Concise Review: Optimized Strategies for Stem Cell-Based Therapy in Myocardial Repair: Clinical Translatability and Potential Limitation

Abstract

Ischemic heart diseases (IHDs) remain major public health problems with high rates of morbidity and mortality worldwide. Despite significant advances, current therapeutic approaches are unable to rescue the extensive and irreversible loss of cardiomyocytes caused by severe ischemia. Over the past 16 years, stem cell-based therapy has been recognized as an innovative strategy for cardiac repair/regeneration and functional recovery after IHDs. Although substantial preclinical animal studies using a variety of stem/progenitor cells have shown promising results, there is a tremendous degree of skepticism in the clinical community as many stem cell trials do not confer any beneficial effects. How to accelerate stem cell-based therapy toward successful clinical application attracts considerate attention. However, many important issues need to be fully addressed. In this Review, we have described and compared the effects of different types of stem cells with their dose, delivery routes, and timing that have been routinely tested in recent preclinical and clinical findings. We have also discussed the potential mechanisms of action of stem cells, and explored the role and underlying regulatory components of stem cell-derived secretomes/exosomes in myocardial repair. Furthermore, we have critically reviewed the different strategies for optimizing both donor stem cells and the target cardiac microenvironments to enhance the engraftment and efficacy of stem cells, highlighting their clinical translatability and potential limitation. STEM CELLS 2018;36:482-500 SIGNIFICANCE STATEMENTStem cell-based therapy has shown therapeutic superiority after ischemic heart diseases. To accelerate such therapy toward successful clinical application, many important issues need to be addressed. This review compared different types of stem cells with their dose, delivery routes and timing based on recent preclinical and clinical findings, discussed the underlying mechanisms of stem cells and particularly explored the importance of secretomes/exosomes in myocardial repair, and critically reviewed the different optimized strategies for stem cell-based therapy with their clinical translatability and potential limitation.

Role and therapeutic effects of skeletal muscle-derived non-myogenic cells in a rat myocardial infarction model

“…Heart failure remains a major cause of death due to a limited regenerative capacity of the cardiac tissue. As a substitute for existing therapy, stem cell transplantations have been widely studied, and some stem cell therapies have already been applied clinically [1,2]. Skeletal myoblasts, which are the progenitors responsible for the regeneration of the skeletal muscle, are a promising cell type with many clinical advantages such as easy expansion, lack of tumorigenic potential, and the possibility for use for autologous transplantation [3].…”

Paracrine potential of adipose stromal vascular fraction cells to recover hypoxia‐induced loss of cardiomyocyte function

“…This result was confirmed also by the significant reduction of released prosurvival factors such as IGF and HGF. This finding might appear in contrast to the beneficial effects of hypoxia preconditioning of adult stem cells before cell transplantation in the cardiac ischemic heart (Wu et al, 2018). However, our experimental setup differed quite a lot from the previous studies in which cells were exposed to hypoxia condition only for few hours, whereas in our case SVF cells were cultured for up to 5 days in anoxia-approaching condition.…”

“…This finding might appear in contrast to the beneficial effects of hypoxia preconditioning of adult stem cells before cell transplantation in the cardiac ischemic heart (Wu et al, 2018). This result was confirmed also by the significant reduction of released prosurvival factors such as IGF and HGF.…”

“…Although the mechanisms are still not fully clarified, cell-based therapies contribute to cardiac function recovery mainly by means of paracrine-mediated effects, promoting tissue repair rather than the direct differentiation towards functional and host-integrated CM . Among the numerous adult stem cell therapies (Wu, Hu, & Wang, 2018), adipose tissue-derived mesenchymal stromal cells (Perin et al, 2014;Qayyum et al, 2012), and, more recently, the freshly isolated stromal vascular fraction (SVF) cells have been extensively investigated for their possible intraoperative direct application (Bai et al, 2010;Ptaszek et al, 2012;Yoshimura et al, 2006), its vasculogenic and angiogenic potential (Klar et al, 2014;Leblanc et al, 2013) and for its broad release of angiogenic and cardioprotective factors (Bayes-Genis et al, 2010;Rehman, 2004). Notwithstanding, after myocardial infarction or in presence of microvascular dysfunctions, low levels of oxygen not only impair the physiological tissue function but can also be a key-factor altering the activity of engrafted cells.…”

The therapeutic impact of human neonatal BMSC in a right ventricular pressure overload model in mice

“…*P < 0.05 palliation provided some benefits in terms of cardiac function, somatic growth, and quality of life [7,28]. Intramyocardial delivery of stem cells can produce higher cell retention as well as a targeted approach into the damaged myocardium [29]. Intramyocardial injection of mesenchymal stem cells in an RV pressure overload model preserved the RV function and attenuated cardiac remodeling [30].…”