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

心脏间充质干细胞和心肌纤维化：血小板衍生生长因子受体信号传导的作用

• 批准号: 10619971
• 负责人: Tariq Hamid
• 金额: $ 11.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-06 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10619971
• 关键词: Cardiac; Mesenchymal; Stem; Cells; Myocardial

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. !

该项目的中心目标是评估PDGF/PDGFR信号，炎症信号

项目成果

Echocardiographic, Biochemical, and Electrocardiographic Correlates Associated With Progressive Pulmonary Arterial Hypertension.

• DOI: 10.3389/fcvm.2021.705666
• 发表时间: 2021
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Zaky A;Zafar I;Masjoan-Juncos JX;Husain M;Mariappan N;Morgan CJ;Hamid T;Frölich MA;Ahmad S;Ahmad A
• 通讯作者: Ahmad A

Cardiac Mesenchymal Stem Cells Promote Fibrosis and Remodeling in Heart Failure: Role of PDGF Signaling.

• DOI: 10.1016/j.jacbts.2022.01.004
• 发表时间: 2022-05
• 期刊: JACC-BASIC TO TRANSLATIONAL SCIENCE
• 影响因子: 9.7
• 作者: Hamid, Tariq;Xu, Yuanyuan;Ismahil, Mohamed Ameen;Rokosh, Gregg;Jinno, Miki;Zhou, Guihua;Wang, Qiongxin;Prabhu, Sumanth D.
• 通讯作者: Prabhu, Sumanth D.