Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010-2015)

Abstract

Mesenchymal stem cells have been used for cardiovascular regenerative therapy for decades. These cells have been established as one of the potential therapeutic agents, following several tests in animal models and clinical trials. In the process, various sources of mesenchymal stem cells have been identified which help in cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Although mesenchymal cell therapy has achieved considerable admiration, some challenges still remain that need to be overcome in order to establish it as a successful technique. This in-depth review is an attempt to summarize the major sources of mesenchymal stem cells involved in myocardial regeneration, the significant mechanisms involved in the process with a focus on studies (human and animal) conducted in the last 6 years and the challenges that remain to be addressed.

Keywords: Cardiac regeneration; Cell therapy; Cell transplantation; Mesenchymal stem cells; Niche hypothesis.

Figures

Fig. 1

Mechanisms of action of MSCs for cardiac regeneration. (a) miR-133a downregulates the expression of Apaf-1 and caspase 3 and 9, leading to attenuated fibrosis. ECs producing growth factors such as VEGF-A help in recruiting the peripheral stem cells, along with coordinating the differentiation of MSCs into endothelial cells, thereby leading to vascularization. BMP7 expressed by MSCs lead to inhibition of fibrosis on counteraction of TGF-β secreted by macrophages. 5-azacytidine induces differentiation of MSCs into cardiomyocyte, thereby mitigating cardiac contractibility. (b) PLGF-induced macrophage polarization from M1 to M2 promotes neovascularization. CardioChimeras are mono-nucleate fusion of CSCs and MSCs which have exclusive growth kinetics, and have proven to be superior to the parent precursors. (c) MSCs pretreated with various compounds show cryoprotective effects along with enhanced cardiomyogenesis and improved heart function.  bFGF basic fibroblast growth factor, CSC cardiac stem cell, EC endothelial cell, HGF hepatocyte growth factor, LV left ventricular, MSC mesenchymal stem cell, PLGF platelet-derived growth factor, TGF tumor growth factor, VCAM vascular cell adhesion molecule, VEGF vascular endothelial growth factor

Fig. 2

Challenges in use of MSCs for cardiac regeneration. Tumour formation in MSCs has been considered inconceivable, but there have been instances of osteosarcoma in patients infused with BM-MSCs for some other disease. Hence, in the context of MSCs in cardiac regeneration, some pathways and processes might exist that still remain unexplored. Additionally, these pathways comprise MSCs obtained from different sources, out of which only a few such as BM-MSCs have been used extensively for clinical applications, in spite of evidences of more proliferative capacity in MSCs obtained from umbilical cord, peripheral blood, etc. This limitation arises due to the lack of an efficient delivery method of MSCs to the target site. Another challenge that has seemed to come in the way of researchers is the prolonged survival of MSCs post engraftment into the host myocardium. This challenge has been overcome to a large extent by using miRNAs and CCs, but more sustainable methods need to be studied further. Studies have gained several advancements in the field of safety and efficacy of the MSC therapy, but success rates in terms of the functional regeneration of cardiac tissue for the loss of functioning cardiomyocytes after any damage remain mediocre. MSC mesenchymal stem cell