Biomedical subjects

M Mayer-Pröschel

Publications and source records attributed to M Mayer-Pröschel.

7 recordsLinked to original sources

PubMed2001

Iron modulates the differentiation of a distinct population of glial precursor cells into oligodendrocytes.

Iron deficiency in children is associated with a number of neural defects including hypomyelination. It has been hypothesized by others that this hypomyelination is due to a failure in myelin production. Other possibilities include failure in the generation of oligodendrocytes from their precursor cells or an interruption in oligodendrocyte maturation. These hypotheses are based on the observations that there is a peak in brain iron uptake in vivo that coincides with the period of greatest myelination and that a shortage of iron leads to myelination deficiency. We now demonstrate that iron availability modulates the generation of oligodendrocytes from tripotential-glial restricted precursor (GRP) cells isolated from the embryonic day 13.5 rat spinal cord. In contrast, we found no effects of iron on oligodendrocyte maturation or survival in vitro, nor did we find that increasing iron availability above basal levels increases oligodendrocyte generation from bipotential oligodendrocyte-type-2 astrocyte/oligodendrocyte precursor cells (O-2A/OPCs). Our results raise the possibility that iron may affect oligodendrocyte development at stages during early embryogenesis rather than during later development.

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PubMed2001

Are hypothyroidism and iron deficiency precursor cell diseases?

It is neither known why hormonal and nutritional deficiencies only cause neurological abnormalities at particular periods of development, nor is it known why repair only occurs if normal metabolic status is restored within a particular temporal window. We propose that these maladies are precursor cell diseases, in which the normal balance between self-renewal and differentiation is compromised in dividing precursor cells. According to this hypothesis, the windows of vulnerability in these disorders correspond to the timing of particular transitions in CNS precursor cells, as seen in our studies on the effects of thyroid hormone and iron on the generation of oligodendrocytes and their immediate ancestor, the O-2A progenitor cell.

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PubMed1999

Cell differentiation in the embryonic mammalian spinal cord.

The acquisition of cell type specific properties in the spinal cord is a process of a sequential restriction in developmental potential. Multipotent neuroepithelial stem cells (NEP cells) can give rise to all the major cell types in the central nervous system. The generation of these multiple cell types occurs via the generation of intermediate precursor cells, which are restricted in their differentiation potential, but are still able to give rise to more than one cell type. These intermediate precursor cells are different from NEP cells and are different from each other. We have identified neuronal restricted precursor cells (NRP's) which can only generate neurons but no longer glial cells and glial restricted precursor cells (GRP's), which give rise to glial cells but not to neurons. These intermediate precursor cells can be purified and expanded in vitro and might offer a new tool for gene discovery, drug screening and transplantation approaches.

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PubMed1998

A tripotential glial precursor cell is present in the developing spinal cord.

We have isolated a tripotential glial precursor cell population from spinal cords of E13.5 rats. In vitro, these A2B5+E-NCAM- glial-restricted precursor (GRP) cells can undergo extensive self-renewal, and can differentiate into oligodendrocytes and two distinct astrocyte populations, but do not differentiate into neurons. The differentiation potential of GRP cells is retained through at least three cycles of expansion and recloning. Unlike oligodendrocyte-type 2 astrocyte progenitor cells, freshly isolated GRP cells do not respond to platelet-derived growth factor as a mitogen or survival factor, nor do GRP cells differentiate into oligodendrocytes--or even survive--when plated in mitogen-free chemically defined medium. Exposure to fetal calf serum induces GRP cells to differentiate into A2B5- fibroblast-like astrocytes, whereas growth in the presence of basic fibroblast growth factor and ciliary neurotrophic factor induces the generation of A2B5+ process-bearing astrocytes. The early appearance of GRP cells during spinal cord development suggests that they may represent the earliest GRP cell population.

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PubMed1997

Growth factors, glia and gliomas.

The abilities of growth factors to cause normal cells to express the properties associated with transformed cells is discussed in specific reference to the oligodendrocyte-type-2 astrocyte (O-2A) progenitor cell. In the O-2A lineage, it has been possible to use growth factors and other defined molecules to induce or promote in normal cells all of the main properties of tumor cells, these being continued cell division in the absence of differentiation, more subtle modulations of self-renewal probabilities, promotion of cell migration and inhibition of programmed cell death. In addition to our studies on primary cells, our application to the growth of human tumor specimens of techniques utilized to study primary glial progenitor cells has allowed us to isolate a human glioblastoma multiforme (GBM)-derived population that expresses many properties otherwise uniquely expressed by oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells. Hu-O-2A/Gb1 (for Human O-2A lineage Glioblastoma number 1) cells responded to similar mitogens and differentiation modulators as rodent O-2A progenitors, and generated cells with features of precursor cells, oligodendrocytes and astrocytes. Moreover, 1H-NMR analysis of amino acid composition demonstrated a striking conservation of types and quantities of free amino acids between the human tumour cells and the rodent primary cells. Hu-O-2A/Gb1 cells represent the first human glioma-derived population for which unambiguous lineage assignment has been possible. Our results thus demonstrate that the human O-2A lineage can contribute to one of the most malignant of glial tumours. Our analyses further indicate that at least two distinct glial lineages can generate glioblastomas. In addition, the highly diagnostic 1H-NMR spectrum expressed by Hu-O-2A/Gb1 cells raises the possibility of eventual non-invasive identification of tumors of this lineage.

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PubMed1996

Evidence for the existence of at least two timing mechanisms that contribute to oligodendrocyte generation in vitro.

We have been studying oligodendrocyte generation in vitro to obtain insights into how the timely generation of these cells might be regulated. Our studies suggest the existence of timing mechanisms quite different from those of existing models, wherein it is proposed that timely oligodendrocyte generation is associated with synchronous and symmetric differentiation controlled by cell-intrinsic biological clocks. Our results are most consistent with the hypothesis that the propensity of a clone of dividing oligodendrocyte type-2 astrocyte (O-2A) progenitors initially to generate at least one oligodendrocyte may be regulated by cell-intrinsic mechanisms, but that cell-extrinsic signals regulate the extent of further oligodendrocyte generation. In cultures of embryonic rat cortex grown in the presence of platelet-derived growth factor (PDGF), oligodendrocytes appeared in a timely manner in the absence of clonal differentiation. In contrast with previous suggestions, the presence or absence of thyroid hormone (T3) did not alter the probability of individual clones of O-2A progenitors generating at least one oligodendrocyte in vitro at a time equal to the rat's day of birth. Instead, T3 increased the proportion of oligodendrocytes generated within clones. For postnatally derived progenitor cells, the initial appearance of oligodendrocytes also was followed by further asymmetric generation of these cells, with the ratio of progenitors to oligodendrocytes within clones being regulated by environmental signals. T3 and ciliary neurotrophic factor increased oligodendrocyte generation, while neurotrophin-3 (NT-3) suppressed oligodendrocyte generation. Also in contrast to previous reports, NT-3 was not required for the promotion of extensive division of O-2A progenitor cells by PDGF.

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PubMedDate not supplied

The cortical ancestry of oligodendrocytes: common principles and novel features.

Studies on the development of cortical oligodendrocytes indicate that although general principles that apply to other parts of the CNS are applicable, there are important differences that appear to be critical to the analysis of this lineage in the cortex. Herein, we review previous studies demonstrating that oligodendrocyte-type-2 astrocyte progenitor cells (or oligodendrocyte precursor cells; aka O-2A/OPCs) of the developing postnatal cortex exhibit a striking cell-intrinsic bias towards undergoing prolonged self-renewal in the relative absence of oligodendrocyte generation [Power et al., Dev Biol 2002;245:362-375]. This phenotype is quite distinct from that observed in comparable cells isolated from the optic tract. This predilection for self-renewal is associated with a lessened response to inducers of oligodendrocyte generation and of possible mechanistic importance in regards to these other properties. We also review studies on stem/progenitor cells isolated from the embryonic cortex that are able to generate oligodendrocytes. As for the studies on O-2A/OPCs, important differences also distinguish these early cells from those studied in other CNS regions in their response to signaling molecules and expression of the Dlx family of transcriptional regulators [He et al., J Neurosci 2001;21:8854-8862; Yung et al., Proc Natl Acad Sci USA 2002;99:16273-16278]. We also present new data on clonal analysis of A2B5+ precursor cells isolated from the E13.5 cortex, demonstrating that this tissue appears to contain a cell similar in properties to the tripotential glial-restricted precursor cell that has been isolated from embryonic spinal cord [Rao et al., Proc Natl Acad Sci USA 1998;95:3996-4001]. Moreover, the A2B5+ precursor cells isolated from embryonic cortex are much more heterogeneous than is seen in the spinal cord at this age, even to the point of including an A2B5/PSA-NCAM double-positive cell that can generate neurons.

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