Follistatin-like 1 protects mesenchymal stem cells from hypoxic damage and enhances their therapeutic efficacy in a mouse myocardial infarction model

• Published in: Stem cell research & therapy Vol. 10; no. 1; p. 17
• Main Authors: Shen, Han, Cui, Guanghao, Li, Yanqiong, Ye, Wenxue, Sun, Yimin, Zhang, Zihan, Li, Jingjing, Xu, Guiying, Zeng, Xiansheng, Zhang, Yanxia, Zhang, Wencheng, Huang, Zan, Chen, Weiqian, Shen, Zhenya
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.01.2019; BioMed Central; BMC
• Subjects: Animals; Anoxemia; Apoptosis; Apoptosis - genetics; Bone marrow; Cardiac function; Cardiomyocytes; Care and treatment; Cell culture; Cell death; Cell growth; Cell Hypoxia - genetics; Cell Proliferation - genetics; Cell Survival; Coronary artery; Disease Models, Animal; EF hand proteins; Flow cytometry; Follistatin; Follistatin-like 1; Follistatin-Related Proteins - genetics; Genetically modified organisms; Heart; Heart attack; Heart attacks; Heart cells; Humans; Hypoxia; Inflammation; Ischemia; Lentivirus - genetics; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mesenchyme; Mice; Myocardial infarction; Myocardial Infarction - genetics; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neovascularization; Neovascularization, Physiologic - genetics; Novels; Retention; Stem cell transplantation; Stem cells; Surgery; Survival; Transplantation; Vascularization; Myocardial infarction; Transplantation; Follistatin-like 1; Survival; Mesenchymal stem cells
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-018-1111-y

Cell therapy remains the most promising approach against ischemic heart injury. However, poor survival of engrafted cells in ischemic sites diminishes its therapeutic efficacy. Follistatin-like 1 (Fstl1) is documented as a novel pro-survival cardiokine for cardiomyocytes, and it is protective during ischemic heart injury. In the present study, we characterize the potential of Fstl1 as an effective strategy to enhance hypoxia resistance of donor cells and optimize stem cell-based therapy. Murine bone marrow-derived mesenchymal stem cells (MSCs) were expanded in monolayer culture and characterized by flow cytometry. MSCs were subjected to hypoxia to mimic cardiac ischemic environment. Expression of Fstl1 was monitored 0, 24, and 48 h following hypoxia. Constitutive expression of Fstl1 in MSCs was achieved by lentivirus-mediated Fstl1 overexpression. Genetically modified MSCs were further collected for cell death and proliferation assay following 48 h of hypoxic treatment. Acute myocardial infarction (MI) model was created by ligating the left anterior descending coronary artery, while control MSCs (MSCs-mCherry) or Fstl1-overexpressing MSCs (MSCs-Fstl1) were injected into the peri-infarct zone simultaneously. Subsequently, retention of the donor cells was evaluated on post-therapy 1, 3, & 7 days. Finally, myocardial function, infarct size, inflammation, and neovascularization of the infarcted hearts were calculated thereafter. Expression of Fstl1 in hypoxic MSCs declines dramatically in a time-dependent manner. In vitro study further demonstrated that Fstl1 promotes survival and proliferation of hypoxic MSCs. Moreover, Fstl1 significantly prolongs MSC survival/retention after implantation. Finally, transplantation with Fstl1-overexpressing MSCs significantly improves post-MI cardiac function by limiting scar formation, reducing inflammatory response, and enhancing neovascularization. Our results suggest Fstl1 is an intrinsic cardiokine promoting survival and proliferation of MSCs, thereby optimizing their engraftment and therapeutic efficacy during cell therapy.