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.
Allen JL, Liu X, Pelkowski S, Palmer B, Conrad K, Oberdörster G, Weston D, Mayer-Pröschel M, Cory-Slechta DA. "Early postnatal exposure to ultrafine particulate matter air pollution: persistent ventriculomegaly, neurochemical disruption, and glial activation preferentially in male mice." Environmental health perspectives. 2014 Sep; 122(9):939-45. Epub 2014 Jun 05.
Greminger AR, Lee DL, Shrager P, Mayer-Pröschel M. "Gestational iron deficiency differentially alters the structure and function of white and gray matter brain regions of developing rats." The Journal of nutrition. 2014 Jul; 144(7):1058-66. Epub 2014 Apr 17.
2013 Oct 16
Wang J, Bushman J, Wang X, Mayer-Proschel M, Johnson M, Noble M. "Oligodendrocyte/type-2 astrocyte progenitor cells and glial-restricted precursor cells generate different tumor phenotypes in response to the identical oncogenes." The Journal of neuroscience : the official journal of the Society for Neuroscience. 2013 Oct 16; 33(42):16805-17.
2013 May 2
Noble M, Mayer-Pröschel M, Pröschel C. "iOPs: a new tool for studying myelin pathologies?" Cell stem cell. 2013 May 2; 12(5):503-4.
2012 Jun 15
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)." The Journal of biological chemistry. 2012 Jun 15; 287(25):21384-95. Epub 2012 Apr 24.