scholarly journals Transforming Growth Factor-β and Notch Signaling Mediate Stem Cell Differentiation into Smooth Muscle Cells

Stem Cells ◽  
2010 ◽  
Vol 28 (4) ◽  
pp. 734-742 ◽  
Author(s):  
Kyle Kurpinski ◽  
Hayley Lam ◽  
Julia Chu ◽  
Aijun Wang ◽  
Ahra Kim ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Notch Signaling ◽  
Transforming Growth Factor ◽  
Stem Cell Differentiation ◽  
Muscle Cells ◽  
Transforming Growth Factor Β

scholarly journals Transforming growth factor-β plays divergent roles in modulating vascular remodeling, inflammation, and pulmonary fibrosis in a murine model of scleroderma

2017 ◽  
Vol 312 (1) ◽  
pp. L22-L31 ◽  
Author(s):  
Kazuyuki Tsujino ◽  
Nilgun Isik Reed ◽  
Amha Atakilit ◽  
Xin Ren ◽  
Dean Sheppard
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Transforming Growth Factor ◽  
Muscle Cells ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Pulmonary Vascular Remodeling ◽  
Global Inhibition

The efficacy and feasibility of targeting transforming growth factor-β (TGFβ) in pulmonary fibrosis and lung vascular remodeling in systemic sclerosis (SSc) have not been well elucidated. In this study we analyzed how blocking TGFβ signaling affects pulmonary abnormalities in Fos-related antigen 2 (Fra-2) transgenic (Tg) mice, a murine model that manifests three important lung pathological features of SSc: fibrosis, inflammation, and vascular remodeling. To interrupt TGFβ signaling in the Fra-2 Tg mice, we used a pan-TGFβ-blocking antibody, 1D11, and Tg mice in which TGFβ receptor type 2 ( Tgfbr2) is deleted from smooth muscle cells and myofibroblasts (α-SMA-CreER; Tgfbr2 flox/flox). Global inhibition of TGFβ by 1D11 did not ameliorate lung fibrosis histologically or biochemically, whereas it resulted in a significant increase in the number of immune cells infiltrating the lungs. In contrast, 1D11 treatment ameliorated the severity of pulmonary vascular remodeling in Fra-2 Tg mice. Similarly, genetic deletion of Tgfbr2 from smooth muscle cells resulted in improvement of pulmonary vascular remodeling in the Fra-2 Tg mice, as well as a decrease in the number of Ki67-positive vascular smooth muscle cells, suggesting that TGFβ signaling contributes to development of pulmonary vascular remodeling by promoting the proliferation of vascular smooth muscle cells. Deletion of Tgfbr2 from α-smooth muscle actin-expressing cells had no effect on fibrosis or inflammation in this model. These results suggest that efforts to target TGFβ in SSc will likely require more precision than simply global inhibition of TGFβ function.

Abstract 433: HDAC7 is Essential for Stem Cell Differentiation into Smooth Muscle Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Andriana Margariti ◽  
Qingzhong Xiao ◽  
Anna Zampetaki ◽  
Yanhua Hu ◽  
Lingfang Zeng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Smooth Muscle Cells ◽  
Stem Cell Differentiation ◽  
Muscle Cells ◽  
Specific Cell ◽  
Western Blots ◽  
Marker Expression

Background: Embryonic stem cells (ESCs) possess the potential to differentiate into specific cell lineages, such as vascular smooth muscle cells (SMCs). The homeostasis of histone acetylation and deacetylation mediated by histone deacetylase (HDAC) is known to play a central role in the regulation of gene expression, through co-operation with other transcription factors. However, it is unknown whether HDAC plays a role in mediating stem cell differentiation into SMCs. Methods and results: Mouse ESCs were seeded on collagen IV-coated flasks and cultured in the absence of Leukemia Inhibitory Factor (LIF) in differentiation medium for 3 to 9 days in order to induce SMCs differentiation. Western blots and double-immunofluorescence staining demonstrated that HDAC7 expressed in parallel with SMC marker genes. Upregulation of HDAC7 expression resulted in increase in SMC marker expression, while downregulation of HDAC7 by siRNA caused decrease of SMC marker expression. In ex vivo culture of embryonic cells from SM22-LacZ transgenic mice, over-expression of HDAC7 significantly increased beta-gal positive cells, indicating a crucial role of HDAC7 in SMC differentiation during embryonic development. An important observation of this study is that HDAC7 undergoes alternative splicing during ESC differentiation, resulting in alternative translation from second ATG codon, giving rise to a short HDAC7 missing the N-terminal 22 amino acids. We also found that PDGF induced SMCs differentiation through the regulation of HDAC7 transcription and splicing, in which siHDAC7 knockdown ablated PDGF-induced SMC marker expression. Spliced HDAC7 increased SMC differentiation, while the short HDAC7 had no effect or even downregulated SMC differentiation. Further experiments revealed that the short HDAC7 isoform bound to MEF2C, while the full length HDAC7 did not, indicating that HDAC7 splicing can induce SMCs differentiation through the modulation of MEF2C-mediated gene expression. Conclusions: Our findings provide novel information on the mechanism involved in SMC differentiation, and identify HDAC7 as a new target in therapeutic intervention on vascular disease, where inhibition of vascular progenitor cell differentiation into SMCs would be beneficial.

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