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.
Highlights
Since the discovery of induced pluripotent stem cells, the field of regenerative medicine has grown exponentially, and the feasibility of ‘adult cell-derived’ therapy is emerging
We found that all three Induced pluripotent stem (iPS) cell lines exhibited morphologic changes consistent with a transition from the undifferentiated pluripotent stage into mature oligodendrocytes (Fig. 1)
Generated iPS-oligodendrocyte progenitors (OPs) from 3 distinct iPS cell lines using 3 different reprogramming strategies. These lines included the BC1 line that was generated with non-integrating, episomally-mediated delivery of the reprogramming factors (OCT4 (O), SOX2 (S), KLF4 (K), MYC (M), LIN28) from adult peripheral blood monocytes and 2 other lines generated from bone marrow-derived, mesenchymal stem cells (A1-4 or HMGA1-OSKM) and fetal lung fibroblasts (MR31) by retroviral delivery of either HMGA1-OSKM factors or OSK, respectively [20,21,22]
Summary
Since the discovery of induced pluripotent stem (iPS) cells, the field of regenerative medicine has grown exponentially, and the feasibility of ‘adult cell-derived’ therapy is emerging. A number of studies have investigated transplantation of oligodendrocyte progenitors (OPs) derived from human embryonic stem (ES) cells or mesenchymal stem cells (MSCs) in animal models of SCI, with some conflicting results. Yoshihara et al reported that after transplantation of MSC in rats with SCI, there was no correlation between cell survival and locomotor improvement [5]. Torres and Espín et al published a promising study in which acutely grafted mesenchymal stromal cells in rat SCI led to improved locomotion [6]. Injections of bone marrow-derived MSCs have been shown to improve hindlimb locomotion, reduce cavity area, and reduce inflammation in rats [7,8,9] and to improve recovery of the panniculus reflex and diminish pain responses in dogs with SCI [10]
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