Open AccessMicro RNA ‐199b Modulates Vascular Cell Fate During i PS Cell Differentiation by Targeting the N otch Ligand J agged1 and Enhancing VEGF Signaling
Author(s) -
Chen Ting,
Margariti Andriana,
Kelaini Sophia,
Cochrane Amy,
Guha Shaunta T.,
Hu Yanhua,
Stitt Alan W.,
Zhang Li,
Xu Qingbo
Publication year - 2015
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1930
Subject(s) - notch signaling pathway , biology , microbiology and biotechnology , jag1 , cellular differentiation , matrigel , angiogenesis , gene knockdown , endothelial stem cell , vascular endothelial growth factor , cell type , cell , signal transduction , cancer research , cell culture , in vitro , genetics , vegf receptors , gene
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. S tem C ells 2015;33:1405–1418