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M Mayer-Proschel

Publications and source records attributed to M Mayer-Proschel.

14 recordsLinked to original sources
PubMed2001

Embryonic-derived glial-restricted precursor cells (GRP cells) can differentiate into astrocytes and oligodendrocytes in vivo.

We have isolated and characterized a unique glial-restricted precursor cell (GRP) from the embryonic spinal cord. Clonal analysis demonstrated that these cells are able to generate oligodendrocytes and two distinct type of astrocytes (type 1 and type 2) when exposed to appropriate signals in vitro. We now show that many aspects of these cells are retained in vivo. GRP cells are restricted to the glial lineage in vivo as they seem to be unable to generate neuronal phenotypes in an in vivo neurogenic environment. GRP cells survive and migrate in the neonatal and adult brain. Transplanted GRP cells differentiate into myelin-forming oligodendrocytes in a myelin-deficient background and also generate immature oligodendrocytes in the normal neonatal brain. In addition, GRP cells also consistently generated glial fibrillary protein-expressing cells in the neonatal and adult brain, a property not consistently expressed by other glial precursor cells like the O-2A/OPC cells. We suggest that the lineage restriction of GRP cells and their ability to generate both oligodendrocytes and astrocytes in vivo together with their embryonic character that allows for extensive in vitro expansion of the population makes the cell useful for clinical application.

Animals↗
PubMed2001

An alternative stochastic model of generation of oligodendrocytes in cell culture.

According to our previous model, oligodendrocyte--type 2 (O-2A) astrocyte progenitor cells become competent for differentiation in vitro after they complete a certain number of critical mitotic cycles. After attaining the competency to differentiate, progenitor cells divide with fixed probability p in subsequent cycles. The number of critical cycles is random; analysis of data suggests that it varies from zero to two. The present paper presents an alternative model in which there are no critical cycles, and the probability that a progenitor cell will divide again decreases gradually to a plateau value as the number of completed mitotic cycles increases. In particular all progenitor cells have the ability to differentiate from the time of plating. The Kiefer-Wolfowitz procedure is used to fit the new model to experimental data on the clonal growth of purified O-2A progenitor cells obtained from the optic nerves of 7 day old rats. The new model is shown to fit the experimental data well, indicating that it is not possible to determine whether critical cycles exist on the basis of these experimental data. In contrast to the fit of the previous model, which suggested that the addition of thyroid hormone increased the limiting probability of differentiation as the number of mitotic cycles increases, the fit of the new model suggests that the addition of thyroid hormone has almost no effect on the limiting probability of differentiation.

Animals↗
PubMed2000

Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell.

We have discovered that intracellular redox state appears to be a necessary and sufficient modulator of the balance between self-renewal and differentiation in dividing oligodendrocyte-type-2 astrocyte progenitor cells. The intracellular redox state of freshly isolated progenitors allows prospective isolation of cells with different self-renewal characteristics. Redox state is itself modulated by cell-extrinsic signaling molecules that alter the balance between self-renewal and differentiation: growth factors that promote self-renewal cause progenitors to become more reduced, while signaling molecules that promote differentiation cause progenitors to become more oxidized. Moreover, pharmacological antagonists of the redox effects of these cell-extrinsic signaling molecules antagonize their effects on self-renewal and differentiation, indicating that cell-extrinsic signaling molecules that modulate this balance converge on redox modulation as a critical component of their effector mechanism.

Acetylcysteine↗
PubMed2000

Gliogenesis in the central nervous system.

Multipotential neuroepithelial stem cells are thought to give rise to all the differentiated cells of the central nervous system (CNS). The developmental potential of these multipotent stem cells becomes more restricted as they differentiate into progressively more committed cells and ultimately into mature neurons and glia. In studying gliogenesis, the optic nerve and spinal cord have become invaluable models and the progressive stages of differentiation are being clarified. Multiple classes of glial precursors termed glial restricted precursors (GRP), oligospheres, oligodendrocyte-type2 astrocyte (O-2A) and astrocyte precursor cells (APC) have been identified. Similar classes of precursor cells can be isolated from human neural stem cell cultures and from embryonic stem (ES) cell cultures providing a non-fetal source of such cells. In this review, we discuss gliogenesis, glial stem cells, putative relationships of these cells to each other, factors implicated in gliogenesis, and therapeutic applications of glial precursors.

Animals↗
PubMed2000

Estimation problems associated with stochastic modeling of proliferation and differentiation of O-2A progenitor cells in vitro.

Our previous research effort has resulted in a stochastic model that provides an excellent fit to our experimental data on proliferation and differentiation of oligodendrocyte type-2 astrocyte progenitor cells at the clonal level. However, methods for estimation of model parameters and their statistical properties still remain far away from complete exploration. The main technical difficulty is that no explicit analytic expression for the joint distribution of the number of progenitor cells and oligodendrocytes, and consequently for the corresponding likelihood function, is available. In the present paper, we overcome this difficulty by using computer-intensive simulation techniques for estimation of the likelihood function. Since the output of our simulation model is essentially random, stochastic optimization methods are necessary to maximize the estimated likelihood function. We use the Kiefer-Wolfowitz procedure for this purpose. Given sufficient computing resources, the proposed estimation techniques significantly extend the spectrum of problems that become approachable. In particular, these techniques can be applied to more complex branching models of multi-type cell systems with dependent evolutions of different types of cells.

Animals↗
PubMed1999

Heparin is a unique marker of progenitors in the glial cell lineage.

The oligodendrocyte-type-2 astrocyte progenitor cells (precursors of oligodendrocytes and type-2 astrocytes) are an excellent system in which to study differentiation as they can be manipulated in vitro. Maintenance of oligodendrocyte-type-2 astrocyte progenitor cells requires basic fibroblast growth factor, a growth factor whose action normally depends on a heparan sulfate coreceptor. Biochemical analysis revealed a most surprising result: that the oligodendrocyte-type-2 astrocyte progenitors did not synthesize heparan sulfate, the near ubiquitous N-sulfated cell surface polysaccharide, but the chemically related heparin in a form that was almost completely N- and O-sulfated. The heparin was detected in the pericellular fraction of the cells and the culture medium. In contrast the differentiated glial subpopulations (oligodendrocytes and type-2 astrocytes) synthesized typical heparan sulfate but with distinctive fine structural features for each cell type. Thus heparin is a unique differentiation marker in the glial lineage. Previously heparin has been found only in a subset of mature mast cells called the connective tissue mast cells. Its presence within the developing nervous system on a precise population of progenitors may confer specific and essential recognition properties on those cells in relation to binding soluble growth and/or differentiation factors and the extracellular matrix.

Animals↗
PubMed1999

A stochastic model of temporally regulated generation of oligodendrocytes in cell culture.

The results of our previous analyses suggest that O-2A progenitor cells become competent for differentiation in vitro after they complete a certain number of critical mitotic cycles. The number of critical cycles varies from clone to clone and should be thought of as a random variable. We propose an approach to the analysis of oligodendrocyte generation in vitro based on a stochastic model allowing for an arbitrary distribution of this random variable with a finite support. When applied to experimental data on clonal growth and differentiation of purified O-2A progenitor cells obtained from optic nerves of 1 and 7 day-old rats, the model provides a good quantitative description not only of the first two moments (mean and variance) of the number of O-2A progenitor cells and oligodendrocytes at different times after the start of experiment, but of the corresponding distributions as well. As our estimates show, there are scarcely any O-2A progenitor cells that divide in vitro more than twice before they acquire the competence for differentiation. Those O-2A cells that have undergone the critical divisions differentiate into an oligodendrocyte in each of the subsequent mitotic cycles with a certain probability. We give estimates of this probability for O-2A cells under different growth conditions. Our analysis suggests that the effect of thyroid hormone is twofold: it reduces the mean duration of the mitotic cycle for progenitor cells, and it increases the probability of their transformation into oligodendrocytes.

Animals↗
PubMed1999

A random walk model of oligodendrocyte generation in vitro and associated estimation problems.

A branching stochastic process proposed earlier to model oligodendrocyte generation by O-2A progenitor cells under in vitro conditions does not allow invoking the maximum likelihood techniques for estimation purposes. To overcome this difficulty, we propose a partial likelihood function based on an embedded random walk model of clonal growth and differentiation of O-2A progenitor cells. Under certain conditions, the partial likelihood function yields consistent estimates of model parameters. The usefulness of this approach is illustrated with computer simulations and data analyses.

Algorithms↗
PubMed1998

Quantitative insight into proliferation and differentiation of oligodendrocyte type 2 astrocyte progenitor cells in vitro.

As part of our attempts at understanding fundamental principles that underlie the generation of nondividing terminally differentiated progeny from dividing precursor cells, we have developed approaches to a quantitative analysis of proliferation and differentiation of oligodendrocyte type 2 astrocyte (O-2A) progenitor cells at the clonal level. Owing to extensive previous studies of clonal differentiation in this lineage, O-2A progenitor cells represent an excellent system for such an analysis. Previous studies have resulted in two competing hypotheses; one of them suggests that progenitor cell differentiation is symmetric, the other hypothesis introduces an asymmetric process of differentiation. We propose a general model that incorporates both such extreme hypotheses as special cases. Our analysis of experimental data has shown, however, that neither of these extreme cases completely explains the observed kinetics of O-2A progenitor cell proliferation and oligodendrocyte generation in vitro. Instead, our results indicate that O-2A progenitor cells become competent for differentiation after they complete a certain number of critical mitotic cycles that represent a period of symmetric development. This number varies from clone to clone and may be thought of as a random variable; its probability distribution was estimated from experimental data. Those O-2A cells that have undergone the critical divisions then may differentiate into an oligodendrocyte in each of the subsequent mitotic cycles with a certain probability, thereby exhibiting the asymmetric type of differentiation.

Animals↗
PubMed1998

A common neural progenitor for the CNS and PNS.

Cultured spinal cord neuroepithelial (NEP) cells can differentiate into neurons, oligodendrocytes and astrocytes and are morphologically and antigenically distinct from neural crest stem cells (NCSCs) that generate the PNS. NEP cells, however, can generate p75/nestin-immunoreactive cells that are morphologically and antigenically similar to previously characterized NCSCs. NEP-derived p75-immunoreactive cells differentiate into peripheral neurons, smooth muscle, and Schwann cells in mass and clonal culture. Clonal analysis of NEP cells demonstrates that a common NEP progenitor cell generated both CNS and PNS phenotypes. Differentiation into NCSCs was promoted by BMP-2/4 and differentiation did not require cells to divide, indicating that BMP played an instructive role in the differentiation process. Thus, individual NEP cells are multipotent and can differentiate into most major types of cell in the CNS and PNS and that PNS differentiation involves a transition from a NEP stem to another more limited, p75-immunoreactive, neural crest stem cell.

Animals↗
PubMed1998

A stochastic model of brain cell differentiation in tissue culture.

The timing of cell differentiation can be controlled both by cellintrinsic mechanisms and by cell-extrinsic signals. Oligodendrocyte type-2 astrocyte progenitor cells are known to be the precursor cells that give rise to oligodendrocytes. When stimulated to divide by purified cortical astrocytes or by platelet-derived growth factor, these progenitor cells generate oligodendrocytes in vitro with a timing like that observed in vivo. The most widely accepted model of this process assumes a cell-intrinsic biological clock that resides in the progenitor cell. The intrinsic clock model originally proposed in 1986 remains as the dominant theoretical concept for the analysis of timed differentiation in this cell lineage. However, the results of a recent experimental study (Ibarrola et al., Developmental Biology, vol. 180, 1-21, 1996) are most consistent with the hypothesis that the propensity of a clone of dividing O-2A progenitor cells initially to generate at least one oligodendrocyte may be regulated by cell-intrinsic mechanisms, but that environmental signals regulate the extent of further oligodendrocyte generation. We propose a stochastic model of cell differentiation in culture to accommodate the most recent experimental findings. Our model is an age-dependent branching stochastic process with two types of cells. The model makes it possible to derive analytical expressions for the expected number of progenitor cells and of oligodendrocytes as functions of time. The model parameters were estimated by fitting these functions through data on the average (sample mean) number of both types of cells per colony at different time intervals from start of experiment. Using this method we provide a biologically meaningful interpretation of the observed pattern of oligodendrocyte generation in vitro and its modification in the presence of thyroid hormone.

Animals↗
PubMed1997

Glial-restricted precursors are derived from multipotent neuroepithelial stem cells.

Neuroepithelial cells in the developing ventricular zone differentiate into neurons, astrocytes, and oligodendrocytes. It is not known, however, whether this differentiation occurs in a single step or is a pathway utilizing intermediate more restricted precursor cells. To characterize the generation of glial cells from multipotent stem cells we have cultured neuroepithelial (NEP) cells from E10.5 rat embryos. Cultured NEP cells do not express any glial differentiation markers when grown on fibronectin/laminin under nondifferentiation conditions. NEP cells, however, differentiate into A2B5 immunoreactive cells which can subsequently give rise to oligodendrocytes and astrocytes. Clonal analysis of NEP cells demonstrates that the A2B5 immunoreactive cells arise in clones that contain neurons and astrocytes, indicating that A2B5(+) cells arise from multipotent NEP precursor cells. A2B5(+) cells, maintained as undifferentiated cells over multiple passages, can subsequently give rise to both oligodendrocytes and astrocytes. A2B5(+) cells, however, do not generate neurons. Thus A2B5(+) cells represent a restricted progenitor cell population that differentiates from a multipotent NEP cell. Based on our results we propose that differentiation of the multipotential NEP cells to terminally differentiated glial cells occurs via intermediate restricted precursors.

Animals↗
PubMed1997

Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells.

We have identified a neuronal-restricted precursor (NRP) cell that expresses E-NCAM (high polysialic-acid NCAM) and is morphologically distinct from multipotent neuroepithelial (NEP) cells (Kalyani et al., 1997) and spinal glial progenitors (Rao and Mayer-Proschel, 1997). NRP cells self renew over multiple passages in the presence of fibroblast growth factor (FGF) and neurotrophin-3 (NT-3) and differentiate in the presence of retinoic acid and the absence of FGF into postmitotic neurons. NRP cells can also be generated from multipotent E10.5 NEP cells. Clonal analysis shows that NRP cells arise from a NEP progenitor that generates other restricted CNS precursors. The NEP-derived NRPs undergo self renewal and can differentiate into multiple neuronal phenotypes. Thus, a direct lineal relationship exists between multipotential NEP cells and more restricted neuronal precursor cells present in vivo at E13.5 in the spinal cord.

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