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Evolving extracellular matrices evoke signaling pathways that govern cardiomyocyte maturation

Award Number: R01HL180774
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/06/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Evolving extracellular matrices evoke signaling pathways that govern cardiomyocyte maturation - PROJECT SUMMARY Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) hold promise for cardiac disease modeling, drug testing, medical device testing, and regenerative medicine. However, their limited functional maturity in vitro remains a major barrier to widespread application. We recognize the crucial role of distinct and specific mechanical loads in cardiac morphogenesis and seek to co-opt signals downstream of mechanical engagement to drive maturation of hPSC-CMs. In particular, we seek to establish a causal link between mechanical stimulation and hPSC-CM maturation by focusing on the contribution of extracellular matrix (ECM) proteins, the primary family of proteins that mediate and confer mechanical force to the cell. Our lab has developed a novel human, chambered cardiac muscle pump model (hChaMP) capable of simulating both stretch and shear forces akin to a native cardiac cycle. We have begun to incorporate epicardial-derived cells (namely cardiac fibroblasts, CF) into the hChaMP (termed epi-ChaMP via a previously funded R01), as CFs remodel the ECM in response to mechanical stimulation. We also have expertise in cutting-edge computational modeling approaches to refine mechanical stimulation parameters and in fully characterizing the composition of the ECM following mechanical stimulation. Given our unique ecosystem, we can test the hypothesis that CM maturation is augmented in the epi-hChaMP via potent signaling of an evolving ECM deposited by CF in response to dynamic volumetric pressure. We will do so by developing and validating a computational fluid-structure interaction model that accurately replicates native cardiac pressure profiles in the epi-hChaMP (Aim 1), testing the mechanistic role of ECM deposition and remodeling by FBs in driving cardiomyocyte and tissue-scale maturation under physiologic loading (Aim 2), and by applying a statistical optimization framework to define dynamic volumetric loading regimes that maximize functional maturation of epi-hChaMP tissues. The proposal directly addresses reviewer feedback through clearer model differentiation, enhanced methodological descriptions, and inclusion of a non- cardiac fibroblast control. Completion of this project will reveal unappreciated contributions of ECM to CM maturation (Basic Science Innovation) and will yield a robust in vitro human muscle pump with unprecedented physiological relevance (Applied Science Innovation).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $543,957 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cardiovascular Diseases Research	000	1	7/3/2026	NEW	$543,957
														Subtotal = $543,957

Grand Total All Awards = $543,957

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Evolving extracellular matrices evoke signaling pathways that govern cardiomyocyte maturation

Award Number: R01HL180774

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/06/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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