New Insights for Mesenchymal Stem Cells in the Treatment of Ischemic Cardiomyopathy

Dear Editor,

We read the article titled “Mesenchymal Stem Cell Insights: Prospects in Cardiovascular Therapy” by Chou et al. (3), published in a recent issue of Cell Transplantation with great interest. We hereby discuss new insights of mesenchymal stromal cells (MSCs) for the treatment of heart failure from the most recent clinical trials.

During the past decade, a large number of clinical trials primarily using bone marrow-derived mononuclear stem cells (BMMNCs) for cardiac repair had been published (2). The safety and feasibility of this approach has been established. However, the results of efficacy were inconsistent (5,12,13,15). Based on these inconsistent results, there has been an increasing focus on MSCs as a new cell source for regenerative therapy. MSCs are a homogeneous population of stem cells, which can be easily expanded and stored and have high self-renewal, paracrine, and differentiation abilities (7,10). Furthermore, MSCs can be used as an allograft because of the absence of major histocompatibility class II antigens (3,8). It is these unique properties that make MSCs one of the most promising cell types for cardiac regeneration, which may be superior to BMMNCs. More than 40 clinical trials of MSC transplantation for treating heart failure have been registered (9), and some recently published results were encouraging.

The Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) trial showed that transendocardial injection of allogeneic and autologous MSCs were associated with neither serious adverse events (SAEs) nor immunologic reactions. MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling. Although limitations existed (without placebo control), this study showed that allogeneic MSCs may be used as an “off-the-shelf” therapeutic agent, avoiding the need for bone marrow aspiration and cell culture delays before treatment (4).

The Transendocardial Autologous Cells (hMSCs or hBMMNCs) in Ischemic Heart Failure Trial (TAC-HFT) is the first study that compared the safety and effectiveness of transendocardial injection of MSCs and BMMNCs with placebo in patients with ischemic cardiomyopathy (ICM) whose left ventricular ejection fraction (LVEF) was less than 50% (6). No treatment-emergent SAEs were observed. Over 1 year, the 6-min walk distance increased with MSCs only. Infarct size was reduced, and regional myocardial function (detected as peak Eulerian circumferential strain at the site of injection) was improved by MSCs but not by BMMNCs or placebo (6). This study showed that MSC transplantation had similar safety and possibly greater efficacy than BMMNCs.

At the American College of Cardiology Congress 2014, the Autotransplantation of Bone-Marrow Derived Mesenchymal Stromal Cells in Patients with Severe Ischemic Heart Failure (MSC-HF) trial was presented (14). This phase II trial enrolled 59 moderate-to-severe heart failure patients with LVEF ≤ 45% who were randomized to receive MSCs or placebo injections intramyocardially. There were no SAEs observed. Moreover, end-systolic volume and LVEF were significantly improved in the MSC group after 6 months. Furthermore, scar tissue mass tended to be reduced by MSC treatment. This is the first double-blind, randomized, placebo-controlled trial that showed that MSC treatment can increase LVEF significantly. Similar effects were also documented in the Cardiopoietic stem Cell therapy in heart failURE (C-CURE) trial, which showed that MSCs pretreated with a cardiogenic cocktail of growth factors can significantly improve the LVEF by 7% in patients with ICM (1).

In conclusion, preliminary clinical trials have shown encouraging results in the safety and therapeutic efficacy of MSCs for cardiac repair. Further studies are needed to optimize transplantation methodology, dosage, and timing of administration for enhancing therapeutic efficacy of MSC-based cardiac therapy (11).