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The Role of Cardiomyogenic Lineage Commitment in Cardiac Mesenchymal Cell-Mediated Extracellular Vesicle Signaling and Cardiac Repair

Award Number: R01HL141081
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Clinical trials for cell therapy reveal only modest benefits on cardiac function in heart failure (HF) patients – leaving the future of this therapeutic modality uncertain. Despite years of research on the topic, the cell therapy field remains engrossed in controversies regarding the mechanism(s) of action of donor cells and the cell type best suited to promote cardiac repair. Two competing hypotheses have been forwarded to explain the mechanisms underlying cell therapy-mediated cardiac repair, namely donor cell direct differentiation (contributing to new cardiac parenchyma) and paracrine signaling (promotion of endogenous repair mechanisms through cytokine and/or extracellular vesicle (EV) secretion). Given that donor cell populations exhibit poor rates of retention and limited long-term persistence after delivery in HF models, paracrine signaling is viewed as a major mechanism of cell-mediated cardiac repair. However, there is also evidence implicating a link between therapeutic efficacy and donor cell cardiovascular fate decisions; although the mechanisms remain unknown. It is known that different cell types possess distinct trophic factor secretion profiles and paracrine signaling activities. Thus, we posit that cardiovascular cell lineage commitment-dependent variations in paracrine signaling are likely to have a significant impact on donor cell reparative capacity in cell-mediated cardiac repair. Further, as EVs have been identified as important mediators of progenitor cell-induced cardiac regeneration, we hypothesize that donor cell cardiomyogenic lineage commitment regulates the expression and synthesis of EV-resident cardiotrophic factors, which mediate cardiac repair. To test this hypothesis, we will use genetic and pharmacologic approaches for enhancing cardiogenic factor expression to assess the effects of cardiomyogenic lineage commitment on the reparative capacity of cardiac mesenchymal cells (CMCs) and lineage-dependent adaptations in CMC EV signaling. Aim 1 will interrogate the impact of genetic- and pharmacologic-mediated induction of cardiogenic factor expression on CMC cardiovascular lineage commitment and EV paracrine signaling. Aim 2 will assess the effect of cardiomyogenic lineage commitment on the reparative capacity of CMCs following administration in a chronic infarct model. Aim 3 will evaluate the consequences of EV administration, derived from naïve and cardiomyogenic lineage-committed CMCs, on cardiac repair. The results of this project will establish an unidentified link between progenitor cell cardiovascular lineage commitment and modifications in EV secretion/paracrine signaling, as well as elucidate novel targets and pathways that may be exploited to enhance the efficacy of cell therapy.


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: 2022 ( Subtotal = $385,000 )
2022	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cardiovascular Diseases Research	001	5	6/29/2022	NON-COMPETING CONTINUATION	$38,500
2022	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cardiovascular Diseases Research	000	5	2/22/2022	NON-COMPETING CONTINUATION	$346,500
														Subtotal = $385,000

Issue Date FY: 2021 ( Subtotal = $385,000 )
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	2/19/2021	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2020 ( Subtotal = $385,000 )
2020	2020	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	2/1/2020	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2019 ( Subtotal = $385,000 )
2019	2019	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cardiovascular Diseases Research	000	2	2/12/2019	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2018 ( Subtotal = $385,000 )
2018	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	3/14/2018	NEW	$385,000
														Subtotal = $385,000

Grand Total All Awards = $1,925,000

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The Role of Cardiomyogenic Lineage Commitment in Cardiac Mesenchymal Cell-Mediated Extracellular Vesicle Signaling and Cardiac Repair

Award Number: R01HL141081

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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