Stem cells: cross-talk and developmental programs.

The thesis advanced in this essay is that stem cells-particularly those in the nervous system-are components in a series of inborn 'programs' that not only ensure normal development, but persist throughout life so as to maintain homeostasis in the face of perturbations-both small and great. These programs encode what has come to be called 'plasticity'. The stem cell is one of the repositories of this plasticity. This review examines the evidence that interaction between the neural stem cell (as a prototypical somatic stem cell) and the developing or injured brain is a dynamic, complex, ongoing reciprocal set of interactions where both entities are constantly in flux. We suggest that this interaction can be viewed almost from a 'systems biology' vantage point. We further advance the notion that clones of exogenous stem cells in transplantation paradigms may not only be viewed for their therapeutic potential, but also as biological tools for 'interrogating' the normal or abnormal central nervous system environment, indicating what salient cues (among the many present) are actually guiding the expression of these 'programs'; in other words, using the stem cell as a 'reporter cell'. Based on this type of analysis, we suggest some of the relevant molecular pathways responsible for this 'cross-talk' which, in turn, lead to proliferation, migration, cell genesis, trophic support, protection, guidance, detoxification, rescue, etc. This type of developmental insight, we propose, is required for the development of therapeutic strategies for neurodegenerative disease and other nervous system afflictions in humans. Understanding the relevant molecular pathways of stem cell repair phenotype should be a priority, in our view, for the entire stem cell field.

[1]  R. Sidman,et al.  Segregation of Human Neural Stem Cells in the Developing Primate Forebrain , 2001, Science.

[2]  Robert Langer,et al.  Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  S. Weiss,et al.  Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. , 1992, Science.

[4]  Melitta Schachner,et al.  Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons , 2002, Nature Biotechnology.

[5]  J. D. Macklis,et al.  Multipotent neural precursors can differentiate toward replacement of neurons undergoing targeted apoptotic degeneration in adult mouse neocortex. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  R. McKay,et al.  Transplanted CNS stem cells form functional synapses in vivo , 2000, The European journal of neuroscience.

[7]  M. Murray,et al.  Intraspinal Delivery of Neurotrophin-3 Using Neural Stem Cells Genetically Modified by Recombinant Retrovirus , 1999, Experimental Neurology.

[8]  A. Tessler,et al.  Transplants of cells genetically modified to express neurotrophin‐3 rescue axotomized Clarke's nucleus neurons after spinal cord hemisection in adult rats , 2001, Journal of neuroscience research.

[9]  Blair R. Leavitt,et al.  Induction of neurogenesis in the neocortex of adult mice , 2000, Nature.

[10]  C. Cepko,et al.  Establishment and characterization of multipotent neural cell lines using retrovirus vector-mediated oncogene transfer. , 1990, Journal of neurobiology.

[11]  Yang D. Teng,et al.  The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue , 2002, Nature Biotechnology.

[12]  R. Sidman,et al.  Differentiation of engrafted multipotent neural progenitors towards replacement of missing granule neurons in meander tail cerebellum may help determine the locus of mutant gene action. , 1997, Development.

[13]  F. Gage,et al.  Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo , 1996, Nature.

[14]  M. Tuszynski,et al.  Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury , 2003, Experimental Neurology.

[15]  O. Lindvall,et al.  Neuronal replacement from endogenous precursors in the adult brain after stroke , 2002, Nature Medicine.

[16]  R. Sidman,et al.  Engraftable human neural stem cells respond to development cues, replace neurons, and express foreign genes , 1998, Nature Biotechnology.

[17]  E. Snyder,et al.  Neural progenitor cell engraftment corrects lysosomal storage throughout the MRS VII mouse brain , 1995, Nature.

[18]  P. Black,et al.  Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[19]  P. Stieg,et al.  Transplantation of neural progenitor and stem cells: developmental insights may suggest new therapies for spinal cord and other CNS dysfunction. , 1999, Journal of neurotrauma.

[20]  E. Snyder,et al.  Transplanted Clonal Neural Stem-Like Cells Respond to Remote Photic Stimulation Following Incorporation within the Suprachiasmatic Nucleus , 2002, Experimental Neurology.

[21]  Ki-Soo Park,et al.  Neural stem cells – a versatile tool for cell replacement and gene therapy in the central nervous system , 1999, Clinical genetics.

[22]  C. Cepko,et al.  Multipotent neural cell lines can engraft and participate in development of mouse cerebellum , 1992, Cell.

[23]  E. Snyder,et al.  "Global" cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain. , 1999, Proceedings of the National Academy of Sciences of the United States of America.