Mizuseki, K. et al. Generation of neural crest-derived peripheral neurons and floor plate cells from mouse and primate embryonic stem cells. Proc. Natl Acad. Sci. USA 100, 5828-5833

Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe 650-0047 Japan.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2003; 100(10):5828-33. DOI: 10.1073/pnas.1037282100
Source: PubMed


To understand the range of competence of embryonic stem (ES) cell-derived neural precursors, we have examined in vitro differentiation of mouse and primate ES cells into the dorsal- (neural crest) and ventralmost (floor plate) cells of the neural axis. Stromal cell-derived inducing activity (SDIA; accumulated on PA6 stromal cells) induces cocultured ES cells to differentiate into rostral CNS tissues containing both ventral and dorsal cells. Although early exposure of SDIA-treated ES cells to bone morphogenetic protein (BMP)4 suppresses neural differentiation and promotes epidermogenesis, late BMP4 exposure after the fourth day of coculture causes differentiation of neural crest cells and dorsalmost CNS cells, with autonomic system and sensory lineages induced preferentially by high and low BMP4 concentrations, respectively. In contrast, Sonic hedgehog (Shh) suppresses differentiation of neural crest lineages and promotes that of ventral CNS tissues such as motor neurons. Notably, high concentrations of Shh efficiently promote differentiation of HNF3beta(+) floor plate cells with axonal guidance activities. Thus, SDIA-treated ES cells generate naive precursors that have the competence of differentiating into the "full" dorsal-ventral range of neuroectodermal derivatives in response to patterning signals.

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    • "Inhibition of BMP signaling caused a significantly greater induction of cell death in the Nestin/GFP cells compared to the Oct4/GFP (Figure 6C). Since BMP signaling inhibits neural differentiation of embryonic stem cells [49,50], we examined whether DMH2 altered the expression of nestin in Oct4/GFP and/or Nestin/GFP cells. DMH2 induced a significant increase in the expression of nestin in the Oct4/GFP cells with a small decrease in expression in the Nestin/GFP cells (Figure 6D). "
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    ABSTRACT: Bone morphogenetic proteins (BMP) are embryonic morphogens that are aberrantly expressed in lung cancer. BMPs mediate cell fate decisions and self-renewal of stem cells, through transcription regulation of inhibitor of differentiation protein/DNA binding proteins (Id1-3). Inhibition of BMP signaling decreases growth and induces cell death of lung cancer cells lines by downregulating the expression of Id proteins. It is not known whether the BMP signaling cascade regulates growth and the expression of Id proteins of lung cancer cells expressing the stem cell markers Oct4 and/or nestin. Lung cancer cells expressing Oct4 or nestin were isolated from lung cancer cell lines by stably transfecting the Oct4 promoter or nestin promoter expression vectors that induce expression of the green fluorescent protein reporter. Our studies suggest that lung cancer cells expressing Oct4 or nestin are different cell populations. Microarray and quantitative RT-PCR demonstrated that the expression of specific stem cell markers were different between isolated Oct4 and nestin cells. Both the Oct4 and nestin populations were more tumorigenic than controls but histologically they were quite different. The isolated Oct4 and nestin cells also responded differently to inhibition of BMP signaling. Blockade of BMP signaling with the BMP receptor antagonist DMH2 caused significant growth inhibition of both the Oct4 and nestin cell populations but only increased cell death in the nestin population. DMH2 also induced the expression of nestin in the Oct4 population but not in the nestin cells. We also show that BMP signaling is an important regulator of Id1 and Id3 in both the Oct4 and nestin cell populations. Furthermore, we show that NeuN is frequently expressed in NSCLC and provide evidence suggesting that Oct4 cells give rise to cancer cells expressing nestin and/or NeuN. These studies show that although biologically different, BMP signaling is growth promoting in cancer cells expressing Oct4 or nestin. Inhibition of BMP signaling decreases expression of Id proteins and suppresses growth of cancer cells expressing Oct4 or Nestin. Small molecule antagonists of the BMP type I receptors represent potential novel drugs to target the population of cancer cells expressing stem cell markers.
    Molecular Cancer 10/2013; 12(1):129. DOI:10.1186/1476-4598-12-129 · 4.26 Impact Factor
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    • "The neural progenitors from ESC even display properties of distinct regionalization responsible for neural patterning [30] [31] [32]. The in vitro induction of neural differentiation in ESC also closely mimics molecular mechanisms of embryonic brain development [33]. "
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    ABSTRACT: There are three controversial and undetermined models of neurogenesis and gliogenesis from neuroepithelial cells in the early neural tube; the first in which neurons and glia were proposed to originate from a single homogenous population, the second from two separate pools of committed glial and neuronal progenitors, or, lastly, from transit radial glial (RG). Issues concerning embryonic neural lineage development in primates are not well understood due to restrictions imposed by ethics and material sources. In this study, early neural lineage development was investigated in vitro with rhesus monkey embryonic stem cells (rESC) by means of immunofluorescence with lineage specific markers. It was revealed that neural differentiation likely progresses in a sequential lineage restriction pathway from neuroepithelial stem/progenitor cells to neurons and glia via RG and intermediate precursors: neuronal precursors and glial progenitors. In conclusion, our results suggest that the early neural lineage development of rESC in vitro supported the model in which neuroepithelial cells develop into RG capable of generating both neurons and glia. This work should facilitate understanding of the mechanism of development of the nervous system in primates.
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    • "In the first report of the derivation of human iPS cells, SDIA was used to promote dopaminergic differentiation.2 Previously, SDIA-promoted differentiation was shown to produce dopaminergic neurons in cynomolgus ES cells37 and rhesus macaque ES cells,38 as well as in human ES cells.39 Marmoset ES and iPS cells can also be differentiated to neural lineages via the SDIA method.40–42 "
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    ABSTRACT: The development of the technology for derivation of induced pluripotent stem (iPS) cells from human patients and animal models has opened up new pathways to the better understanding of many human diseases, and has created new opportunities for therapeutic approaches. Here, we consider one important neurological disease, Parkinson's, the development of relevant neural cell lines for studying this disease, and the animal models that are available for testing the survival and function of the cells, following transplantation into the central nervous system. Rapid progress has been made recently in the application of protocols for neuroectoderm differentiation and neural patterning of pluripotent stem cells. These developments have resulted in the ability to produce large numbers of dopaminergic neurons with midbrain characteristics for further study. These cells have been shown to be functional in both rodent and nonhuman primate (NHP) models of Parkinson's disease. Patient-specific iPS cells and derived dopaminergic neurons have been developed, in particular from patients with genetic causes of Parkinson's disease. For complete modeling of the disease, it is proposed that the introduction of genetic changes into NHP iPS cells, followed by studying the phenotype of the genetic change in cells transplanted into the NHP as host animal, will yield new insights into disease processes not possible with rodent models alone.
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