Physiology Seminar: Disease-in-a-dish modelling using iPSCs

To personalize medicine, we must be able to model disease on a patient-specific basis. We have enrolled >200 patients diagnosed with dilated cardiomyopathy (DCM) of diverse etiologies and at various stages of disease progression who currently take a wide array of standard heart failure medications. Using peripheral blood mononuclear cells (PBMCs), we generate induced pluripotent stem cell (iPSC) lines and derive cardiovascular-relevant cells from them. Experimental evidence suggests that cellular signalling networks or signalling “hubs” that control cell function and fate are cell- and tissue-type specific. Each signalling “hub” is also influenced by a patient’s personalized genetic profile. Spatiotemporal aspects of signalling are thus determined by how these signalling hubs are altered in disease. Considering that DCM is largely characterized as ventricular dilation with systolic dysfunction, we anticipate that the underlying pathophysiological mechanisms leading to this state are not unique in each patient but recur in several patients. We believe that the systematic mapping of signalling outcomes in healthy versus DCM patient-derived iPSC-CMs will help identify of a core number of deregulated pathways and will facilitate our understanding of the influence of cell context on disease evolution. Our iPSC-based platforms give us the means to study these events in multiple cell types relevant to the cardiovascular system in health and disease right down to the single cell level using resonance energy transfer-based biosensors. Our working hypothesis is that the molecular underpinnings of dilated cardiomyopathy can be clustered into a finite number of phenotypic and signalling subtypes. Our strategy is to leverage patient-derived cardiomyocytes to understand how to approach survival and function of these cells in response to currently used therapies.

This seminar will take place both in-person and online. Details in attached poster