Mechanism of progressive lineage restriction

The concept of progressive lineage restriction is well accepted for hematopoeisis but has not been established in such detail in the developing CNS. We are pursuing how lineage restriction is regulated in various brain regions of the CNS. For example, we have discovered that embryonic glial precursor cells do not directly generate terminally differentiated cell types, but give rise to other, more restricted precursor cell types before terminal differentiation (Gregori et al, 2002, J. Neurosci.). Moreover, we showed that specification of postnatal oligodendrocyte precursor cells in tissues as closely related as optic nerve and optic chiasm is distinct in that glial precursor cells derived from the different regions of the brain respond in different ways to their environment (Mayer-Proschel et al 2002 Dev. Biol). We also have begun to extend our investigations of precursor cell populations to the developing cortex, one of the most complex tissues in the brain. As we are characterizing the cell pools that reside in various regions and define their lineage restrictions, we are also interested in whether such a lineage restriction has plasticity and whether or when the restriction becomes irreversible.

CNS precursor cells in human disease and tissue repair paradigms

Another part of our research program is dedicated to the application of our precursor cell work to the analysis and possible treatment of human diseases.

The insights we have gained from studying CNS glial precursor cells has led to the idea that precursor cell populations are the targets for a considerable number of developmental abnormalities associated with myelination defects in humans. Interestingly, defects in myelination are associated with insults as diverse as genetic defects, exposure to toxicant or to nutritional deficiencies. Based on our precursor cell work, we hypothesize that adequate myelination of large areas of the mammalian brain will only be possible if precursor cells arise in adequate numbers and continue to develop normally throughout development. It is thus conceivable that even small disturbances in the behavior of precursor cell populations during embryogenesis can lead to devastating defects in the myelination pattern during the postnatal peak of myelination. This idea points to precursor cells as an entirely new target for dysmyelinating diseases.

The majority of data that support this novel hypothesis come from our studies that are focused on iron deficiency, one of the world most prevalent nutritional deficiencies. In this paradigm we have shown for the first time that embryonic CNS tissue is not protected from iron deficiency during pregnancy, as commonly thought, and that early glial precursor cell populations are highly sensitive to changes in tissue iron concentrations. Thus, iron deprivation may lead to a failure to produce sufficient amounts of myelin by perturbing normal development of the precursor cell populations that ultimately generate myelinating cells (Morath and Mayer-Proschel, 2001, Dev. Biol, 2002, Dev. Neurosci). Support for this hypothesis comes also from the observation that iron deficiency-associated defects cannot be cured by application of dietary iron during postnatal development. This line of research has evoked an enthusiastic response among scientists established in the field of nutritional health.

Our discovery that precursor cells might be a major target in a number of demyelinating diseases suggest novel approaches for clinical interventions. For example, if a disease like that associated with iron deficiency is indeed a consequence of disrupted precursor cell proliferation, it may be possible to treat such defects by precursor cell transplantation.

In addition we are collaboratively engaged in the more classical application of transplantation of precursor cells in circumstances of acute and chronic injury models. The ideas of using precursor cells in injury paradigms is not solely directed to replacing a destroyed cell population, but is also targeted to provide signals that will encourage the endogenous ability of self repair. It has been shown over the past decade that embryonic cells maintain their ability to support de novo neurite outgrowth even when exposed to an injured adult environment. The embryonic glial precursor cells that we can isolate and purify in large quantities may provide an ideal candidate for such transplantation approaches. To pursue the possibility that GRP cells can contribute to neuronal regeneration in acute and chronic injury models we collaborate with two of the top transplantation and injury laboratories in the US. Together with our colleagues here Chris Proschel and Mark Noble and our colleagues Stephen and Jeanette Davies at the Baylor College, Texas we were able to show that GRP derived astrocytes that are transplanted into acute lesions spinal cord can not only modulate glial scar formation but lead to significant behaviors repair (Davies et al, 2006, J of Biology). Further, in collaboration with Jacqueline and Michael Bresnahan, Ohio State University, Mark Noble and Chris Proschel we characterized the behavior of our GRP cells (in contrast to GRP derived astrocytes) in contusion lesions of the spinal cord. Objectives here were to fill the lesion cavity with cells that do not generate impenetrable scar tissue and to provide molecular signals via the graft that will encourage the outgrowth or sprouting of endogenous neurons (Hill et al, 2005, Exp. Neurology)

In the ever-growing interest of applying our precursor cell expertise to human disease paradigms, we have also begun a human-specific research program that has already led to the characterization and isolation of human-specific precursor cells. It is difficult to understate the extent to which the ability to study defined human precursor cell populations is opening new opportunities for analysis of glial development, as well as providing insight into problems of much broader relevance. We are applying the knowledge we gained from studying human glial precursor cells to the characterization of multiple pathological conditions, ranging from the impact of viral infections in collaboration with D. Mock, (see Dietrich et al, 2005 J of Neuroscience) to damage associated with toxicant exposure (in collaboration with Mark Noble) to genetic impairments of precursor cell function (in collaboration of C. Proschel).

Future research plans:

The approach we have taken of combining basic biological research with translational applications to the human system provides a research path that adds a new dimension to stem cell and precursor cell biology. While the transplantation of CNS stem cells was initially focused on injury paradigms it has become increasingly clear from our own research that various neuro-degenerative diseases may target precursor cells. Our research has extended this view to nutritional and possible virally-induced CNS dysfunctions.

Our immediate goals are to understand the molecular mechanisms that are involved in the dysregulation of precursor cells in light of nutritional or viral insults with the longer term goal of developing intervention strategies that are suitable for the initiation of clinical trials. For example, our preliminary data suggest that iron deficiency leads to cell cycle deregulation in proliferating precursor cell populations. We do not know whether this arrest is transient or terminal and which transcription factors are involved in this cell cycle arrest. It is also not clear whether this arrest is coupled to an inability to differentiate or is associated with apoptotic cell death. Another line of research focuses on the question of whether precursor cells react identically or differently to iron depletion caused by nutritional deficiency versus that caused by genetic mutations in iron transport genes. In addition, we will continue the discovery of novel precursor cell populations and analysis of the underlying mechanisms involved in lineage restriction, as well as extending our activities in area of cell transplantation for repair of CNS injury.

1. Groves A., Barnett S.C., Franklin R.J.M., Crang A.J, Mayer M., Blakemore W.F. and Noble M. Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells (1993) Nature 362: 453-455
2. Mayer M. and Noble M. N-Acetyl-L-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro (1994) Proc. Natl. Acad. Sci. USA 91: 7496-7500
3. Ibarrola N., Mayer-Pröschel M., Rodrigez-Pena A., Noble M. Evidence for the existence of multiple timing mechanism controlling the generation of oligodendrocytes in vitro (1996) Dev. Biol.180:1-21
4. Rao M.S. and Mayer-Pröschel M. Glial-restricted precursors are derived from multipotent neuroepithelial stem cells (1997) Dev. Biology 188:48-63
5. Mayer-Pröschel M., Kalyani A., Mujiaba T. and Rao M.S. Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells (1997) Neuron 19:773-785
6. Rao M.S., Noble M. and Mayer-Pröschel M. A tripotential glial precursor cell is present in the developing spinal cord (1998) Proc. Natl. Acad. Sci. USA 95: 3996-4001.
7. Yakovlev A, Mayer-Pröschel, M and Noble, M (1998). A stochastic model of brain cell differentiation in tissue culture. J. Math. Biol. 1: 48-60
8. Yakovlev, A.Y., Boucher, K., Mayer-Pröschel, M., Noble, M. Quantitative insight into proliferation and differentiation of oligodendrocyte-type-2 astrocytes progenitor cells in vitro (1998) Proc. Natl. Acad. Sci. USA 95: 14164-14167
9. Smith, J. Ladi, E, Mayer-Pröschel, M. and Noble M. Redox state is a central modulator of the balance between self-renewal and differentiation in oligodendrocyte-type 2 astrocyte progenitor cells. (2000) Proc. Natl. Acad. Sci. USA 18: 10032-10037
10. Morath D. and Mayer-Proschel, M. The role of iron during gliogenesis in vitro (2001) Developmental Biology, 237: 232-243
11. Mayer-Pröschel M., Morath D. and Noble M. Are hypothyroidism and iron deficiency precursor cell diseases? (2001) Developmental Neuroscience, 23: 277-286
12. Herrera J., Zhang S., Pröschel C., Tresco P., Duncan I., Luskin M., and Mayer-Proschel M. Embryonic derived glial restricted precursor cells (GRP cells) can differentiate into astrocytes and oligodendrocytes in vivo (2001) Experimental. Neurology 171:11-21
13. Gregori, N, Pröschel, C, Noble M and M. Mayer-Pröschel. The tripotential glial-restricted precursor cell (GRP) cell and glial development in the spinal cord: Generation of bipotential oligodendrocyte-type-2 astrocyte progenitor cells and dorsal-ventral differences in GRP cell function (2002) J. Neuroscience 22: 259-265
14. Mayer-Pröschel, M, Power, J., Smith, J., and Noble, M. Oligodendrocyte precursor cells from different brain regions express divergent properties consistent with the differing time courses of myelination in these regions (2002) Dev. Biol 245:362-75
15. Dietrich, J., Noble M., and M. Mayer-Pröschel. Characterization of A2B5+ glial precursor cells from cryopreserved human fetal brain progenitor cells (2002) Glia, 40: 65-78
16. Morath D and Mayer-Pröschel M . Iron deficiency during embryogenesis and consequences for oligodendrocyte generation in vivo (2002) Dev. Neurosci. 24:194-207
17. Noble M, Arhin A, Gass D. and Mayer-Pröschel M. The cortical ancestry of oligodendrocytes: Common principles and novel features (2003) Dev. Neurosci 25: 217-133
18. Noble M., Pröschel, C. and Mayer-Pröschel M. Getting a GR(i)P on oligodendrocyte development (2003) Dev. Biology 265, 33-52
19. N.J. Maragakis, V. Wong, H. Xue, M.S. Rao J. Dietrich, M. Mayer-Pröschel and J.D. Rothstein. Glutamate transporter expression and function in human glial progenitors (2003) Glia 45:133-143
20. Dietrich J., Blumberg B., Roshad M., Baker J., Hurley S., Mayer-Pröschel M (shared senior authorship) and D. Mock. Infection with endemic human Herpesvirus disrupts critical glial precursor cell properties (2004) J. Neuroscience 24:4875-4883
21. Hill C.E., Pröschel C., Noble M., Mayer-Pröschel M., Gensel J., Beattie M.S., and J. C. Bresnahan. Acute transplantation of glial restricted precursor cells into spinal cord contusion injuries: survival, differentiation and effects on lesion environment and axonal regeneration. (2004) Exp. Neurology. 190:289-310
22. Hyrien, O., Mayer-Pröschel, M., Noble, M., and Yakovlev, A. Estimating the life-span of oligodendrocytes from clonal data on their development in cell culture, (2005) Mathematical Biosciences 193(2):255-74
23. Dietrich J., Lacagnina M., Gass D., Richfield E., Mayer-Pröschel M., Noble M., Torres C. and C. Pröschel. EIF2B5 mutations compromise generation of GFAP+ astrocytes from neural precursors in Vanishing White Matter leukodystrophy (2005) Nature Medicine 11(3):277-83
24. Davies JE, Huang C, Pröschel C, Noble M, Mayer-Pröschel M, Davies SJ. Astrocytes derived from glial-restricted precursors promote spinal cord repair. (2006) J Biol. Apr 27 5(3):7

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