Myocardin Overexpression Is Sufficient for Promoting the Development of a Mature Smooth Muscle Cell-Like Phenotype from Human Embryonic Stem Cells

Raphel, Linda; Talasila, Amarnath; Cheung, Christine; Sinha, Sanjay

doi:10.1371/journal.pone.0044052

Cited by 29 publications

(26 citation statements)

References 23 publications

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“…Indeed, Myocd alone can induce the mature SM marker SMMHC expression (Fig. 3, A and B), consistent with previous reports (24,36). Because Cdc7 played a very important role in regulating mature SM marker gene expression, and Cdc7 was induced much earlier than Myocd by TGF-␤ (20), we sought to determine whether Cdc7 induces mature SM marker expression through Myocd.…”

Section: Cdc7 Induces Mature Sm Marker Through Myocd/srf-supporting

confidence: 87%

Cell Division Cycle 7 Mediates Transforming Growth Factor-β-induced Smooth Muscle Maturation through Activation of Myocardin Gene Transcription

Shi

Chen

2013

Journal of Biological Chemistry

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Background: Cell division cycle 7 (Cdc7) plays a role in cell fate determination in the early stage of smooth muscle (SM) differentiation. Results: Cdc7 activated myocardin gene transcription by interacting with Nkx2.5, leading to the induction of a mature SM marker smooth muscle myosin heavy chain (SMMHC). Conclusion: Cdc7 regulates SM maturation by activation of myocardin expression. Significance: Cdc7 regulates SM differentiation and maturation through different mechanisms.

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Section: Cdc7 Induces Mature Sm Marker Through Myocd/srf-supporting

confidence: 87%

Cell Division Cycle 7 Mediates Transforming Growth Factor-β-induced Smooth Muscle Maturation through Activation of Myocardin Gene Transcription

Shi

Chen

2013

Journal of Biological Chemistry

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“…In subsequent work the same group determined that MYOCD is a master regulator of smooth muscle gene expression and is capable of activating smooth muscle expression in various non-muscle cell types by associating with SRF 9 . In a more recent study it was reported that forced MYOCD expression in human ESC derived-embryoid bodies only selectively regulated CArG-dependent smooth muscle genes and allowed an increase in the number of SMC-like cells derived following one month of differentiation 40 . Altogether, these reports align with our findings that transient over-expression of MYOCD can convert EPC to SMC.…”

Section: Discussionmentioning

confidence: 99%

Transdifferentiation of human endothelial progenitors into smooth muscle cells

Atchison

Chen

et al. 2016

Biomaterials

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Access to smooth muscle cells (SMC) would create opportunities for tissue engineering, drug testing, and disease modeling. Herein we report the direct conversion of human endothelial progenitor cells (EPC) to induced smooth muscle cells (iSMC) by induced expression of MYOCD. The EPC undergo a cytoskeletal rearrangement resembling that of mesenchymal cells within 3 days post initiation of MYOCD expression. By day 7, the reprogrammed cells show upregulation of smooth muscle markers ACTA2, MYH11, and TAGLN by qRT-PCR and ACTA2 and MYH11 expression by immunofluorescence. By two weeks, they resemble umbilical artery SMC in microarray gene expression analysis. The iSMC, in contrast to EPC control, show calcium transients in response to phenylephrine stimulation and a contractility an order of magnitude higher than that of EPC as determined by traction force microscopy. Tissue-engineered blood vessels constructed using iSMC show functionality with respect to flow- and drug-mediated vasodilation and vasoconstriction.

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“…In contrast, myocardin overexpression promotes VSMC differentiation and increases the expression of other VSMC marker proteins (38). Factors that inhibit myocardin expression are associated with dedifferentiation (35).…”

Section: Irs-1 Prevents Vsmc Dedifferentiationmentioning

confidence: 99%

Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation

Wai

White

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinDiabetes is a major risk factor for the development of atherosclerosis, but the mechanism by which hyperglycemia accelerates lesion development is not well defined. Insulin and insulinlike growth factor I (IGF-I) signal through the scaffold protein insulin receptor substrate 1 (IRS-1). In diabetes, IRS-1 is downregulated, and cells become resistant to insulin. Under these conditions, the IGF-I receptor signals through an alternate scaffold protein, SHPS-1, resulting in pathophysiologic stimulation of vascular smooth muscle cell (VSMC) migration and proliferation. These studies were undertaken to determine whether IRS-1 is functioning constitutively to maintain VSMCs in their differentiated state and, thereby, inhibit aberrant signaling. Here we show that deletion of IRS-1 expression in VSMCs in nondiabetic mice results in dedifferentiation, SHPS-1 activation, and aberrant signaling and that these changes parallel those that occur in response to hyperglycemia. The mice showed enhanced sensitivity to IGF-I stimulation of VSMC proliferation and a hyperproliferative response to vascular injury. KLF4, a transcription factor that induces VSMC dedifferentiation, was up-regulated in IRS-1 ؊/؊ mice, and the differentiation inducer myocardin was undetectable. Importantly, these changes were replicated in wild-type mice during hyperglycemia. These findings illuminate a new function of IRS-1: that of maintaining cells in their normal, differentiatedstate.BecauseIRS-1isdown-regulatedinstatesofinsulinresistance that occur in response to metabolic stresses such as obesity and cytokine stimulation, the findings provide a mechanism for understanding how patients with metabolic stress and/or diabetes are predisposed to developing vascular complications.Diabetes is a major predisposing factor for the development of atherosclerosis. The diabetes control complications trial showed that patients with type 1 diabetes who maintained a hemoglobin A-1 C value 1.2% lower than control subjects for 7 years had a significantly reduced rate of vascular disease events during the 20-year follow-up period (1). Similarly the United Kingdom prospective trial demonstrated a significant benefit of lowering glucose in type 2 diabetics on cardiovascular risk (2). Despite intense analysis, the molecular mechanism by which glucose lowering results in a clinical benefit has remained poorly defined. Insulin and insulin-like growth factor I (IGF-I) 2 signal through a scaffold protein termed insulin receptor substrate 1 (IRS-1) (3). The insulin and IGF-I receptor tyrosine kinases directly phosphorylate IRS-1, and these phosphotyrosines recruit the p85 subunit of PI3K and Grb-2, thereby activating the PI3K and MAPK pathways (4). In differentiated cells, these IRS-1-linked signaling cascades promote glucose influx; glycogen, lipid, and protein synthesis; as well as changes in gene expression (5). Under normal physiologic conditions, both insulin and IGF-I stimulate differentiated cell functions through IRS-1 activation (6 -7). In re...

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Myocardin Overexpression Is Sufficient for Promoting the Development of a Mature Smooth Muscle Cell-Like Phenotype from Human Embryonic Stem Cells

Cited by 29 publications

References 23 publications

Cell Division Cycle 7 Mediates Transforming Growth Factor-β-induced Smooth Muscle Maturation through Activation of Myocardin Gene Transcription

Cell Division Cycle 7 Mediates Transforming Growth Factor-β-induced Smooth Muscle Maturation through Activation of Myocardin Gene Transcription

Transdifferentiation of human endothelial progenitors into smooth muscle cells

Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation

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