Differentiation of Adipose-Derived Stem Cells into Contractile Smooth Muscle Cells Induced by Transforming Growth Factor-β1 and Bone Morphogenetic Protein-4

Abstract

Smooth muscle cells (SMCs) play an essential role in maintaining the structural and functional integrity of blood vessel and thus is a critical element for blood vessel construction via tissue engineering approach. Adipose-derived stem cells (ASCs) represent a reliable source of mesenchymal stem cells with multidifferentiation potential. In this study, the feasibility of differentiation of human ASCs (hASCs) into cells with phenotypic and functional properties of SMCs was explored. hASCs isolated from human lipoaspirate were expanded to passage 5 and then induced with administration of transforming growth factor-beta1 (TGF-beta1) and bone morphogenetic protein-4 (BMP4) either alone or in combination with culture medium. Expression of SMC-related markers including alpha-SM actin (alpha-SMA, SM22alpha, calponin, and SM myosin heavy chain) were detected by immunofluorescent staining, reverse transcription (RT)-polymerase chain reaction, and western blot analysis. It was found that only under the circumstance of a combined stimulation with TGF-beta1 and BMP4, both early and mid markers (alpha-SMA, SM22alpha, calponin) as well as a late marker (SM myosin heavy chain) of SMC differentiation were identified to similar levels as those in human umbilical artery SMCs. More importantly, these SM differentiated cells showed the function of contracting collagen matrix lattice when they were entrapped inside. The contractile function of differentiated hASCs was further enhanced by direct exposure to 60 mM KCl, consistent with what occurred in human umbilical artery SMCs. These results provide evidence that ASCs possess the potential to differentiate into contractile SM-like cells when stimulated by TGF-beta1 and BMP4 together. SMCs differentiated from hASCs may provide an abundant source as seed cells for blood vessel engineering.

Functional expression of smooth muscle-specific ion channels in TGF-β1-treated human adipose-derived mesenchymal stem cells

“…TGF-␤ 1 has been reported to induce differentiation of mesenchymal stem cells into SMCs (34,46,63). The present study demonstrated that TGF-␤ 1 increased the expression of the SMC-specific transcription factor myocardin in hASCs.…”

Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis

“…WNT signaling, particularly through the WNT3a ligand, seems to mediate TGFβ-induced mesenchymal fibrogenic responses and loss of adipose tissue in skin fibrosis (Akhmetshina et al, 2012;Wei et al, 2012). Furthermore, the differentiation of adipose-derived stem cells to contractile SMCs has shown to be dependent on TGFβ1 and BMP4 (Wang et al, 2010). Under culture conditions permissive for adipogenesis, skeletal muscle is capable of transdifferentiating to mature adipocytes via PPAR activation and upregulation of lipogenic markers Pparg and C/ebpa (Hu et al, 1995).…”

Adipose Stromal Cells Differentiate Along a Smooth Muscle Lineage Pathway Upon Endothelial Cell Contact via Induction of Activin A

“…Adipose tissue represents an abundant source of mesenchymal stromal cells that possess a high level of plasticity, 10 including differentiation into smooth muscle cells (SMC) 11,12 and show significant potential in cardiac and vascular cell therapies. [13][14][15][16][17][18][19] We and others have shown that isolated ASC phenotypically and functionally overlap substantially with pericytes and SMC.…”