Human Spinal Oligodendrogenic Neural Progenitor Cells Enhance Pathophysiological Outcomes and Functional Recovery in a Clinically Relevant Cervical Spinal Cord Injury Rat Model.

Traumatic spinal cord injury (SCI) results in the loss of neurons, oligodendrocytes, and astrocytes. Present interventions for SCI include decompressive surgery, anti-inflammatory therapies, and rehabilitation programs. Nonetheless, these approaches do not offer regenerative solutions to replace the lost cells, fiber tracts, and circuits. Neural stem/progenitor cell (NPC) transplantation is a promising strategy that aims to encourage regeneration. However, NPC differentiation remains inconsistent, thus, contributing to suboptimal functional recovery. As such, we have previously engineered oligodendrogenically biased NPCs (oNPCs) and demonstrated their efficacy in a thoracic model of SCI. Since the majority of patients with SCI experience cervical injuries, our objective in the current study was to generate human induced pluripotent stem cell-derived oNPCs (hiPSC-oNPCs) and to characterize these cells in vitro and in vivo, utilizing a clinically relevant rodent model of cervical SCI. Following transplantation, the oNPCs engrafted, migrated to the rostral and caudal regions of the lesion, and demonstrated preferential differentiation toward oligodendrocytes. Histopathological evaluations revealed that oNPC transplantation facilitated tissue preservation while diminishing astrogliosis. Moreover, oNPC transplantation fostered remyelination of the spared tissue. Functional analyses indicated improved forelimb grip strength, gait, and locomotor function in the oNPC-transplanted rats. Importantly, oNPC transplantation did not exacerbate neuropathic pain or induce tumor formation. In conclusion, these findings underscore the therapeutic potential of oNPCs in promoting functional recovery and histopathological improvements in cervical SCI. This evidence warrants further investigation to optimize and advance this promising cell-based therapeutic approach.

Incorporating Combinatorial Approaches to Encourage Targeted Neural Stem/Progenitor Cell Integration Following Transplantation in Spinal Cord Injury.

Spinal cord injury (SCI) severely diminishes quality of life and presents patients with a substantial financial burden. The lack of a curative treatment has guided efforts toward identifying potential regenerative treatments. Neural stem/progenitor cell (NSPC) transplantation represents a promising strategy for the regeneration of the injured spinal cord due to the ability of these cells to replace neural cells lost post-injury. However, the transplant-derived oligodendrocytes and neurons need to be able to associate and integrate within the appropriate endogenous circuits to guarantee optimal functional recovery. To date, the integration of these transplant-derived cells has lacked specificity and remains a challenge. As such, it appears that the transplanted cells will require additional guidance cues to instruct the cells where to integrate. In the present review, we propose a variety of combinatorial techniques that can be used in conjunction with NSPC transplantation to direct the cells toward particular circuits of interest. We begin by introducing distinct molecular signatures that assist in the formation of specific circuits during development, and highlight how favorable molecular cues can be incorporated within the cells and their environment to guide the grafted cells. We also introduce alternative methods including task-specific rehabilitation, galvanotaxis, and magnet-based tools, which can be applied to direct the integration of the grafted cells toward the stimulated circuits. Future research examining these combinatorial efforts may serve to improve outcomes following SCI.

Regenerative replacement of neural cells for treatment of spinal cord injury.

Introduction: Traumatic Spinal Cord Injury (SCI) results from primary physical injury to the spinal cord, which initiates a secondary cascade of neural cell death. Current therapeutic approaches can attenuate the consequences of the primary and secondary events, but do not address the degenerative aspects of SCI. Transplantation of neural stem/progenitor cells (NPCs) for the replacement of the lost/damaged neural cells is suggested here as a regenerative approach that is complementary to current therapeutics.Areas Covered: This review addresses how neurons, oligodendrocytes, and astrocytes are impacted by traumatic SCI, and how current research in regenerative-NPC therapeutics aims to restore their functionality. Methods used to enhance graft survival, as well as bias progenitor cells towards neuronal, oligodendrogenic, and astroglia lineages are discussed.Expert Opinion: Despite an NPC's ability to differentiate into neurons, oligodendrocytes, and astrocytes in the transplant environment, their potential therapeutic efficacy requires further optimization prior to translation into the clinic. Considering the temporospatial identity of NPCs could promote neural repair in region specific injuries throughout the spinal cord. Moreover, understanding which cells are targeted by NPC-derived myelinating cells can help restore physiologically-relevant myelin patterns. Finally, the duality of astrocytes is discussed, outlining their context-dependent importance in the treatment of SCI.