Early Intervention for Spinal Cord Injury with Human Induced Pluripotent Stem Cells Oligodendrocyte Progenitors

Abstract

Induced pluripotent stem (iPS) cells are at the forefront of research in regenerative medicine and are envisaged as a source for personalized tissue repair and cell replacement therapy. Here, we demonstrate for the first time that oligodendrocyte progenitors (OPs) can be derived from iPS cells generated using either an episomal, non-integrating plasmid approach or standard integrating retroviruses that survive and differentiate into mature oligodendrocytes after early transplantation into the injured spinal cord. The efficiency of OP differentiation in all 3 lines tested ranged from 40% to 60% of total cells, comparable to those derived from human embryonic stem cells. iPS cell lines derived using episomal vectors or retroviruses generated a similar number of early neural progenitors and glial progenitors while the episomal plasmid-derived iPS line generated more OPs expressing late markers O1 and RIP. Moreover, we discovered that iPS-derived OPs (iPS-OPs) engrafted 24 hours following a moderate contusive spinal cord injury (SCI) in rats survived for approximately two months and that more than 70% of the transplanted cells differentiated into mature oligodendrocytes that expressed myelin associated proteins. Transplanted OPs resulted in a significant increase in the number of myelinated axons in animals that received a transplantation 24 h after injury. In addition, nearly a 5-fold reduction in cavity size and reduced glial scarring was seen in iPS-treated groups compared to the control group, which was injected with heat-killed iPS-OPs. Although further investigation is needed to understand the mechanisms involved, these results provide evidence that patient-specific, iPS-derived OPs can survive for three months and improve behavioral assessment (BBB) after acute transplantation into SCI. This is significant as determining the time in which stem cells are injected after SCI may influence their survival and differentiation capacity.

The advancement of human pluripotent stem cell-derived therapies into the clinic

“…Therefore, numerous studies have been conducted in animal models of spinal injury, in which remyelinating cells were transplanted with the expectation that they differentiate into mature myelinating oligodendrocytes in vivo and restore axonal conduction. This therapeutic approach has demonstrated improved motor function in animal models Bambakidis and Miller, 2004;Cao et al, 2005;Lee et al, 2005, Biernaskie et al, 2007Yasuda et al, 2011;Hawryluk et al, 2014;All et al, 2015). However, it is worth noting that the beneficial effects of trophic factors secreted by transplanted cells might also contribute to functional efficacy (Zhang et al, 2006).…”

Progress in the Use of Induced Pluripotent Stem Cell-Derived Neural Cells for Traumatic Spinal Cord Injuries in Animal Populations: Meta-Analysis and Review

“…Out of a total of 22 reports that assessed iPSC‐derived neural cells for SCI treatment, the following studies were incorporated into the meta‐analysis . A few studies were excluded, because statistical significance could not be verified, motor recovery was not assessed, used a different scale to assess motor recovery, or focused on a cervical SCI model. Other studies were conducted in primates using iPSCs, and insufficient data were provided to perform a separate t ‐statistic.…”

Applications of induced pluripotent stem cell technologies in spinal cord injury

“…), one strategy is to generate and transplant more committed cells, such as OPCs (All et al . ; Kawabata et al . ) or neurogenic cells (Fujimoto et al .…”