Abstract
Aims: Recent ability to derive endothelial cells (ECs) from induced pluripotent stem (iPS) cells holds a great therapeutic potential for personalized medicine and stem cell therapy. We aimed that better understanding of the complex molecular signals that are evoked during iPS cell differentiation toward ECs may allow specific targeting of their activities to enhance cell differentiation and promote tissue regeneration. Methods and Results: In this study, we have generated mouse iPS cells from fibroblasts using established protocol. When iPS cells were cultivated on type IV mouse collagen‐coated dishes in differentiation medium, cell differentiation toward vascular lineages were observed. To study the molecular mechanisms of iPS cell differentiation, we found that miR‐199b is involved in EC differentiation. A step‐wise increase in expression of miR‐199 was detected during EC differentiation. Notably, miR‐199b targeted the Notch ligand JAG1, resulting in vascular endothelial growth factor (VEGF) transcriptional activation and secretion through the transcription factor STAT3. Upon shRNA‐mediated knockdown of the Notch ligand JAG1, the regulatory effect of miR‐199b was ablated and there was robust induction of STAT3 and VEGF during EC differentiation. Knockdown of JAG1 also inhibited miR‐199b‐mediated inhibition of iPS cell differentiation toward smooth muscle markers. Using the in vitro tube formation assay and implanted Matrigel plugs, in vivo, miR‐199b also regulated VEGF expression and angiogenesis. Conclusions: This study indicates a novel role for miR‐199b as a regulator of the phenotypic switch during vascular cell differentiation derived from iPS cells by regulating critical signaling angiogenic responses. Stem Cells 2015;33:1405–1418
Highlights
Induced pluripotent stem cells are able to differentiate into most types of cells [1,2,3]
We provide evidence that miR-199b is implicated in endothelial cells (ECs) differentiation derived from induced pluripotent stem (iPS) cells by modulating vascular endothelial growth factor (VEGF) expression under transcriptional control of STAT3
(E): iPS cells were forced to differentiate toward ECs for 4 days, and cotransfections of Pre-199b or locked nucleic acid (LNA)-199b with the luciferase plasmid of the 30UTR-JAG1 were performed
Summary
Induced pluripotent stem (iPS) cells are able to differentiate into most types of cells [1,2,3]. This unique characteristic offers significant potential for cell-replacement therapies to repair tissues or organs damaged by injury, degenerative diseases, aging, or cancer [4,5,6]. Better understanding of the cellular players and molecular signals that constitute stem cell niches under different physiological and pathological conditions will facilitate development of more refined models of stem cell responses. This may allow specific targeting of their activities to promote tissue regeneration. For instance it is speculated that if information regarding chromatin states with global views of noncoding RNAs and their regulatory signaling are combined, it is possible to obtain an integrative picture of the molecular mechanisms that govern cell fate specification
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