Development and characterization of human cardiac microtissues for a microphysiological multi-organ system

Abstract

Better research models are needed to overcome the lack of translatability from preclinical studies into the clinical phase and to increase the success rates in drug development. Microphysiological systems (MPS) are potential in vitro models that can recapitulate physiologically relevant organ-level functions and interactions. These systems are prospective especially for multi-organ disease modeling. Three-dimensional human cardiac microtissues combined with human liver microtissues and pancreatic islets in a microfluidic platform could be used to model cardiometabolic diseases. To facilitate the development of the model, this master’s thesis aimed to design cardiac microtissues with different compositions and characterize them in a healthy and diseased environment in static culture conditions. Long-term exposure to high glucose levels was used to induce insulin resistance in the cardiac microtissues.

The cardiac microtissues were generated from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and human cardiac fibroblasts (CFs), or hiPSC-CMs, CFs, and human microvascular endothelial cells. A robust method for self-assembly of cardiac cells was utilized to create cardiac microtissues that remained viable in long-term culture for 25 days in an optimized co-culture medium. The microtissues demonstrated spontaneous beating, expression of cardiac genes and proteins, and metabolic activity. However, hyperglycemic culture conditions did not induce significant differences in either of the microtissue compositions in comparison to normoglycemia. Further improvement of the maturity of the hiPSC-CMs in the future could make the microtissues more suited for use in the multi-organ MPS. The model represents new possibilities to elucidate cardiometabolic disease mechanisms and to investigate the effects of novel pharmaceuticals or identify new drug targets.