The practical limitations on both fetal and adult cell acquisition for human allograft have driven research on deriving tissue-specific progenitor cells from both human embryonic stem (hES) cells and iPS cells. Oligodendrocytes derived from hES cells were recently shown to myelinate demyelinated foci in spinal cord contusions.58
This latter observation paralleled earlier studies that reported myelination in the injured spinal cord by implanted murine embryonic stem cells.59
However, neither of these studies isolated GPCs or oligodendrocytes prior to transplant, and neither followed up animals for the long periods required to ensure the long-term survival and phenotypic stability of the engrafted cells. These are notable deficiencies, in that hES-based approaches may prove limited by the potential for tumorigenesis by any undifferentiated embryonic stem cells in the donor pool, which might yield either teratomas or undifferentiated neuroepithelial tumors after implantation.60
Although protocols have been reported that appear to minimize the possibility of tumorigenesis—one of which has already been approved for a phase 1 clinical trial in subacute spinal cord injury (http://clinicaltrials.gov
, identifier NCT01217008)—one must exercise caution in using unpurified hES progeny as clinical vectors, given the persistent risk of including undifferentiated cells in the transplant pool.
Broad enthusiasm has recently developed for the potential use of iPS cells as a source of new oligodendrocytes for myelin repair. Induced pluripotential stem cells are pluripotential cells that have been generated by the reprogramming of somatic cells to a less phenotypically committed stem cell ground state, through the concurrent forced expression of a small set of transcription factors critical to maintenance of the self-renewing stem cell phenotype.61,62
Most typically, iPS cells have been generated from dermal fibroblasts, cotransduced with a number of stem cell–associated transcription factors, including POU5F1(OCT3/4), SOX2, MYC, KLF4, and/or NANOG.63,64
Induced pluripotential stem cells are pluripotential, as defined by their ability to generate cells of all major germ layers and teratomas in vivo. Induced pluripotential stem cells were first generated from mouse65
fibroblasts and have since been generated from a variety of cell types and differentiated into an even broader variety of committed progenitor cells and somatic phenotypes. Most notably among these, the production of dopaminergic neurons from iPS cells validated their ability to generate postmitotic neuronal derivatives.68
Induced pluripotential stem cells have the decided advantage over hES cells of being readily derived from adult somatic cells, such as dermal fibro-blasts or marrow stromal cells. Once so derived, they may be used to produce cell types of interest that may be transplanted as autologous grafts back to the very patients from whom they were generated, thereby obviating the need for posttransplant immune modulation. Yet, to date, no terminally differentiated myelinogenic oligodendrocytes have yet been reported from human iPS cells. Once this important milestone is reached, we may begin to explore the potential for generating populations of iPS-derived oligodendrocytes for autologous grafting in the myelin disorders. That being said, the hurdles that will need to be overcome are similar to those facing hES-derived GPCs and oligodendrocytes: GPCs derived from iPS cells share the same risks as those derived from hES cells, in terms of both unintended differentiation of unrestricted contaminants, as well as frank tumorigenesis. Just as with the use of GPCs derived from hES cells, those generated from iPS cells will need to be purified before use, so as to minimize the risk of any potentially tumorigenic contaminants accompanying the transplanted cell populations. That being said, this risk should be obviated by the many fluorescence- and magnetic-activated cell sorting techniques now available for enriching neural and GPCs to clinically appropriate purity.1,2
As a result of these considerations, future studies will need to consider the stringent selection for committed GPCs before any attempt at hES or iPS cell-based therapy.
Taken together, these data suggest the great promise of embryonic stem– and iPS-based production of potentially myelinogenic donor cells. Yet, they also argue that before these promising embryonic stem– or iPS-based strategies may be translated to the clinic, stringent differentiation and isolation of committed GPCs will have to be achieved, so as to ensure both the safety and efficacy of implanted donor cell pools. Until that time, the implantation of tissue-derived GPCs will necessarily be the more clinically feasible option for treatment of the pediatric leukodystrophies and allied myelin disorders.