Investigating the interplay between viscoelastic and growth factor sequestering cues in iPSC-CMs

About This Grant

Project Summary Heart failure (HF) is the leading cause of death; resulting in a variety of physical and biochemical changes within the heart. Better understanding how physical and biochemical cues influence CMs, can help in the development of better HF therapies. We aim to investigate how viscoelasticity and growth factor (GF) sequestering influence healthy and diseased human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) using engineered biomaterials. We hypothesize that mimicking cardiac viscoelasticity will increase maturity of iPSC-CMs and enhance GF signaling. We further hypothesize that iPSC-CMs will sense viscoelasticity through TRVP4 channel protein and ERK pathway activation. We measured human tissue viscoelasticity via stress relaxation testing, and found that slower relaxing tissues exhibited higher fibrosis, indicated by increased picrosirius red staining. We then engineered viscoelastic hydrogels to mimic cardiac stress relaxation, elastic hydrogels that exhibited no relaxation, and relaxation speeds in between. We found that iPSC-CM on viscoelastic alginate were more cylindrical in morphology, exhibiting a significant increase of 0.1 in sphericity. This morphology is similar to mature cardiomyocytes in the heart. Additionally, the cells on viscoelastic gels beat at higher speed (0.16 µm/s increase) than those on elastic hydrogels. These data indicate that iPSC-CMs exhibit a more mature morphology and function on viscoelastic hydrogels. We further investigated the effect of cell secreted GFs. We found that mesenchymal stromal cell (MSC) conditioned media, or the MSC secretome, which is known to contain high concentrations of growth factors including IL-8, FGF-6 and IGF-1, resulted in an increase of 0.8 µm/s in contraction velocity, and a trend in increasing contraction displacement. To deliver GFs, we engineered a viscoelastic hydrogel capable of sequestering growth factors via sulfate group modification. Alginate sulfation resulted in increased regeneration in a rat soleus crush injury. We hypothesize that the combined influence of our material to sequestered growth factors and exhibit viscoelasticity will lead to growth factor receptor clustering, increased growth factor signaling, and drive disease and maturity in iPSC-CMs that are healthy or have point mutations linked to hypertrophic or dilated cardiomyopathy.