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Using a Cardiac Microtissue System to Evaluate and Replicate Clinical Therapy Responses using Patient Cell-Derived Exosomes

Award Number: R21HL144244
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2022

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Using a Cardiac Microtissue System to Evaluate and Replicate Clinical Therapy Responses using Patient Cell-Derived Exosomes - Summary Cell therapy for post-infarct cardiac repair has shown limited and mixed results, most likely due to patients' individual cell characteristics or to the infarct environment experienced by the transplanted cells. Identifying the potential molecular and cellular components that contribute to patient-specific responses and ways to minimize the environmental stress on transplanted cells may lead to the development of new strategies for cardiac repair. Additionally, numerous studies have shown that the effects of at least some cell-based therapies can be attributed primarily to secreted cellular factors that are packaged inside exosomes. These exosomes are considered critical mediators of intercellular information and play a direct role in injury-induced tissue repair processes in multiple physiological systems. Our group is particularly interested in the characterization of exosomes from cardiovascular disease patients who improved in a cell therapy study and in the utilization of these exosome cargos in the development of tissue-engineered cardiac patches for optimal functional myocardial repair. We are also interested in using our in vitro cardiac microtissue system as a testbed to evaluate patient cell-exosome interactions and associations with clinical trial responses. We will derive bone marrow mesenchymal stem cells (MSCs), MSC exosomes, and human induced pluripotent stem cells (hiPSCs) from healthy individuals and patients in the Cardiovascular Cell Therapy Research Network (CCTRN)-FOCUS clinical trial categorized as improvers at 6 months, [i.e., improved left ventricular ejection fraction, end-systolic volume and maximal oxygen consumption], or as non-improvers (declined in the 3 outcomes). Cardiac microtissues, containing cardiac cells derived from healthy control hiPSCs, cultured in native and infarct-like conditions will be treated with improvers' exosomes. Changes in microtissue function, cardiomyocyte maturation, cell survival and proliferation will be compared among improvers, placebo and non-improvers exosomes. Meanwhile, high throughput assays will be used to identify differences in the exosome cargos of the top 3 clinical improvers and non-improvers and correlated with in vitro responses. We expect that improver's exosomes will contain potent beneficial factors to enhance cell and microtissue maturation and function under infarct-like stress. Next, patient- specific microtissues containing hiPSC-derived cardiac cells generated from bone marrow of the top 3 improvers and non-improvers will be treated with autologous or allogenic (improver, non-improver or, healthy) exosomes under infarct-like conditions. By exposing patient-specific “infarcted” cardiac microtissues to autologous or allogeneic exosomes, we can evaluate patient-specific cell-exosome interactions in a controlled in vitro setting that mimics the clinical condition. Ultimately, these studies will provide new insights into cell-exosome interactions in an infarct as well as their relative potency and association with clinical trial responses, thus providing an innovative new approach to developing cardiac patches with superior regenerative properties.


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: 2023 ( Subtotal = $0 )
2023	2020	TEXAS HEART INSTITUTE	6770 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	2	11/10/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $203,750 )
2020	2020	TEXAS HEART INSTITUTE	6770 BERTNER AVE MC3 117	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	2	6/4/2020	NON-COMPETING CONTINUATION	$203,750
														Subtotal = $203,750

Issue Date FY: 2019 ( Subtotal = $244,500 )
2019	2019	TEXAS HEART INSTITUTE	6770 BERTNER AVE MC3 117	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	1	5/1/2019	NEW	$244,500
														Subtotal = $244,500

Grand Total All Awards = $448,250

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Using a Cardiac Microtissue System to Evaluate and Replicate Clinical Therapy Responses using Patient Cell-Derived Exosomes

Award Number: R21HL144244

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2022

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