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Cardiac Mesenchymal Stem Cells and Myocardial Fibrosis: Role of Platelet Derived Growth Factor Receptor Signaling

Award Number: R01HL137046
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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View Award Abstract

The central objective of this project is to evaluate how PDGF/PDGFR signaling, inflammatory signaling responses modulate the functional outcomes of resident cardiac mesenchymal stem cells (cMSCs) in failing hearts. Ischemic myocardial injury initiates a cascade of two self-amplifying events that intend to promote tissue repair. The initial events are mediated by the concerted action of infiltrating pro-inflammatory immune cells. Although, reparative initially, prolonged infiltration of activated monocyte/macrophage populations within the injured myocardium further exaggerate inflammatory responses and delay the manifestation of wound healing. Chronically these processes induce extracellular-matrix (ECM) remodeling by activating proliferation of collagen producing myofibroblasts. Although multipotent in nature, MSCs often differentiate into myofibroblasts in vivo in a number of pathologies, suggesting that tissue microenvironment influences are paramount in guiding MSC fate. The precise role of cMSCs in the etiology and progression of ischemic HF is unknown. More importantly, factors regulating cMSC function and differentiation in the failing hearts are not clearly understood. During both acute myocardial infarction (MI) and chronic heart failure (HF), there is increased abundance of pro-inflammatory cardiac macrophages. More importantly, macrophage expansion in chronic HF is accompanied by sustained activation of myofibroblasts that promote cardiac fibrosis. Platelet derived growth factor (PDGF) is a well-recognized mediator of tissue fibrosis and angiogenesis. Like macrophages, MSCs secrete PDGF and express PDGF receptors (PDGFRs), resulting in a PDGF-rich and PDGF-responsive microenvironment in the failing heart. Importantly, however, whether cMSC-localized PDGF signaling, in response to such factors as chronic inflammation and macrophage infiltration, regulates cMSC fate and responses in HF is unknown. In this proposal we will test the hypothesis that augmented cMSC-localized PDGF signaling preferentially channels cMSCs toward a myofibroblast fate (and away from an endothelial cell fate) in the failing heart, thereby augmenting fibrosis and reducing angiogenesis and repair. Three aims are being proposed. Aim 1 will define the role of PDGFR signaling and macrophage interactions on the in vitro differentiation fate of cMSCs derived from normal and failing hearts. Aim 2 will determine the in vivo role of cMSC-localized PDGFRs on LV remodeling and function during ischemic HF. These studies will use transgenic mice with inducible and cMSC-specific ablation of PDGFRs. Aim 3 will establish the therapeutic efficacy of cMSC cell therapy after reperfused-MI when used in combination with PDGFR inhibition in vivo. These studies will use the clinically approved PDGFR inhibitor imatinib mesylate (Gleevac®). Collectively the proposed studies will answer critical questions relevant to HF related to both the pathophysiological import of altered cMSC fate in myocardial fibrosis, and the potential therapeutic use of cMSCs and pharmacological PDGFR inhibition to induce tissue repair. !


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: 2024 ( Subtotal = $0 )
2024	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cardiovascular Diseases Research	000	5	4/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	003	5	8/12/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$47,062
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	001	5	6/28/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$111,515
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	6/27/2022	NON-COMPETING CONTINUATION	-$111,515
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	002	4	8/12/2022	NON-COMPETING CONTINUATION	-$47,062
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $371,250 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	4	5/18/2021	NON-COMPETING CONTINUATION	$37,125
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	12/9/2020	NON-COMPETING CONTINUATION	$334,125
														Subtotal = $371,250

Issue Date FY: 2020 ( Subtotal = $371,250 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	3	1/25/2020	NON-COMPETING CONTINUATION	$18,563
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	11/27/2019	NON-COMPETING CONTINUATION	$352,687
														Subtotal = $371,250

Issue Date FY: 2019 ( Subtotal = $371,250 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	2	12/14/2018	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2018 ( Subtotal = $371,250 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	12/6/2017	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $1,485,000

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Cardiac Mesenchymal Stem Cells and Myocardial Fibrosis: Role of Platelet Derived Growth Factor Receptor Signaling

Award Number: R01HL137046

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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