Disease in a dish: pluripotent stem cells as model systems for cardiac research233Human pluripotent stem cell-derived vascular smooth muscle subtypes reveal embryological origin-dependent disease susceptibility

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Abstract

Purpose

Heterogeneity is a hallmark of vascular smooth muscle cell (SMC) development, physiology and pathology. Interestingly, lineage tracking studies have shown that SMCs in different vessels and vascular territories have distinct embryological origins. The diversity of SMC origins may in part influence the development of vascular diseases. Differentiation of human pluripotent stem cells (hPSCs) into SMCs is possible but the derivation of embryological origin-specific SMC subtypes remains elusive.

Methods

In this study, we have generated origin-specific SMC subtypes from hPSCs using chemically defined conditions free of animal-derived components. A stepwise differentiation protocol was established according to developmental principles. HPSCs were initially induced to form three intermediate lineages, namely the lateral plate mesoderm, paraxial mesoderm and neuroectoderm, then followed by SMC differentiation of these intermediate populations. We used this in vitro system to predict the responses of different SMC subtypes to an inflammatory mediator, and validated the results using rat aortic SMCs of distinct origins.

Results

The SMC subtypes were derived with high efficiency (>80% MYH11 + and ACTA2 + ). Their functional properties were confirmed by calcium signalling and contractile ability in response to vasoconstrictors. They also invested perivascular regions in vivo, reminiscent of their biological niche in blood vessel formation. Furthermore, the derived SMC subtypes recapitulated the unique proliferative and secretory responses to cytokines previously documented in studies using aortic SMCs of distinct origins. Importantly, our finding reveals that the SMC subtypes exhibit differential proteolytic ability upon inflammatory activation, suggesting an origin-dependent susceptibility to pathological vascular remodelling.

Conclusions

Collectively, this work will have broad applications in vascular SMC disease modelling and in bio-engineered vascular grafts for regenerative medicine.

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