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Exploring the regulation of human neural precursor cell differentiation using arrays of signaling microenvironments.

ABSTRACT: Cells of a developing embryo integrate a complex array of local and long-range signals that act in concert with cell-intrinsic determinants to influence developmental decisions. To systematically investigate the effects of molecular microenvironments on cell fate decisions, we developed an experimental method based on parallel exposure of cells to diverse combinations of extracellular signals followed by quantitative, multi-parameter analysis of cellular responses. Primary human neural precursor cells were captured and cultured on printed microenvironment arrays composed of mixtures of extracellular matrix components, morphogens, and other signaling proteins. Quantitative single cell analysis revealed striking effects of some of these signals on the extent and direction of differentiation. We found that Wnt and Notch co-stimulation could maintain the cells in an undifferentiated-like, proliferative state, whereas bone morphogenetic protein 4 induced an 'indeterminate' differentiation phenotype characterized by simultaneous expression of glial and neuronal markers. Multi-parameter analysis of responses to conflicting signals revealed interactions more complex than previously envisaged including dominance relations that may reflect a cell-intrinsic system for robust specification of responses in complex microenvironments.

SUBMITTER: Soen Y

PROVIDER: S-EPMC1681508 | biostudies-literature | 2006

REPOSITORIES: biostudies-literature

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Exploring the regulation of human neural precursor cell differentiation using arrays of signaling microenvironments.

Soen Yoav Y Mori Akiko A Palmer Theo D TD Brown Patrick O PO

Molecular systems biology 20060704

Cells of a developing embryo integrate a complex array of local and long-range signals that act in concert with cell-intrinsic determinants to influence developmental decisions. To systematically investigate the effects of molecular microenvironments on cell fate decisions, we developed an experimental method based on parallel exposure of cells to diverse combinations of extracellular signals followed by quantitative, multi-parameter analysis of cellular responses. Primary human neural precursor ...[more]

PMID: 16820778

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Project description:: Phosphatase and tension homolog (PTEN) is a widely known negative regulator of insulin/phosphatidylinositol 3-kinase (PI3K) signaling. The PI3K/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) and Ras-extracellular signal-regulated kinase (Ras-ERK) signaling pathways are the chief mechanisms controlling the survival, proliferation, and differentiation of neural stem cells (NSCs). However, the roles of PTEN in Akt/mTOR and ERK signaling during proliferation and neuronal differentiation of human NSCs (hNSCs) are poorly understood. Treatment of proliferating hNSCs with a specific inhibitor of PTEN or overexpression of the PTEN inactive mutant G129E resulted in an increase in the expression levels of Ki67, p-S6 kinase (p-S6K), and p-ERK without affecting p-Akt expression during proliferation of hNSCs. Therefore, we focused on the regulatory effect of PTEN in S6K and ERK signaling during dopaminergic neuronal differentiation of hNSCs. Overexpression of PTEN during neuronal differentiation of hNSCs caused an increase in p-S6K expression and a decrease in p-ERK expression. Conversely, inhibition of PTEN increased p-ERK expression and decreased p-S6K expression. Inhibition of ERK by a specific chemical inhibitor, U0126, promoted neuronal generation, especially of tyrosine hydroxylase-positive neurons. p-S6K expression increased in a time-dependent manner during differentiation, and this effect was enhanced by U0126. These results indicated that PTEN promoted neuronal differentiation by inhibition of ERK signaling, which in turn induced activation of S6K. Our data suggest that ERK pathways participate in crosstalk with S6K through PTEN signaling during neuronal differentiation of hNSCs. These results represent a novel pathway by which PTEN may modulate the interplay between ERK and S6K signaling, leading to increased neuronal differentiation in hNSCs.SignificanceThis article adds to the body of knowledge about the mechanism of extracellular signal-regulated kinase (ERK)-mediated differentiation by describing the molecular function of phosphatase and tension homolog (PTEN) during the neuronal differentiation of human neural stem cells (hNSCs). Previous studies showed that S6K signaling promoted neuronal differentiation in hNSCs via the phosphatidylinositol 3-kinase Akt-mammalian target of rapamycin signaling pathway. A further series of studies investigated whether this S6 kinase-induced differentiation in hNSCs involves regulation of ERK signaling by PTEN. The current study identified a novel mechanism by which PTEN regulates neuronal differentiation in hNSCs, suggesting that activating PTEN function promotes dopaminergic neuronal differentiation and providing an important resource for future studies of PTEN function.

Dataset Information

Exploring the regulation of human neural precursor cell differentiation using arrays of signaling microenvironments.

Publications

Exploring the regulation of human neural precursor cell differentiation using arrays of signaling microenvironments.

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