Transplantation and Differentiation of Neural “Stem-Like” Cells: Possible Insights Into Development and Therapeutic Potential

When neural progenitors are immortalized, they appear in many ways to behave as neural stem cells. In fact, they have been called “stem-like cells.” We have demonstrated that immortalized, multipotent, clonal neural progenitors or stem-like cells can, following transplantation, integrate appropriately into recipient mouse nervous system (from embryo to adult) and differentiate into a range of neurons and glia throughout the neuraxis. Donor progenitors appear to intermingle nondisruptively with endogenous progenitors and respond to many of the same spatial and temporal developmental signals in the same manner as host progenitors. Immortalization does not abrogate their ability to respond to normal cues (e.g. withdraw from the cell cycle, differentiate, intract with host cells). Because engrafted progenitors are recognized by expression of retrovirally/transduced lacZ, these data also support the feasibility of transplanting neural stem-like cells — expressing genes of developmental or therapeutic importance (either intrinsically or following ex vivo genetic manipulation) — as a strategy for sustained delivery of such factors directly to the CNS as integral members of the cytoarchitecture. Furthermore, progenitors might also replace injured cells and/or provide nondiffusible factors (myelin, “bridges,” cell-cell contact signals, extracellular matrix) that might allow the injured host to reform its own connections. Some of our studies have suggested successful therapeutic gene expression throughout the brains of mouse models of genetic metabolic neurodegenerative disease; repletion of degenerated or developmentally impaired neurons in new-born and adult mouse cerebrum and spinal cord; and differentiation into oligodendroglia that improve myelination in mouse mutants with diffuse white matter disease. We suggest that the inherent biologic properties of neural progenitors make them appealingly suited to be efficient, multifaceted vehicles for cell replacement, repair, and gene transfer in CNS dysfuncion. Their apparent ability to address widespread neuropathology is intriguing because most neurologic disease is not focal, but rather multifocal or global. The use of neural stem-like cells may, therefore, allow a cellular therapy like transplantation to address those therapeutic challenges usually consigned to pharmacologic or genetic interventions. Such stem-like cell lines may also provide models for the study of the commitment, differentation, and plasticity of neural progenitors and stem cells. We have hypothesized that some multipotent neural stem cells may have intrinsic ferentiation programs that may nevertheless be influenced by appropriately timed microenvironmental factors. Therefore, a system such as this may facilitate exploration of the reciprocal interactions between external cues and instrinsic programs.