Dr. Sanjay Sinha
Regulation of Vascular Smooth Muscle Cell Development and Disease
Department of Medicine, University of Cambridge, Sinha Group Members
Post-docs: Dr Alex Granata; Dr Felipe Serrrano; Dr Laure Gambardella
PhD Students: Ms Dharini Iyer; Mr Will Bernard; Dr Johannes Bargehr; Ms Loukia Yiangou
Our work focuses on the mechanisms underlying vascular smooth muscle cell (SMC) development and their relevance to cardiovascular disease and/or new vessel growth. We have developed in vitro systems using murine and human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells in which pure populations of mature contractile vascular SMCs may be generated.
These and other model systems are currently being used to investigate how SMCs and their precursors initially develop from multipotent cells and how perturbation of developmental mechanisms may contribute to disease. The group's focus is on the role of the myogenic transcription factor, myocardin and transforming growth factor (TGF)-β signalling as well as other transcription factors and signalling cascades that interact with these pathways.
Further studies are underway to establish in vitro models of vascular genetic diseases such as Marfans using patient-derived iPS cells. Finally, we are investigating whether cardiovascular progenitor cells derived from ES or iPS cells can revascularise ischaemic tissues in vivo and whether this process can be tracked non-invasively using state-of-the-art genetic reporters.
Fig. 1: Vascular smooth muscle cells: immunofluorescent staining for vinculin (red), -actin (green) and DAPI (blue).
Fig. 2: Smooth muscle cells generated by directed differentiation of human embryonic stem cells under chemically defined conditions.
Fig. 3: Confocal imaging of mouse carotid injury and neointimal. Smooth muscle -actin (green), DAPI (blue).
Fig. 4: Schematic diagram of smooth muscle cell development from embryological and embryonic stem cell differentiation studies. Derivatives of cardiac mesoderm, haemagioblast, somitic mesoderm and neural crest are indicated by red, blue, purple and green arrows respectively. Dotted arrows denote speculative differentiation pathways where there is still insufficient evidence at present. (Reproduced from Cheung & Sinha. J Mol Cell Cardiol 2011).
Plain EnglishWe are investigating how cells in the blood vessel wall form and what goes wrong in cardiovascular diseases. We use stem cell based models to analyse the mechanisms involved in vascular development and disease, and are investigating whether we can use stem cells to grow new blood vessels. We also use patient-derived skin samples to generate stem cells and are using this approach to model genetic diseases such as Marfans.
Ackers-Johnson M, Talasila A, Long X, Bot I, Morrell NW, Bennett MR, Miano JM and Sinha S. Myocardin Regulates Vascular Smooth Muscle Cell Inflammatory Activation and Disease. ATVB (in press).
Granata A, Bernard WG, Zhao N, McCafferty J, Lilly B and Sinha S. Temporal- and embryonic lineage-dependent regulation of human vascular SMC development by Notch3. Stem Cells & Dev (in press).
Cheung C, Bernardo AS, Pedersen RA and Sinha S. Directed differentiation of embryonic origin-specific vascular smooth muscle subtypes from human pluripotent stem cells. Nature Protocols 2014;9:929-38.
Talasila A, Yu H, Ackers-Johnson M, Bot M, van Berkel T, Bennett M, Bot I, Sinha S. Myocardin Regulates Vascular Response to Injury Through miR-24/-29a and Platelet-Derived Growth Factor Receptor β. ATVB 2013;33:2355-65.
- Raphel L, Talasila A, Cheung C and Sinha S. Myocardin overexpression is sufficient for promoting the development of a mature SMC-like phenotype from human embryonic stem cells. PLoSOne 2012;7(8):e44052.
- Cheung C, Bernardo AS, Trotter MW, Pedersen RA, Sinha S. Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility. Nature Biotechnol. 2012;30:165-73.
- Cheung C, Sinha S. Human embryonic stem cell-derived vascular smooth muscle cells in therapeutic neovascularisation. J Mol Cell Cardiol. 2011 Nov;51(5):651-64.