Abstract
BackgroundCell 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.MethodsMurine 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.ResultsExpression 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.ConclusionsOur results suggest Fstl1 is an intrinsic cardiokine promoting survival and proliferation of MSCs, thereby optimizing their engraftment and therapeutic efficacy during cell therapy.
Highlights
Cell therapy remains the most promising approach against ischemic heart injury
Follistatin-like 1 (Fstl1), known as TSC-36, is a secreted glycoprotein induced by transforming growth factor-β1 (TGF-β1) [4]
Fstl1 expression declines dramatically in hypoxic mesenchymal stem cells (MSCs) MSCs were isolated from the bone marrow of C57BL/ 6J mice
Summary
Cell therapy remains the most promising approach against ischemic heart injury. 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. Bone marrow-derived mesenchymal stem cells (MSCs) have unique properties that make them ideally suited for off-shelf clinical cell transplantation; they are extractable and are immune-privileged with multilineage potential [2]. Their therapeutic efficacy has been hindered by poor survival, retention, and engraftment of transplanted cells due to insufficient blood supply, poor nourishment of cells, and generation of free radicals [3]. We propose that supplementation of intrinsic Fstl may further improve survival and engraftment of donor MSCs
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