Conversion of human fibroblasts to angioblast-like progenitor cells

1] Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA. [2].
Nature Methods (Impact Factor: 32.07). 12/2012; 10(1). DOI: 10.1038/nmeth.2255
Source: PubMed


Lineage conversion of one somatic cell type to another is an attractive approach for generating specific human cell types. Lineage conversion can be direct, in the absence of proliferation and multipotent progenitor generation, or indirect, by the generation of expandable multipotent progenitor states. We report the development of a reprogramming methodology in which cells transition through a plastic intermediate state, induced by brief exposure to reprogramming factors, followed by differentiation. We use this approach to convert human fibroblasts to mesodermal progenitor cells, including by non-integrative approaches. These progenitor cells demonstrated bipotent differentiation potential and could generate endothelial and smooth muscle lineages. Differentiated endothelial cells exhibited neo-angiogenesis and anastomosis in vivo. This methodology for indirect lineage conversion to angioblast-like cells adds to the armamentarium of reprogramming approaches aimed at the study and treatment of ischemic pathologies.

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Available from: Leo Kurian, Oct 13, 2015
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    • "It is of note that our induction strategy includes two major steps: an initial chemical-induced intermediary transition, followed by a lineage-specific induction. Considering that other cell lineages, such as cardiomyocytes and endothelial cells, can also be induced directly from mouse fibroblasts by defined factors44,45,46, and differentiation of stem cells to different cell types is practicable in vitro, it should be possible to generate other desired cell types from differentiated somatic cells with similar strategies by using chemical cocktails and lineage-specific conditions. "
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    ABSTRACT: Neural progenitor cells (NPCs) can be induced from somatic cells by defined factors. Here we report that NPCs can be generated from mouse embryonic fibroblasts by a chemical cocktail, namely VCR (V, VPA, an inhibitor of HDACs; C, CHIR99021, an inhibitor of GSK-3 kinases and R, Repsox, an inhibitor of TGF-β pathways), under a physiological hypoxic condition. These chemical-induced NPCs (ciNPCs) resemble mouse brain-derived NPCs regarding their proliferative and self-renewing abilities, gene expression profiles, and multipotency for different neuroectodermal lineages in vitro and in vivo. Further experiments reveal that alternative cocktails with inhibitors of histone deacetylation, glycogen synthase kinase, and TGF-β pathways show similar efficacies for ciNPC induction. Moreover, ciNPCs can also be induced from mouse tail-tip fibroblasts and human urinary cells with the same chemical cocktail VCR. Thus our study demonstrates that lineage-specific conversion of somatic cells to NPCs could be achieved by chemical cocktails without introducing exogenous factors.Cell Research advance online publication 18 March 2014; doi:10.1038/cr.2014.32.
    Cell Research 03/2014; 24(6). DOI:10.1038/cr.2014.32 · 12.41 Impact Factor
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    • "Interestingly , the resulting ''mesendoderm enriched'' data sets highlighted genes present in both mouse and human PSCs. The expression of genes typically associated with lineage specification in PSCs, even though at low levels, together with reports of the expression of traditional pluripotency factors in differentiated lineages (Kurian et al., 2013; Loh and Lim, 2011; Suzuki et al., 2006; Wang et al., 2012), further indicated that there is overlap between pluripotency and lineage marker expression. "
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    ABSTRACT: Since the initial discovery that OCT4, SOX2, KLF4, and c-MYC overexpression sufficed for the induction of pluripotency in somatic cells, methodologies replacing the original factors have enhanced our understanding of the reprogramming process. However, unlike in mouse, OCT4 has not been replaced successfully during reprogramming of human cells. Here we report on a strategy to accomplish this replacement. Through a combination of transcriptome and bioinformatic analysis we have identified factors previously characterized as being lineage specifiers that are able to replace OCT4 and SOX2 in the reprogramming of human fibroblasts. Our results show that it is possible to replace OCT4 and SOX2 simultaneously with alternative lineage specifiers in the reprogramming of human cells. At a broader level, they also support a model in which counteracting lineage specification networks underlies the induction of pluripotency.
    Cell stem cell 07/2013; 13(3). DOI:10.1016/j.stem.2013.06.019 · 22.27 Impact Factor
  • Nature Methods 01/2013; 10(1):44-5. DOI:10.1038/nmeth.2325 · 32.07 Impact Factor
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