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Transplantation therapies aimed at repairing neurodegenerative and neuropathological conditions of the central nervous system (CNS) have utilized and tested a variety of cell candidates, each with its own unique set of advantages and disadvantages. The use and popularity of each cell type is guided by a number of factors including the nature of the experimental model, neuroprotection capacity, the ability to promote plasticity and guided axonal growth, and the cells' myelination capability. The promise of stem cells, with their reported ability to give rise to neuronal lineages to replace lost endogenous cells and myelin, integrate into host tissue, restore functional connectivity, and provide trophic support to enhance and direct intrinsic regenerative ability, has been seen as a most encouraging step forward. The advent of the induced pluripotent stem cell (iPSC), which represents the ability to “reprogram” somatic cells into a pluripotent state, hails the arrival of a new cell transplantation candidate for potential clinical application in therapies designed to promote repair and/or regeneration of the CNS. Since the initial development of iPSC technology, these cells have been extensively characterized in vitro and in a number of pathological conditions and were originally reported to be equivalent to embryonic stem cells (ESCs). This review highlights emerging evidence that suggests iPSCs are not necessarily indistinguishable from ESCs and may occupy a different “state” of pluripotency with differences in gene expression, methylation patterns, and genomic aberrations, which may reflect incomplete reprogramming and may therefore impact on the regenerative potential of these donor cells in therapies. It also highlights the limitations of current technologies used to generate these cells. Moreover, we provide a systematic review of the state of play with regard to the use of iPSCs in the treatment of neurodegenerative and neuropathological conditions. The importance of balancing the promise of this transplantation candidate in the light of these emerging properties is crucial as the potential application in the clinical setting approaches. The first of three sections in this review discusses (A) the pathophysiology of spinal cord injury (SCI) and how stem cell therapies can positively alter the pathology in experimental SCI. Part B summarizes (i) the available technologies to deliver transgenes to generate iPSCs and (ii) recent data comparing iPSCs to ESCs in terms of characteristics and molecular composition. Lastly, in (C) we evaluate iPSC-based therapies as a candidate to treat SCI on the basis of their neurite induction capability compared to embryonic stem cells and provide a summary of available in vivo data of iPSCs used in SCI and other disease models.

We have developed a new type of polymer/cell/matrix implant and tested whether it can promote the regrowth of retinal ganglion cell (RGC) and other axons across surgically induced tissue defects in the CNS. The constructs, which consisted of 2–2.5-mm-long polycarbonate tubes filled with lens capsule-derived extracellular matrix coated with cultured neonatal Schwann cells, were implanted into lesion cavities made in the left optic tract (OT) of 18–21-day-old rats. In one group, to promote Schwann cell proliferation and perhaps also to stimulate axon regrowth, basic fibroblast growth factor (bFGF) was added to the lens capsule matrix prior to implantation. In another group, to determine whether application of growth factors to the somata of cells enhances the regrowth of distally injured axons, the neurotrophin NT-4/5 was injected into the eye contralateral to the OT lesion. NT-4/5 and bFGF treatments were combined in some rats. After medium-term (4–10 weeks) or long-term (15–20 weeks) survivals, axon growth into implants was assessed immunohistochemically using a neurofilament (RT97) antibody. RGC axons were visualized after injection of WGA/HRP into the right eye. Viable Schwann cells were present in implants at all times after transplantation. Large numbers of RT97 + axons were consistently found within the bridging implants, often associated with the peripheral glia. Axons were traced up to 1.7 mm from the nearest CNS neuropil and there was immunohistochemical evidence of myelination by Schwann cells and by host oligodendrocytes. There were fewer RGC axons in the implants, fibers growing up to 1.6 mm from the thalamus. Neither NT-4/5 nor bFGF, alone or in combination, significantly increased the extent of RGC axon growth within the implants. A group of OT-lesioned rats was implanted with polymer tubes filled with 2–2.5-mm-long pieces of predegenerate peripheral nerve. Surprisingly, polymer/cell/matrix constructs contained comparatively greater numbers of RGC and other axons and supported more extensive axon elongation. Thus, implants of this type may potentially be useful in bridging large tissue defects in the CNS.

Poly (2-hydroxyethylmethacrylate) (PolyHEMA) hydrogels, when combined with extracellular matrix molecules and infiltrated with cultured Schwann cells, have the capability to induce CNS axonal regrowth after injury. We have further investigated these PolyHEMA hydrogels and their potential to bridge CNS injury sites. Collagen IV-impregnated hydrogels containing Schwann cells were implanted into the lesioned optic tract in 14 rats. On examination 2–4 months later, there was good adherence between the implants and CNS tissue, and large numbers of viable Schwann cells (S100 + , GFAP + , Laminin + , and LNGFR + ) were seen within the hydrogel matrices. Immunohistochemical analysis showed that the collagen IV-impregnated PolyHEMA hydrogels preferentially supported the transplanted Schwann cells and not host glial cells such as astrocytes (GFAP + ) or oligodendroglia (CAII + ). Macrophages (ED1 + ) were also seen within the sponge structure. Eighty-three percent of the implanted hydrogels contained RT97 + axons within their trabecular networks. Regrowing axons were associated with the transplanted Schwann cells and not with the small number of infiltrating astrocytes. RT97 + axons were traced up to 510 μm from the nearest host neuropil. These axons were sometimes myelinated by the transplanted Schwann cells and expressed the peripheral myelin marker Po + . WGA/HRP-labeled retinal axons were seen within transplanted hydrogel sponges, with 40% of the cases growing for distances up to 350–450 μm within the polymer network. The data indicate that impregnating PolyHEMA sponges with collagen IV can modify the host glial reaction and support the survival of transplanted Schwann cells. This study thus provides new information on how biomaterials could be used to modify and bridge CNS injury sites.