Cardiomyopathy is a debilitating complication of type-2 diabetes that predisposes patients towards increased risk of heart failure due to the disorder of the heart muscle that compromises its ability to circulate blood through the body and maintain a normal electrical rhythm, effectively. Despite its immense clinical impact, there is a lack of targeted treatment regimen for diabetic cardiomyopathy due to the intricate pathophysiology of the condition that makes drug screening problematic. Current therapeutic strategies developed on results originating from animal experiments, do not transform well to humans in vivo. Hence, studies should be based on laboratory engineered ?cardiac tissue? models biofabricated from human induced pluripotent stem cell (iPSC) differentiated cardiomyocytes that are essential to preserve in vivo physiology, and mimic disease progression. But, there is lack of such preclinical human tissue based models to establish a screening platform for the identification of potential therapeutics that will preserve cardiac cell physiology and function when exposed to diabetic stress. To address this need, we will develop a unique ?cardiac organoid? system that will be assembled using bioprinting of human cardiac cells, including cardiomyocytes (CM), fibroblasts (CF) and endothelial cells (EC), specifically sourced from diabetic donors. Bioprinting will enable the creation of an environment to nurture the development of physiologically relevant cues, resulting in a functional tissue construct with appropriate consistency. Cells derived from diabetic donors will retain their disease phenotype or `metabolic memory', which will be valuable to observe and study their structural and functional changes when exposed to hyperglycemic environments. Human iPSC sourced from type-2 diabetic donors will be custom differentiated into CM and mixed with CF and EC for bioprinting of ?cardiac organoids? that will be exposed to normal and hyperglycemic conditions to delineate between the effects caused by metabolic memory, hyperglycemia and a combination of both. Results will help in understanding the role of the signaling pathways involved in disease progression, which may guide and inform us towards designing an enhanced therapeutic approach for rescuing cardiac tissues from hyperglycemic insult. The successful completion of these studies will lead to establishment of a patient-specific iPSC model of human type-2- diabetes, and reveal the power of this approach for discovery of new therapeutic strategies for a complex metabolic condition with rising clinical significance.
Diabetes is an important public health problem and type-2 diabetes is the most common form of diabetes affecting up to 29.1 million people in the United States that negatively affects the quality of life of the affected individuals and additionally creates an enormous socio-economic burden. Diabetic cardiomyopathy refers to diabetes-associated pathophysiological changes in the structure and function of the myocardium (heart wall) that leads to the development of left ventricular hypertrophy, thereby increasing the susceptibility of the heart to ischemic injury and the overall likelihood of developing heart failure. The proposed project will develop and validate a 3D bioprinted ?cardiac organoid? model, using cardiac cells differentiated from human induced pluripotent stem cells from Type-2 diabetic patients, to replenish the inadequacies of the use of current cellular and animal models and to define the pathways leading to disease progression and reveal mechanisms to prevent it.