Mesenchyme homeobox 1 mediates transforming growth factor-β (TGF-β)–induced smooth muscle cell differentiation from mouse mesenchymal progenitors

Abstract

Differentiation of smooth muscle cells (SMCs) is critical for proper vasculogenesis and angiogenesis. However, the molecular mechanisms controlling SMC differentiation are not completely understood. During embryogenesis, the transcription factor mesenchyme homeobox 1 (Meox1) is expressed in the early developing somite, which is one of the origins of SMCs. In the present study, we identified Meox1 as a positive regulator of SMC differentiation. We found that transforming growth factor-β (TGF-β) induces Meox1 expression in the initial phase of SMC differentiation of pluripotent murine C3H10T1/2 cells. shRNA-mediated Meox1 knockdown suppressed TGF-β-induced expression of SMC early markers, whereas Meox1 overexpression increased expression of these markers. Mechanistically, Meox1 promoted SMAD family member 3 (Smad3) nuclear retention during the early stage of TGF-β stimulation because Meox1 inhibited protein phosphatase Mg/Mn-dependent 1A (PPM1A) and thereby prevented PPM1A-mediated Smad3 dephosphorylation. Meox1 appears to promote PPM1A degradation, leading to sustained Smad3 phosphorylation, thus allowing Smad3 to stimulate SMC gene transcription. , Meox1 knockdown in mouse embryos impaired SMC marker expression in the descending aorta of neonatal mice, indicating that Meox1 is essential for SMC differentiation during embryonic development. In summary, the transcriptional regulator Meox1 controls TGF-β-induced SMC differentiation from mesenchymal progenitor cells by preventing PPM1A-mediated Smad3 dephosphorylation, thereby supporting SMC gene expression.

Spatio-temporal model of Meox1 expression control involvement of Sca-1-positive stem cells in neointima formation through the synergistic effect of Rho/CDC42 and SDF-1α/CXCR4

“…More importantly, Meox1-induced SDF-1α in VSMC acts as a signpost to guide the directional migration of these cells into the intimal. These results are consistent with previous studies that found that Meox1 could induce MSC differentiation into VSMC [ 33 ]. In a word, the spatio-temporal model of Meox1 expression could trigger the engagement of Sca-1+ progenitor stem cells during the neointima formation.…”

Dynamic Interstitial Cell Response during Myocardial Infarction Predicts Resilience to Rupture in Genetically Diverse Mice

“…PLSs were relatively stable across all time points (Figure 2B), expressed genes associated to cell migration and morphogenesis, known stromal cell markers Cd248 (Smith et al, 2015), Pi16 (Regn et al, 2016;Xie et al, 2018), and relatively higher levels of Ly6a, previously used as a marker to enrich for putative cardiac progenitor cells (Tang et al, 2018;Farbehi et al, 2019;Oh et al, 2003;Figures 2C-2E and S4C). LR fibroblasts were prevalent at d14-d28 (maturation phase), expressing a relatively higher level of genes associated with cell differentiation, osteogenesis, and regulation of matrix remodeling and deposition, including Adamtls2 and Cilp, secreted proteins involved in the negative regulation of TGF-b availability (Le Goff et al, 2008) and activity (Zhang et al, 2018), fibrillogen-esis (Koo et al, 2007), and fibrosis (van Nieuwenhoven et al, 2017;Zhang et al, 2018); Col8a1, an extracellular matrix (ECM) component conferring tensile strength that supports vessel integrity and structure (Kittelberger et al, 1990) upregulated in the presence of vascular injury (Gerth et al, 2007;Kittelberger et al, 1990;Lopes et al, 2013); and the transcription factor Meox1, which is involved in embryonic somitogenesis and TGF-b-induced differentiation of SMCs (Dong et al, 2018;Figures 2C-2E and S4C). Meox1 is also implicated in cardiac pathological hypertrophy (Lu et al, 2018) and is downregulated during in vitro phenoconversion from fibroblasts to Acta2 + Myofb (Cunnington et al, 2014).…”

Dynamic Interstitial Cell Response During Myocardial Infarction Predicts Resilience to Rupture in Genetically Diverse Mice

“…Seurat analysis with 24 PC and resolution 0.5 was used to define 16 main clusters. the presence of vascular injury (Gerth et al, 2007;Kittelberger et al, 1990;Lopes et al, 2013); and the transcription factor Meox1, which is involved in embryonic somitogenesis and TGF-b-induced differentiation of SMCs (Dong et al, 2018;Figures 2C-2E and S4C). Meox1 is also implicated in cardiac pathological hypertrophy (Lu et al, 2018) and is downregulated during in vitro phenoconversion from fibroblasts to Acta2 + Myofb (Cunnington et al, 2014).…”