iPSC-NPCs, especially at chronic phase of SCI, administration of a chondroitinase or semaphorin3A inhibitor represents a potentially important means of promoting axonal regeneration through the lesion site. The combined use of rehabilitation with such cell therapy approaches is also important, as repetitive training enhances neurite outgrowth of transplanted cells and strengthens neural circuits at central pattern generators. Our group has already evaluated clinical grade iPSC-derived NPCs, and we look forward to initiating clinical testing as the next step toward determining whether this approach is safe and effective for clinical use.

Induced Pluripotent Stem Cell Transplantation Improves Locomotor Recovery in Rat Models of Spinal Cord Injury: a Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…A possible explanation for this might be that iPSC are one of the most widely used cell types for transplantation performed to recover the functions impaired as a result of injury [32]. In addition, the mechanism by which iPSC transplantation mediated functional improvements after SCI is multifaceted [33][34][35] although it is commonly accepted that iPSC transplantation can [7]: 1) reduce the area of syringomyelia and increase the area of spared tissue; 2) promote local microvascular regeneration and nerve regeneration for the repair of damaged cells; 3) reduce inflammation and inhibit oxidative stress after SCI; and 4) improve axonal growth and reconstruction of neural pathways by secreting substrates. Moreover, our findings are consistent with the data obtained in the study reported by Führmann et al, which demonstrated that transplantation of pluripotent stem cells and their differentiated progeny has the potential to regenerate functional pathways and improve locomotor function after SCI [36].…”

“…Within the past 5 years, laboratories around the world have reported functional improvements following iPSC transplantation in animal models of SCI [16,17]. This effect may be associated with significantly enhanced secretion of regenerative molecules and growth factors [7]. However, several studies have demonstrated poor survival of the cells and no significant functional recovery after the transplantation [18,19].…”

“…However, no neuroprotective and regenerative therapies capable of producing directly beneficial effects are currently available [7]. It has been demonstrated that high-dose methylprednisolone may have good effects on SCI, but there remains no consensus on the efficacy of this approach [8].…”

Transplanted enteric neural stem cells integrate within the developing chick spinal cord: implications for spinal cord repair

“…; Goulao & Lepore, ; Assinck et al. ; Nagoshi & Okano, ). Stem cells offer the potential to support endogenous recovery and replace lost neurons in SCI as well as to form bridging structures and allow axonal regeneration across the injury site (Moreno‐Manzano et al.…”

60th Anniversary of the Japanese Society for Neurochemistry

“…Hideyuki Okano and his group have accomplished a remarkable achievement in the field of NPC transplantation for spinal cord injury (Nagoshi and Okano ). Since the development of induced pluripotent stem cells (iPSCs), they have demonstrated the efficacy of iPSCs‐derived NPCs in animal models, and challenged safety issues such as tumorigenicity.…”