Biochemical and Biophysical Research Communications
Mini ReviewMyocardial regeneration potential of adipose tissue-derived stem cells
Research highlights
► Various tissue resident stem cells are receiving tremendous attention from basic scientists and clinicians and hold great promise for myocardial regeneration. ► For practical reasons, human adipose tissue-derived stem cells are attractive stem cells for future clinical application in repairing damaged myocardium. ► This review summarizes the characteristics of cultured and freshly isolated stem cells obtained from adipose tissue, their myocardial regeneration potential and the, underlying mechanisms, and safety issues.
Introduction
Myocardial infarction (MI) caused by an obstruction of coronary arteries leads to loss of cardiomyocytes. Despite advances in traditional pharmacological therapies for heart disease, MI is still a leading cause of mortality worldwide. Currently, heart transplantation is the only effective treatment of end-stage ischemic heart disease. Unfortunately, the insufficient number of available donor hearts and immunorejection limit the use of transplantation. Given this limitation, new therapeutic approaches for MI are required. In recent years, stem cells have received attention from basic scientists and clinicians and hold great promise for myocardial regeneration. Stem cells are either embryonic or adult cells. Embryonic stem (ES) cells exhibit strong proliferation and differentiation potential both in vitro and in vivo [1]. However, several major issues, including ethical concerns, immunorejection, and teratoma formation, limit the practical use of ES cells. Investigators have identified adult stem cells in numerous organs and tissues. Unlike the use of ES cells, that of autologous adult stem cells does not come with any ethical, immunorejection, or oncological concerns. However, isolation of adult stem cells from heart, skeletal muscle, or bone marrow is painful, time-consuming, and costly, and carries a risk of damage to donor tissues and organs. Compared with other tissue sources of adult stem cells, adipose tissue has the following advantages: (1) Adipose tissue is abundant in most individuals and can be harvested using a simple liposuction procedure that is less invasive and causes less discomfort and donor-site damage; (2) Adipose tissue has a significantly higher stem cell density than does bone marrow (5% versus 0.01%) [2], suggesting that a small amount of adipose tissue can yield sufficient stem cells with proliferation and differentiation potential for autologous cell transplantation. Given these advantages, ASCs are promising cell candidates for myocardial regeneration, especially in acute clinical settings. In this review, we will focus on the characteristics of both cultured and freshly isolated stem cells obtained from adipose tissue, their therapeutic effect on cardiac function, and the underlying mechanisms of beneficial effect on myocardial regeneration.
Section snippets
Characteristics of ASCs
Stem cells can be obtained from adipose tissue using collagenase digestion. Freshly isolated cells from human adipose tissue (fADCs) were reported to be heterogeneous. These cells included not only a significant number of multipotent stem cells, identified by expression of CD44 (35.13 ± 8.16%) and CD105 (40.32 ± 7.15%), but also cells of hematopoietic lineage, identified by CD11b (4.72 ± 0.33%), CD34 (46.50 ± 5.53%), and CD45 (6.21 ± 2.05%), endothelial cells (ECs) positive for CD31 (9.96% ± 1.43%), and
Cardiac repair potential
A growing body of experimental evidence has shown that injection of both cultured ASCs and fADCs could improve cardiac function after myocardial injury. Representative studies with such results are summarized in Table 1.
Bai et al. [3] experimentally induced MI in severe combined immunodeficiency (SCID) mice by ligating left anterior descending coronary artery (LAD). Human fADCs, ASCs (5 × 105), or phosphate-buffered saline (PBS) were then injected into the peri-infarct region of the hearts in
Survival of transplanted ASCs in injured hearts
Tracking the survival and migration of injected ASCs in vivo is important for elucidating the mechanisms underlying their favorable therapeutic effects. Most animal studies have used histological analysis to assess the location, count, and differentiation of injected stem cells, revealing poor survival rates for injected ASCs in injured hearts. For example, Mazo et al. [13] did not observe ASCs in mouse hearts 30 days after cell transplantation. Also, Cai et al. [9] found engrafted human ASCs in
Mechanisms underlying the beneficial effect of ASCs on cardiac function
The mechanisms underlying the beneficial effects of both cultured and freshly isolated ASCs on myocardial regeneration remain critical but uncertain. Experimental evidence indicates that both direct differentiation potential and indirect paracrine effects may contribute to myocardial regeneration.
Differentiation of ASCs into cardiomyocytes and vascular cells
Several reports have demonstrated that ASCs were able to differentiate into cardiomyocytes and vascular cells, including ECs and SMCs, both in vitro and in vivo, suggesting that ASCs have the potential to repopulate all myocardial tissue elements and eventually benefit cardiac function.
Human ASCs could spontaneously differentiate into cardiomyocytes in a normal culture medium. These cells expressed cardiac-specific markers troponin I and myosin light chain 2 but did not show rhythmic
Paracrine effect of ASCs in myocardial regeneration
ASCs may exert their regenerative effect through differentiation into cardiomyocytes and vascular cells. However, various independent groups have commonly observed the low differentiation efficiency of ASCs in vivo [3], [9], [25]. Growing evidence indicates that secretion of soluble factors by ASCs could lead to the following effects, including enhancement of angiogenesis, reduction of apoptosis rates, and promotion of nerve sprouts, which are eventually attributable to myocardial regeneration.
Safety issues
To date, no authors have reported cases of arrhythmia or tumorigenesis in any studies regarding the myocardial regeneration of ASCs. Human ASCs were reported to express four types of ion channels including delayed rectifier-like K+ current , Ca2+ activated K+ current, transient outward K+ current, and TTX-sensitive transient inward sodium current [28]. A separate in vivo experimental study demonstrated clusters of injected human ASCs and fADCs in the border zones and infarct regions of hearts
Future studies
Both cultured ASCs and fADCs have shown the capacity to promote cardiac function. Engrafted cells were able to engraft, differentiate into cardiomyocytes and vascular cells in a fusion-independent differentiation pathway, produce paracrine growth factors to enhance neovascularization and nerve sprouts, and to reduce apoptosis rates. To further improve the efficacy of ASC-based therapy for MI, following investigations might be performed in future studies: (1) Determining whether the therapeutic
Sources of funding
This work was supported in part by Alliance of Cardiovascular Researchers grant 543102 (to E. Alt).
Disclosures
None.
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