Mission
The Sinha Lab’s overall aim is to develop new treatments for cardiovascular diseases, using our expertise in cardiovascular development,
regeneration and disease modelling.
What we do
Our work combines the fields of stem cell biology and cardiovascular biology to provide new insights into human cardiovascular development and novel treatments for vascular diseases. Underpinning this work is our development of lineage-specific differentiation protocols to obtain various cardiovascular cell types from human pluripotent stem cells.
We have pioneered the generation of embryonic lineage-specific vascular smooth muscle cells (SMC) from human embryonic stem cells (hESC) and induced pluripotent stem cells, using chemically defined conditions. We have used this system to model genetically triggered
aortopathies, such as Marfan and Loeys-Dietz syndromes. These "disease-in-a-dish" models are being used to understand the pathophysiology of these conditions and to screen for new treatments.
Additionally we are testing the regenerative potential of hESC-derived epicardium and other cardiovascular cell types for heart repair after myocardial infarction, either through direct injection or in the form of an in vitro generated myocardial "patch".
Epicardial biology & cardial regeneration
Heart failure is most commonly due to the irreversible loss of heart muscle. Patients have only a 1 in 2 chance of surviving more than 5 years and suffer greatly from their weak heart. We focus on identifying cellular and/or drug therapies using human pluripotent stem cells (hPSC). We have two main research arms:
1) Understanding the regulation of the epicardium at the single cell level
During development, the epicardium, the outermost heart cell layer, stimulates proliferation and maturation of cardiomyocytes. In a rat model of myocardial injury, we demonstrated that injections of hPSC-derived epicardium improve engraftment and beneficial effects of hPSC-derived cardiomyocytes. Therefore, we investigate the cross-talk between hPSC-epicardium, hPSC-cardiomyocytes and host tissues. In parallel, we study the function and regulation of the hPSC-epicardial cell heterogeneity in order to produce efficient epicardium for cell therapy.
2) Designing patches to deliver suitable hPSC-derived cells to the injured heart
We are developing a multicellular collagen-based patch to deliver cardiomyocytes and other epicardium to the damaged heart. We focus on the cell/material interface to develop a material with appropriate biochemical, mechanical, and architectural properties to achieve optimal engraftment with the native tissue that will result in heart function improvement.
modelling genetic disorders
using patient-derived stem cells
The aorta is the major vessel which carries blood from the heart to the rest of the body. In individuals with diseases such as Marfan, Loeys-Dietz and vascular Ehlers-Danlos syndromes, mutations can lead to the enlargement and rupture of the aorta – a life-threatening event.
A major focal point for our group is to model these genetic disorders using inducible pluripotent stem cells (iPSCs). These stem cells can be derived from patients, which in turn can be differentiated into a variety of cells, including lineage-specific vascular smooth muscle cells (SMCs) – major constituents of the aorta. We and others have hypothesised that the development origin of SMCs has an impact on aortic disease risk.
Through our collaborations with various clinical scientists, we have a collection of patient-derived iPSCs, and developed a variety of methods to phenotype and characterise SMCs. Using these resources, we aim to tease out causal disease mechanisms, and identify novel treatments for these disorders.
Stem cell medicine is poised to transform the treatment of
numerous intractable cardiovascular diseases.
How we work
We combine state of the art cell biology, CRISPR-mediated genetic modification, single cell analyses, complex in vivo models and bioinformatics to define disease mechanisms and uncover new treatment strategies. This work has the potential to transform the treatment of numerous intractable cardiovascular diseases.