Dr. Sanjay Sinha
Regulation of Vascular Smooth Muscle Cell Development and Disease
Department of Medicine, University of Cambridge, Sinha Group Members
Post-docs: Dr Amar Talasila; Dr Alex Granata; Dr Lucy Low
PhD Students: Ms Dharini Iyer; Mr Will Bernard
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.
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. Arterioscler Thromb Vasc Biol. 2013 Jul 3. [Epub ahead of print] PubMed PMID: 23825366.
Trigueros-Motos L, Cheung C, Fernandez O, Sanchez-Cabo F, Dopazo A, Sinha S, Andres V. Embryological-origin-dependent differences in Hox expression in adult aorta and role in regional phenotypic variability. ATVB 2013;33:1248-56.
- Sinha S. Vascular disease in a dish: All the right ingredients? Circulation 2012;126(14):1676-7 (editorial).
- 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. Nat 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.
- Sinha S, Hoofnagle MH and Owens GK. Derivation of Contractile SMCs from ES Cells. (Book Chapter) in Stem Cells in Regenerative Medicine. Eds. Audet J and Stanford WL, Humana Press 2009 (ISBN: 978-1-58829-797-6).
- Sinha S, Wamhoff BR, Hoofnagle MH, Thomas J, Neppl RL, Deering T, Helmke BP, Bowles DK, Somlyo AV, Owens GK. Assessment of Contractility of Purified SMCs Derived from ESCs. Stem Cells 2006;24:1678-88.
- Pipes GC, Sinha S, Qi X, Zhu CH, Gallardo TD, Shelton J, Creemers EE, Sutherland L, Richardson JA, Garry DJ, Wright WE, Owens GK, Olson EN. Stem cells and their derivatives can bypass the requirement of myocardin for smooth muscle gene expression. Dev Biol 2005;288:502-13.
- Sinha S, Hoofnagle MH, Kingston PA and Owens GK. TGF- signaling contributes to the development of SMC from embryonic stem cells. AJPhysiol – Cell Physiol 2004;287:C1560-C1568.