NIH grant: Investigating the interplay between viscoelastic and growth factor sequestering cues in iPSC-CMs (1K99HL181293-01)

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NIH grant 1K99HL181293-01: Investigating the interplay between viscoelastic and growth factor sequestering cues in iPSC-CMs
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: Marissa Ann Gionet-Gonzales. Award: $130955.
Start: 2026-08-15T00:00:00.
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.

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