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Leveraging the HIF-alpha pathway to improve the engraftment and therapeutic efficacy of human nanowired cardiac organoids

Award Number: F31HL156541
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/16/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Leveraging the HIF-alpha pathway to improve the engraftment and therapeutic efficacy of human nanowired cardiac organoids - PROJECT SUMMARY: Heart disease accounts for nearly 1 in 4 deaths in the United States each year, highlighting the urgent need for therapies that can repair damaged hearts. Human induced pluripotent stem cell- derived cardiomyocytes (hiPSC-CMs) have emerged as a powerful cell source for cardiac repair, but their potential has been limited by poor survival and engraftment after injection. To address these challenges, our lab has pioneered the development of nanowired human cardiac organoids composed of electrically conductive silicon nanowires (e-SiNWs), hiPSC-CMs, and supporting cells. Our preliminary in vivo studies showed that nanowired cardiac organoids successfully engraft in ischemia/reperfusion (I/R) injured rat hearts and develop more organized contractile structures compared to non-nanowired cardiac organoids. Despite this progress, less than half (~30%) of injected organoids remained engrafted in infarcted hearts 7 days post-transplantation, which can be attributed to inadequate prevascularization and hypoxic/ischemic preconditioning of the organoids in vitro. To address this, we have explored pharmacological stabilization of HIF-a as a strategy to promote prevascularization and ischemic tolerance within the organoids. My preliminary in vitro data showed that treatment with Molidustat, a prolyl hydroxylase domain (PHD) inhibitor, significantly improved endothelial network and lumen formation (i.e., ~150% increase of CD31+ coverage) within the cardiac organoids. While these results are promising, further investigation is necessary to reveal phenotypic and genotypic changes in HIF-α stabilized cardiac organoids and how they correlate with transplantation efficiency. The goals of this proposal are to determine the effects of HIF-α stabilization on vascular maturation, cardiac function, cell and tissue-level metabolism, and transcriptomic changes in cardiac organoids (Aim 1), and to demonstrate therapeutic efficacy of HIF-α stabilized organoids in a rat model of myocardial I/R injury (Aim 2). The central hypothesis of this proposal is that stabilization of HIF-α signaling in cardiac organoids improves the survival and engraftment of hiPSC-CMs in infarcted myocardium and enhances their capacity to promote cardiac functional recovery in injured hearts. The proposal is innovative in that, for the first time, we will investigate how hypoxia mimetic agents precondition human engineered cardiac tissue to enhance the transplantation efficiency of hiPSC-CMs. My long-term goal is to develop clinically applicable cardiac regenerative therapies to treat cardiovascular diseases. Accordingly, we will pursue the following specific aims: 1) Determine how pharmacological HIF-α stabilization reprograms and preconditions human cardiac organoids for ischemic protection, and 2) Determine the effects of HIF-α stabilization on graft-host anastomosis, long-term engraftment, and therapeutic efficacy of nanowired human cardiac organoids in injured hearts. This research will inform emergent clinical applications of hypoxia mimetic agents to treat cardiovascular disease and will help advance our human cardiac organoid platform towards large animal studies to accelerate their clinical translation.


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: 2025 ( Subtotal = $0 )
2025	2023	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Cardiovascular Diseases Research	000	3	5/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,351 )
2024	2023	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Cardiovascular Diseases Research	001	3	5/4/2024	NON-COMPETING CONTINUATION	-$7,902
2024	2023	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Cardiovascular Diseases Research	000	3	11/21/2023	NON-COMPETING CONTINUATION	$9,253
														Subtotal = $1,351

Issue Date FY: 2023 ( Subtotal = $24,908 )
2023	2023	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Cardiovascular Diseases Research	000	3	7/18/2023	NON-COMPETING CONTINUATION	$24,908
														Subtotal = $24,908

Issue Date FY: 2022 ( Subtotal = $40,005 )
2022	2022	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Cardiovascular Diseases Research	000	2	7/3/2022	NON-COMPETING CONTINUATION	$40,005
														Subtotal = $40,005

Issue Date FY: 2021 ( Subtotal = $39,289 )
2021	2021	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Cardiovascular Diseases Research	001	1	3/30/2021	NEW	$0
2021	2021	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Cardiovascular Diseases Research	000	1	3/30/2021	NEW	$39,289
														Subtotal = $39,289

Grand Total All Awards = $105,553

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Leveraging the HIF-alpha pathway to improve the engraftment and therapeutic efficacy of human nanowired cardiac organoids

Award Number: F31HL156541

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/16/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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