Research of MSC Exosomes in Cardiovascular Regeneration

MSC in Cardiovascular Regeneration: Emerging Research Directions and Clinical Applications

Abstract
Experimental and early clinical data suggest that, due to several unique properties, mesenchymal stem cells (MSCs) may be more effective than other cell types for diseases that are difficult to treat or untreatable. Owing to their ease of isolation and culture as well as their secretory and immunomodulatory abilities, MSCs are the most promising option in the field of cell-based therapies. Although MSCs from various sources share several common characteristics, they also exhibit several important differences. These variations may reflect, in part, specific regional properties of the niches from which the cells originate. Moreover, morphological and functional features of MSCs are susceptible to variations across isolation protocols and cell culture conditions. These observations suggest that careful preparation of manufacturing protocols will be necessary for the most efficient use of MSCs in future clinical trials. A typical human myocardial infarct involves the loss of approximately 1 billion cardiomyocytes and 2–3 billion other (mostly endothelial) myocardial cells, leading (despite maximized medical therapy) to a significant negative impact on the length and quality of life. Despite more than a decade of intensive research, search for the “best” (safe and maximally effective) cell type to drive myocardial regeneration continues. In this review, we summarize information about the most important features of MSCs and recent discoveries in the field of MSCs research, and describe current data from preclinical and early clinical studies on the use of MSCs in cardiovascular regeneration.

Significant Statement
This concise review discusses present and future applications of mesenchymal stem cells (MSC) in therapy of cardiovascular disorders. It summarizes both preclinical and clinical trials conducted in this area with strong emphasis on mechanisms of MSCs action. Its main impact lies in comprehensive summary of ongoing and finished studies.

Introduction
Cardiovascular diseases (CVDs) are the number one cause of death worldwide [1]. CVDs affect not only elderly people but also middle-aged people at the peak of their working and social capacities; hence, CVDs are an enormous medical and economic problem in society.

Recent decades have witnessed tremendous progress in pharmacological and endovascular therapies, as well as in surgical techniques, and today, a great amount of effort is being directed toward cardiac disease prevention [1]. Nevertheless, CVDs remain a chronic and progressive burden in a significant proportion of patients, leading to heart failure that requires heart transplantation or permanent left ventricular support [1]. Among the experimental therapies of the future, artificial (mechanical) heart replacement [2] and cardiac regenerative approaches (including biological hearts) remain the most promising. Today, stem cells are a major focus in regenerative therapeutic strategies.

Discovered in 1970 [3], mesenchymal stem cells (MSCs) possess several specific features that make them important candidates for future regenerative cardiac therapies. Today, MSCs are defined by the International Society for Cellular Therapy as self-renewing, multipotent cells that exhibit plastic adherence under standard culture conditions and express CD73 and CD90 but not CD45, CD34, CD14, CD11b, CD79a, CD19, or HLADR surface markers, with in vitro multilineage differentiation capacity [4]. MSCs are also known as mesenchymal stromal stem cells, multipotent adult progenitor cells, medicinal signaling cells, and mesenchymal progenitor cells (MPCs); however, MPCs are also occasionally classified as a separate population of cells [5].

Among the sources ofMSCs, bone marrow [3] and adipose tissue [6] have been the most commonly studied to date. However, MSCs are also found in umbilical cord blood [7], dental pulp [8], synovial fluid [9], amniotic fluid [10], and urine [11]. Umbilical cord Wharton’s jelly (WJ)-derived MSCs have recently been gaining significant attention, owing to some of their unique properties and their feasibility of use as an “unlimited” off-the-shelf source of regenerative cells [12, 13]. Although MSCs from various sources share several characteristics, they also exhibit several differences. These variations in MSCs populations may reflect particular regional properties of the niches from which they originate. MSCs features are also susceptible to variations in cell culture conditions and isolation protocols [14–16]. Properties of MSCs derived from bone marrow (BM-MSCs), adipose tissue (AT-MSCs) and WJ (WJ-MSCs) vary in different culture conditions and during differentiation [15–17]. For instance, WJ-MSCs express the highest proliferative potential independently of cell culture conditions [18, 19]. AT-MSCs and BM-MSCs, but not WJ-MSCs, cultured in the presence of serum produce high amounts of extracellular matrix components. Only AT-MSCs are able to produce collagen (I, II, and III). Regardless of cell culture conditions, BM-MSCs preserve high proangiogenic features [15–17]. Other studies have shown that BM-MSCs are the most immunosuppressive cells. These observations suggest that the properties of MSCs strongly depend on cell source and culture conditions [18, 20, 21] and might suggest the most efficient use of various MSCs types in future clinical trials. This review is intended to present concise information on recent discoveries and the clinical use of MSCs in the field of cardiovascular research.

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