Allogeneic Mesenchymal Stem Cells Restore Endothelial Function in Heart Failure by Stimulating Endothelial Progenitor Cells

Abstract

BackgroundEndothelial dysfunction, characterized by diminished endothelial progenitor cell (EPC) function and flow-mediated vasodilation (FMD), is a clinically significant feature of heart failure (HF). Mesenchymal stem cells (MSCs), which have pro-angiogenic properties, have the potential to restore endothelial function. Accordingly, we tested the hypothesis that MSCs increase EPC function and restore flow-mediated vasodilation (FMD).MethodsIdiopathic dilated and ischemic cardiomyopathy patients were randomly assigned to receive autologous (n = 7) or allogeneic (n = 15) MSCs. We assessed EPC-colony forming units (EPC-CFUs), FMD, and circulating levels of vascular endothelial growth factor (VEGF) in patients before and three months after MSC transendocardial injection (n = 22) and in healthy controls (n = 10).FindingsEPC-colony forming units (CFUs) were markedly reduced in HF compared to healthy controls (4 ± 3 vs. 25 ± 16 CFUs, P < 0.0001). Similarly, FMD% was impaired in HF (5.6 ± 3.2% vs. 9.0 ± 3.3%, P = 0.01). Allogeneic, but not autologous, MSCs improved endothelial function three months after treatment (Δ10 ± 5 vs. Δ1 ± 3 CFUs, P = 0.0067; Δ3.7 ± 3% vs. Δ-0.46 ± 3% FMD, P = 0.005). Patients who received allogeneic MSCs had a reduction in serum VEGF levels three months after treatment, while patients who received autologous MSCs had an increase (P = 0.0012), and these changes correlated with the change in EPC-CFUs (P < 0.0001). Lastly, human umbilical vein endothelial cells (HUVECs) with impaired vasculogenesis due to pharmacologic nitric oxide synthase inhibition, were rescued by allogeneic MSC conditioned medium (P = 0.006).InterpretationThese findings reveal a novel mechanism whereby allogeneic, but not autologous, MSC administration results in the proliferation of functional EPCs and improvement in vascular reactivity, which in turn restores endothelial function towards normal in patients with HF. These findings have significant clinical and biological implications for the use of MSCs in HF and other disorders associated with endothelial dysfunction.

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

“…Histopathologic analyses have revealed a greater prevalence of replacement fibrosis and a lesser degree of myocardial hypertrophy in patients with ICM compared to DCM 13. The mechanisms by which MSCs may have improved cardiac function in patients with DCM include the restoration of endothelial function, which enhances coronary circulation,6, 38 and the reduction of fibrosis and tumor necrosis factor–α, an inflammatory biomarker associated with worsening HF and contractility 39, 40. Those with ICM likely benefit mostly from the stem cells’ antifibrotic properties through reduction in scar size and subsequent reverse remodeling as indicated by a reduction in SI and ESV 7, 29.…”

“…MSCs are immunoprivileged secondary to their lack of major histocompatibility complex class II and costimulatory factors,5 which allows their use as an allogeneic graft. While the safety of both autologous and allogeneic MSCs is reasonably well established, studies have demonstrated that allogeneic MSCs derived from young, healthy donors are more efficacious 1, 5, 6. Notably, these cells are shown to be a safe method to improve cardiac structure and function in preclinical and clinical trials 1, 2, 7, 8, 9, 10, 11, 12.…”

The Proangiogenic Potential of Mesenchymal Stem Cells and Their Therapeutic Applications

“…There are three mechanisms of postnatal neovascularization: (1) angiogenesis, (2) arteriogenesis, and (3) postnatal vasculogenesis [54] with progenitor cells migrating from the bone marrow and to site of sites of tissue damage resulting in the generation of new capillaries. Whether the formation of new capillary networks and vessel integration into neighboring tissue is associated with direct differentiation of MSCs to endothelial cells is still unknown or the importance of secreted factors [55,56]. MSCs have been shown to exist in perivascular niches with similarities to pericytes, which may account for their ability to promote vascularization [57].…”

Is the regulation of SIRT1 by miRNA-34a the key to mesenchymal stem cell survival?

“…Mesenchymal stem cells (MSCs) are currently being used clinically to treat cardiovascular diseases, including ischemic heart disease, heart failure, and peripheral vascular disease (1,2). To date, these trials have proven MSCs to be a safe and effective option for the improvement of vascular function, reduction of scar size, and reversal of remodeling in heart failure (3,4). Despite the positive data being collected, there are still a number of challenges that reduce the effectiveness of MSC cell therapy.…”