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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) and may influence the development of vascular disease. Differentiation of human pluripotent stem cells (hPSCs) into developmental origin-specific SMC subtypes remains elusive. Here we describe a chemically defined protocol in which hPSCs were initially induced to form neuroectoderm, lateral plate mesoderm or paraxial mesoderm. These intermediate populations were further differentiated toward 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. Notably, this system predicted increased extracellular matrix degradation by SMCs derived from lateral plate mesoderm, which was confirmed using rat aortic SMCs from corresponding origins. This differentiation approach will have broad applications in modeling origin-dependent disease susceptibility and in developing bioengineered vascular grafts for regenerative medicine.

SUBMITTER: Cheung C

PROVIDER: S-EPMC3272383 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Cheung Christine C Bernardo Andreia S AS Trotter Matthew W B MW Pedersen Roger A RA Sinha Sanjay S

Nature biotechnology 20120115 2

Heterogeneity of embryological origins is a hallmark of vascular smooth muscle cells (SMCs) and may influence the development of vascular disease. Differentiation of human pluripotent stem cells (hPSCs) into developmental origin-specific SMC subtypes remains elusive. Here we describe a chemically defined protocol in which hPSCs were initially induced to form neuroectoderm, lateral plate mesoderm or paraxial mesoderm. These intermediate populations were further differentiated toward SMCs (>80% MY ...[more]

PMID: 22252507

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Project description:UnlabelledVascular smooth muscle cells (SMCs) from distinct anatomic locations derive from different embryonic origins. Here we investigated the respective potential of different embryonic origin-specific SMCs derived from human embryonic stem cells (hESCs) to support endothelial network formation in vitro. SMCs of three distinct embryological origins were derived from an mStrawberry-expressing hESC line and were cocultured with green fluorescent protein-expressing human umbilical vein endothelial cells (HUVECs) to investigate the effects of distinct SMC subtypes on endothelial network formation. Quantitative analysis demonstrated that lateral mesoderm (LM)-derived SMCs best supported HUVEC network complexity and survival in three-dimensional coculture in Matrigel. The effects of the LM-derived SMCs on HUVECs were at least in part paracrine in nature. A TaqMan array was performed to identify the possible mediators responsible for the differential effects of the SMC lineages, and a microarray was used to determine lineage-specific angiogenesis gene signatures. Midkine (MDK) was identified as one important mediator for the enhanced vasculogenic potency of LM-derived SMCs. The functional effects of MDK on endothelial network formation were then determined by small interfering RNA-mediated knockdown in SMCs, which resulted in impaired network complexity and survival of LM-derived SMC cocultures. The present study is the first to show that SMCs from distinct embryonic origins differ in their ability to support HUVEC network formation. LM-derived SMCs best supported endothelial cell network complexity and survival in vitro, in part through increased expression of MDK. A lineage-specific approach might be beneficial for vascular tissue engineering and therapeutic revascularization.SignificanceMural cells are essential for the stabilization and maturation of new endothelial cell networks. However, relatively little is known of the effect of the developmental origins of mural cells on their signaling to endothelial cells and how this affects vessel development. The present study demonstrated that human smooth muscle cells (SMCs) from distinct embryonic origins differ in their ability to support endothelial network formation. Lateral mesoderm-derived SMCs best support endothelial cell network complexity and survival in vitro, in part through increased expression of midkine. A lineage-specific approach might be beneficial for vascular tissue engineering and therapeutic revascularization.

Project description:Mitochondria are widely described as being highly dynamic and adaptable organelles, and their movement is thought to be vital for cell function. Yet, in various native cells, including those of heart and smooth muscle, mitochondria are stationary and rigidly structured. The significance of the differences in mitochondrial behavior to the physiological function of cells is unclear and was studied in single myocytes and intact resistance-sized cerebral arteries. We hypothesized that mitochondrial dynamics is controlled by the proliferative status of the cells.High-speed fluorescence imaging of mitochondria in live vascular smooth muscle cells shows that the organelle undergoes significant reorganization as cells become proliferative. In nonproliferative cells, mitochondria are individual (? 2 ?m by 0.5 ?m), stationary, randomly dispersed, fixed structures. However, on entering the proliferative state, mitochondria take on a more diverse architecture and become small spheres, short rod-shaped structures, long filamentous entities, and networks. When cells proliferate, mitochondria also continuously move and change shape. In the intact pressurized resistance artery, mitochondria are largely immobile structures, except in a small number of cells in which motility occurred. When proliferation of smooth muscle was encouraged in the intact resistance artery, in organ culture, the majority of mitochondria became motile and the majority of smooth muscle cells contained moving mitochondria. Significantly, restriction of mitochondrial motility using the fission blocker mitochondrial division inhibitor prevented vascular smooth muscle proliferation in both single cells and the intact resistance artery.These results show that mitochondria are adaptable and exist in intact tissue as both stationary and highly dynamic entities. This mitochondrial plasticity is an essential mechanism for the development of smooth muscle proliferation and therefore presents a novel therapeutic target against vascular disease.

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

Publications

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

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