Generation of human vascular smooth muscle subtypes provides insight into embryological origin–dependent disease susceptibility

Abstract

Heterogeneity of embryological origins is a hallmark of vascular smooth muscle cells (SMCs), which may influence vascular disease development. Differentiation of human pluripotent stem cells (hPSCs) into developmental origin-specific SMC subtypes remains elusive. In this study, we have established a chemically defined protocol where hPSCs were initially induced to form neuroectoderm, lateral plate mesoderm or paraxial mesoderm. These intermediate populations were further differentiated towards SMCs (>80% MYH11+ and ACTA2+) which displayed contractile ability in response to vasoconstrictors and invested perivascular regions in vivo. Derived SMC subtypes recapitulated the unique proliferative and secretory responses to cytokines previously documented in studies using aortic SMCs of distinct origins. Importantly, this system predicted increased extracellular matrix degradation by SMCs derived from lateral plate mesoderm, which was confirmed using rat aortic SMCs from corresponding origins. Collectively, this work will have broad applications in modeling origin-dependent disease susceptibility and in bio-engineered vascular grafts for regenerative medicine.

Adipogenesis: new insights into brown adipose tissue differentiation

“…The purification/isolation of highly pure brown adipocytes should be facilitated by the ability to engineer stem cell lines in which key markers of the BAT lineage are marked with fluorescent, antibiotic or neutral cell-surface reporters. The combination of genetic lineage marking using site-specific recombinases like Cre and highly defined human stem cell differentiation systems that mimic the progression of paraxial mesoderm formation during embryonic development (Francetic & Li 2011, Cheung et al 2012, Sakurai et al 2012) may help to resolve some of the outstanding controversial questions regarding the origin of both human classical BAT and brite cells and test the importance of various factors in directing BAT/brite cell fate. Engineered reporter lines could also be employed in largescale chemical screening for compounds that influence BAT formation/activity and are potential therapeutic drugs for metabolic disease.…”

Endothelial Cells Direct Mesenchymal Stem Cells Toward a Smooth Muscle Cell Fate

“…During development, the formation of blood vessels is dependent upon the ability of endothelial cells to recruit precursor smooth muscle cells and promote their differentiation [9,10]. The recruitment and differentiation of vascular smooth muscle cells by endothelial cells is regulated by platelet-derived growth factor (PDGF), transforming growth factor-b (TGFb), and Notch signaling [11]; all factors which have been implicated in regulating mesenchymal stem cell differentiation [12][13][14]. Thus, the presence of endothelial cells within the mesenchymal stem cell environment likely plays a substantial role in their differentiation decisions.…”

Toward pluripotency by reprogramming: mechanisms and application

“…In addition to neuronal lineage differentiation, significant progresses have also been made in the differentiation of iPSCs towards many other cell types including cardiovascular fate, especially into cardiomyocytes, smooth muscle cells, and endothelial cells (Kattman et al, 2011;Cheung et al, 2012;Lian et al, 2012;Minami et al, 2012;Cao et al, 2013). These cells will be valuable applications in vascular diseases such as congenital vascular malformation, with abnormal blood vessels occur at birth.…”