1. Identification of lineage restricted precursor cells for cell replacement
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 and 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. The identification of these different cell pools is critical for identifying ideal transplantable cells for therapeutic cell replacement approaches.
The therapeutic translation of our knowledge of precursor cells and their derivatives is demonstrated in our collaborative efforts on designing optimal repair strategies for spinal cord injuries. With our colleagues Drs. Chris Proschel, Mark Noble and Stephen and Jeanette Davies at the University of Colorado we showed that the transplantation of a defined embryonic astrocyte population into a dorsal transection models of SCI results in extensive regeneration associated with complete functional recovery. We are now in the process of extending these finding by devising a rational approach to identify the optimal cell source and cell population for SCI repair and by characterizing the graft cells and the injury site in respect to cell death, inflammation and cell division.
2. CNS precursor cells and their derivatives in human disease paradigms
The insights we have gained from studying CNS glial precursor cells has led to the idea that precursor cell populations are targets for a large number of developmental abnormalities associated with myelination defects in humans. 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. Any disruption of the precursor cell pool might hence be associated with myelination defects later in development.
Gestational Iron deficiency.
Our hypothesis of precursor cells being a major target during development is especially relevant for the pathology seen as a result of gestational nutritional iron deficiency. This world's most prevalent nutritional deficiency is associated with impaired myelination and results in cognitive defects in affected children. We have shown 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. We have established rat and mouse models of gestation iron deficiency with and without anemia to determine the impact of gestational iron deficiency on brain development with a focus on (i) early embryonic telencephalic development and (ii) myelination of the auditory nerve postnatally.
Ataxia Telangiectasia (AT)
A genetic disorder associated with widespread neurological defects is the devastating disease Ataxia telangiectasia (AT), caused by mutations in the ATM gene. The pathology is characterized by crippling ataxia beginning in late infancy followed by progressive CNS degeneration of the cerebellum. While the majority of research has been focused on the neuronal cell population affected in the cerebellum, we began to determine the extent of glial dysfunction on the progression of AT. Our result indicate that astrocytic function is severely impaired in AT CNS tissue and we show that AT mutant astrocytes are unable to maintain neuronal integrity and survival. This new discovery opens the possibility for generating new therapeutic strategies that target the dysfunction astrocytes in order to halt or abolish neuronal degeneration.

• Wang G, Dinkins M, He Q, Zhu G, Poirier C, Campbell A, Mayer-Proschel M, Bieberich E. Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4): POTENTIAL MECHANISM OF APOPTOSIS INDUCTION IN ALZHEIMER DISEASE (AD). J Biol Chem. 2012 Jun 15; 287(25):21384-95.
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• Lee DL, Strathmann FG, Gelein R, Walton J, Mayer-Pröschel M. Iron deficiency disrupts axon maturation of the developing auditory nerve. J Neurosci. 2012 Apr 4; 32(14):5010-5.
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• Tanner DC, Cherry JD, Mayer-Pröschel M. Oligodendrocyte progenitors reversibly exit the cell cycle and give rise to astrocytes in response to interferon-?. J Neurosci. 2011 Apr 20; 31(16):6235-46.
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• Mihaila C, Schramm J, Strathmann FG, Lee DL, Gelein RM, Luebke AE, Mayer-Pröschel M. Identifying a window of vulnerability during fetal development in a maternal iron restriction model. PLoS One. 2011; 6(3):e17483.
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• Davies SJ, Shih CH, Noble M, Mayer-Proschel M, Davies JE, Proschel C. Transplantation of specific human astrocytes promotes functional recovery after spinal cord injury. PLoS One. 2011; 6(3):e17328.
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• Strathmann FG, Wang X, Mayer-Pröschel M. Identification of two novel glial-restricted cell populations in the embryonic telencephalon arising from unique origins. BMC Dev Biol. 2007; 7:33.
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• Mock DJ, Strathmann F, Blumberg BM, Mayer-Proschel M. Infection of murine oligodendroglial precursor cells with Human Herpesvirus 6 (HHV-6)--establishment of a murine in vitro model. J Clin Virol. 2006 Dec; 37 Suppl 1:S17-23.
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• Hyrien O, Ambeskovic I, Mayer-Proschel M, Noble M, Yakovlev A. Stochastic modeling of oligodendrocyte generation in cell culture: model validation with time-lapse data. Theor Biol Med Model. 2006; 3:21.
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• Davies JE, Huang C, Proschel C, Noble M, Mayer-Proschel M, Davies SJ. Astrocytes derived from glial-restricted precursors promote spinal cord repair. J Biol. 2006; 5(3):7.
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• Dietrich J, Han R, Yang Y, Mayer-Pröschel M, Noble M. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol. 2006; 5(7):22.
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• Hyrien O, Mayer-Pröschel M, Noble M, Yakovlev A. A stochastic model to analyze clonal data on multi-type cell populations. Biometrics. 2005 Mar; 61(1):199-207.
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• Dietrich J, Lacagnina M, Gass D, Richfield E, Mayer-Pröschel M, Noble M, Torres C, Pröschel C. EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nat Med. 2005 Mar; 11(3):277-83.
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• Hyrien O, Mayer-Pröschel M, Noble M, Yakovlev A. Estimating the life-span of oligodendrocytes from clonal data on their development in cell culture. Math Biosci. 2005 Feb; 193(2):255-74.
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• Hill CE, Proschel C, Noble M, Mayer-Proschel M, Gensel JC, Beattie MS, Bresnahan JC. Acute transplantation of glial-restricted precursor cells into spinal cord contusion injuries: survival, differentiation, and effects on lesion environment and axonal regeneration. Exp Neurol. 2004 Dec; 190(2):289-310.
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• Dietrich J, Blumberg BM, Roshal M, Baker JV, Hurley SD, Mayer-Pröschel M, Mock DJ. Infection with an endemic human herpesvirus disrupts critical glial precursor cell properties. J Neurosci. 2004 May 19; 24(20):4875-83.
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• Maragakis NJ, Dietrich J, Wong V, Xue H, Mayer-Proschel M, Rao MS, Rothstein JD. Glutamate transporter expression and function in human glial progenitors. Glia. 2004 Jan 15; 45(2):133-43.
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• Noble M, Arhin A, Gass D, Mayer-Pröschel M. The cortical ancestry of oligodendrocytes: common principles and novel features. Dev Neurosci. 2003 Mar-Aug; 25(2-4):217-33.
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• Dietrich J, Noble M, Mayer-Proschel M. Characterization of A2B5+ glial precursor cells from cryopreserved human fetal brain progenitor cells. Glia. 2002 Oct; 40(1):65-77.
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• Power J, Mayer-Pröschel M, Smith J, Noble M. Oligodendrocyte precursor cells from different brain regions express divergent properties consistent with the differing time courses of myelination in these regions. Dev Biol. 2002 May 15; 245(2):362-75.
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• Morath DJ, Mayer-Pröschel M. Iron deficiency during embryogenesis and consequences for oligodendrocyte generation in vivo. Dev Neurosci. 2002; 24(2-3):197-207.
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• Morath DJ, Mayer-Pröschel M. Iron modulates the differentiation of a distinct population of glial precursor cells into oligodendrocytes. Dev Biol. 2001 Sep 1; 237(1):232-43.
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• Herrera J, Yang H, Zhang SC, Proschel C, Tresco P, Duncan ID, Luskin M, Mayer-Proschel M. Embryonic-derived glial-restricted precursor cells (GRP cells) can differentiate into astrocytes and oligodendrocytes in vivo. Exp Neurol. 2001 Sep; 171(1):11-21.
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• Boucher K, Zorin A, Yakovlev AY, Mayer-Proschel M, Noble M. An alternative stochastic model of generation of oligodendrocytes in cell culture. J Math Biol. 2001 Jul; 43(1):22-36.
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• Mayer-Pröschel M, Morath D, Noble M. Are hypothyroidism and iron deficiency precursor cell diseases? Dev Neurosci. 2001; 23(4-5):277-86.
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• Zorin A, Mayer-Proschel M, Noble M, Yakovlev AY. Estimation problems associated with stochastic modeling of proliferation and differentiation of O-2A progenitor cells in vitro. Math Biosci. 2000 Oct; 167(2):109-21.
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• Smith J, Ladi E, Mayer-Proschel M, Noble M. Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci U S A. 2000 Aug 29; 97(18):10032-7.
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• Lee JC, Mayer-Proschel M, Rao MS. Gliogenesis in the central nervous system. Glia. 2000 Apr; 30(2):105-21.
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• Rao MS, Mayer-Proschel M. Precursor cells for transplantation. Prog Brain Res. 2000; 128:273-92.
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• Kaas JH. The reorganization of somatosensory and motor cortex after peripheral nerve or spinal cord injury in primates. Prog Brain Res. 2000; 128:173-9.
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• Stringer SE, Mayer-Proschel M, Kalyani A, Rao M, Gallagher JT. Heparin is a unique marker of progenitors in the glial cell lineage. J Biol Chem. 1999 Sep 3; 274(36):25455-60.
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• von Collani E, Tsodikov A, Yakovlev A, Mayer-Proschel M, Noble M. A random walk model of oligodendrocyte generation in vitro and associated estimation problems. Math Biosci. 1999 Jul; 159(2):189-204.
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• Boucher K, Yakovlev AY, Mayer-Proschel M, Noble M. A stochastic model of temporally regulated generation of oligodendrocytes in cell culture. Math Biosci. 1999 Jun; 159(1):47-78.
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• Yakovlev AY, Boucher K, Mayer-Proschel M, Noble M. Quantitative insight into proliferation and differentiation of oligodendrocyte type 2 astrocyte progenitor cells in vitro. Proc Natl Acad Sci U S A. 1998 Nov 24; 95(24):14164-7.
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• Mujtaba T, Mayer-Proschel M, Rao MS. A common neural progenitor for the CNS and PNS. Dev Biol. 1998 Aug 1; 200(1):1-15.
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• Yakovlev AY, Mayer-Proschel M, Noble M. A stochastic model of brain cell differentiation in tissue culture. J Math Biol. 1998 Jul; 37(1):49-60.
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• Rao MS, Noble M, Mayer-Pröschel M. A tripotential glial precursor cell is present in the developing spinal cord. Proc Natl Acad Sci U S A. 1998 Mar 31; 95(7):3996-4001.
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• Noble M, Mayer-Pröschel M. Growth factors, glia and gliomas. J Neurooncol. 1997 Dec; 35(3):193-209.
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• Mayer-Proschel M, Kalyani AJ, Mujtaba T, Rao MS. Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron. 1997 Oct; 19(4):773-85.
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• Rao MS, Mayer-Proschel M. Glial-restricted precursors are derived from multipotent neuroepithelial stem cells. Dev Biol. 1997 Aug 1; 188(1):48-63.
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• Ibarrola N, Mayer-Pröschel M, Rodriguez-Peña A, Noble M. Evidence for the existence of at least two timing mechanisms that contribute to oligodendrocyte generation in vitro. Dev Biol. 1996 Nov 25; 180(1):1-21.
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• Mayer M, Bhakoo K, Noble M. Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro. Development. 1994 Jan; 120(1):143-53.
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• Groves AK, Barnett SC, Franklin RJ, Crang AJ, Mayer M, Blakemore WF, Noble M. Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature. 1993 Apr 1; 362(6419):453-5.
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