White adipose tissue consists of mature adipocytes and intercellular tissue or SVF. Adipocytes, the most abundant cells in adipose tissue, contain a single large cytoplasmic vacuole that mainly stores triglycerides and cholesterol esters. Depending on nutritional status, adipocytes can alter their size to between 25 μm and 200μm. Adipocytes contain the machinery necessary for lipid metabolism (Figure 1).9 These pathways can be altered by an increase in weight, triggering insulin resistance syndrome. Indeed, fatty acids not only show an energy function, but also act as regulatory signals of the gene expression of proteins involved in lipid metabolism,10 favor a prothrombotic state, and are associated with inflammatory processes.11 Thus, an excess of circulating fatty acids (lipotoxicity) is one of the strongest links between obesity and the development of metabolic syndrome and/or cardiovascular disease. When calorie consumption exceeds energy expenditure, a metabolic state develops that promotes adipocyte hypertrophy (increased size) and hyperplasia (increased number).12 The latter involves mobilization of stem cells toward the adipocyte lineage (adipogenesis). New or small adipocytes are more sensitive to insulin and show a marked capacity for the uptake of free fatty acids and triglycerides in the postprandial period.4 As adipocytes increase in size (hypertrophy), they become dysfunctional, losing their ability to protect against systemic lipotoxicity, and ectopic fat begins to accumulate. These distended adipocytes become hyperlipolytic and resistant to insulin and its antilipolytic signals. Another important function performed by adipocytes is that of endocrines cells, as discussed below.

Figure 1.

Diagram illustrating the lipogenesis and lipolysis processes occurring in mature adipocytes. After eating and an increase in blood insulin, lipogenesis is activated in adipocytes. In this process, adipocytes, via lipoprotein lipase, degrade the triglycerides of chylomicrons and of very-low-density lipoprotein to fatty acids. These molecules enter the adipocyte to be esterified with glycerol-3 phosphate and synthesize the triglycerides that are stored in the lipid vacuole. In the adipocyte, insulin not only stimulates lipoprotein lipase synthesis, but also stimulates uptake and metabolism of glucose to glycerol-3 phosphate. In contrast, during lipolysis, the triglycerides stored are mobilized to produce free fatty acids and glycerol to meet the energy requirements of the body. Catabolic hormones, secreted in response to a low blood concentration of glucose, activate the synthesis and movement of hormone-sensitive lipase from the cytosol to the surface of the lipid vacuole, where hormone-sensitive lipase hydrolyzes triglycerides. The fatty acids produced are secreted as free fatty acids to the circulation, where they will be transported by albumin to the target organs to be oxidized to produce energy. Similarly, the glycerol derived from lipolysis is also released into the circulation to be used by the liver as a source of carbon. AQP7, aquaporin-7; CM, chylomicrons; FABP, fatty acid-binding protein; FAT/CD36, fatty acid translocase; FATP, fatty acid transport protein; GLUT4, glucose transporter type 4; HSL, hormone-sensitive lipase; LPL, lipoprotein lipase; TG, triglycerides; VLDL, very-low-density lipoprotein.

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The other component of WAT is the SVF. Although the cells constituting the SVF remain to be fully defined, they include adipocyte precursors and vascular and blood cells.13 Pericytes form the vasculature of adipose tissue, together with endothelial and smooth muscle cells. The extent and characteristics of this capillary network are crucial for processes such as the growth, function, and development of adipose tissue.14 Adipocytes and other cells of the SVF secrete proangiogenic factors, ensuring that the tissue has a generous blood supply. In addition, adipose tissue, via its resident immune system cells, strongly controls the metabolism of the body. In nonobese individuals, these cells are involved in elimination of necrotic adipocytes, remodeling of the extracellular matrix, angiogenesis, adipogenesis, and maintaining insulin sensitivity. However, in obese individuals, the number of immune system cells increases; these cells acquire a proinflammatory phenotype and release a huge number of cytokines in charge of recruiting and activating other immune system cells and inducing insulin resistance syndrome in adipose tissue.15 Macrophages are the cells with the most important role in the acquisition of the low-grade chronic proinflammatory state that characterizes obesity. During adipose tissue expansion, there is a greater recruitment of M1 macrophages (a proinflammatory phenotype). These macrophages secrete most of the proinflammatory cytokines found in obese adipose tissue,16 whereas the resident M2 macrophages show an anti-inflammatory phenotype.17 Finally, in the SVF, there are adipose-derived stem cells (ADSCs) and preadipocytes. These cell populations are in charge of maintaining adipocyte population renewal in physiological conditions and play a vital role in the obesity-related expansion of adipose tissue. The differences between these 2 cell groups are poorly defined. Both ADSCs and preadipocytes show a similar morphology. However, whereas ADSCs can differentiate into other lineages and show a large capacity for self-renewal, preadipocytes have lost these differentiation capabilities and can only generate mature adipocytes.18

The WAT secretes a multitude of bioactive peptides, known under the umbrella term of adipocytokines or adipokines (Table 1).19,20 However, many of these factors are not only secreted by adipocytes, but also by the cells constituting the SVF, such as macrophages and ADSCs. Through these secreted factors, adipose tissue participates in the autocrine and paracrine regulation of adipose tissue itself, as well as affecting the function of other organs. In addition, adipose tissue is in charge of regulating energy homeostasis and body weight, insulin sensitivity, and various functions of the immune, vascular, and reproductive systems.20 This endocrine function of adipose tissue explains the pathophysiological relationship between excess body fat and its associated pathological states, because obesity and/or metabolic syndrome trigger a dysregulation of the secreted amounts of these molecules.21

In recent years, numerous preclinical studies and some clinical studies have analyzed the safety, behavior, and efficacy of ADSCs in the treatment of ischemic injury, especially that of cardiac origin.47–51 The first study was performed in a rat model of heart cryoinjury and involved the injection of recently isolated ADSCs into the left ventricular cavity to simulate intracoronary administration.51 That study was the first to show that ADSCs home to the myocardium and express specific markers of cardiac cells. Similarly, functional and pathological analyses of the ADSC-treated animals revealed significantly improved global cardiac function and increased capillary density in the injury border zone compared with controls.51 Since then, the capacity of ADSCs to generate cardiomyocytes and vascular cells has become a topic of great experimental interest, as shown in Table 351-91 (studies performed in rodents and rabbits) and Table 492–101 (studies performed in porcine models). Notably, controversy surrounds the efficacy of the ADSCs. Whereas some studies have found engrafted ADSCs expressing specific cardiac markers (troponin I and myosin light chain),51,102–105 von Willebrand factor, and/or smooth muscle actin, other studies failed to discern the differentiation capacity of ADSCs (Tables 3 and 4).52,92 These differences in the in vivo differentiation potential of ADSCs could be due to differences in ADSC sources, procurement processes or culture media, animal models, or means of administration, or be due to the limits of histological analysis. Various groups have similarly found a low differentiation capacity of ADSCs in studies in vivo.52,53,92 All of these observations have led scientists to question whether the benefits derived from ADSC administration are directly related to the differentiation processes or if, in contrast, they are conditioned by ADSC secretion of paracrine factors.106–108

Another important function of ADSCs related to ischemic heart disease is derived from their angiogenic potential.52,109 Because ADSCs secrete a large number of proangiogenic cytokines and cytoprotective factors, they are an ideal cellular source for angiogenic therapy and apoptosis inhibition.29,110–112 An in vivo study showed that intramyocardial injection of human ADSCs significantly promoted angiogenesis and inhibited cell apoptosis in an infarcted heart 4 weeks after their injection.54 Moreover, ADSCs showed an increased expression of vascular endothelial and fibroblast growth factors and stromal cell-derived factor 1.54 Indeed, the interaction of stromal cell-derived factor 1 with its receptor induces the rapid mobilization of stem/progenitor cells from the bone marrow,113 which is essential for the revascularization of body systems.114 All of these results indicate that injected ADSCs cooperate with stem/progenitor cells of the bone marrow via cellular mobilization, which is promoted by stromal cell-derived factor 1 and which boosts angiogenesis and vasculogenesis in myocardial ischemia.54

The functional response of ADSCs can also be affected by oxygen concentration.29,115 Rehman et al29 found that ADSCs secreted up to 5 times more vascular endothelial growth factors if they were cultured under hypoxic conditions. Additionally, the conditioned supernatant of ADSCs cultured under hypoxic conditions increased the growth of endothelial cells and reduced their apoptosis. Recently, a study reported that hypoxic preconditioning of ADSCs increased their survival and paracrine effects in a hypoxia-inducible factor 1-mediated manner.116 Indeed, our laboratory group has shown that ADSCs cultured under hypoxic conditions had greatly improved proliferative capacity.40 These results showed that ADSCs respond to ischemic situations and promote angiogenesis via the secretion of vascular endothelial growth factors. As already mentioned, various experimental studies have shown that ADSCs are safe and efficacious (Tables 3 and 4). As can be seen in Table 4, 2 studies showed an increased capillary density in the area surrounding the infarcted heart and an increased cardiac function 1 month after a myocardial infarction when animals were treated with ADSCs, results similar to those observed after bone marrow-derived MSCs administration.93,94 A long-term follow-up study showed that, despite an inability to detect ADSCs in the myocardium 3 months after their injection, ADSC transplantation was associated with increased cardiac function, positive remodeling, and increased angiogenesis and vasculogenesis, confirming the long-term paracrine effect of these cells.95 However, these observations indicate that, despite all of the advantages of ADSCs, their low capacity for homing to ischemic tissue is an obstacle to their clinical use.117 Accordingly, various strategies are being explored to resolve the problem of ADSC survival and engraftment in host tissue, such as the administration of ADSCs together with a combination of growth factors,118 injection of genetically modified ADSCs,119 and/or the use of grafts/biomaterial scaffolds.120,121 Finally, it is necessary to mention that various studies have indicated that ADSCs, both in vitro and in vivo, can boost the differentiation of the vasculature into pericytes, cells capable of creating microvessels, preventing vascular regression, and promoting long-term microvessel maintenance.122,123

The evidence found in the experimental studies of the potential of ADSCs to repair the ischemic myocardium and restore its functional capacity has prompted the performance of clinical trials in this area. However, although some researchers believe that ADSCs will be used in the coming years as a cell therapy aimed at repairing the damaged heart, others believe that there are many unknowns to be resolved before these cells can be clinically used. So far, ADSCs have been satisfactorily used to treat some diseases, such as Crohn's fistula, osteogenesis imperfecta, and breast reconstruction after a partial mastectomy (Table 5). However, the use of ADSCs in the field of ischemic heart disease is still in phase I-II. Various clinical trials have been initiated to determine the feasibility, safety, and efficacy of the use of ADSCs in patients who have had an acute myocardial infarction (APOLLO, ADI-ME-CHF-002, ADVANCE, and ACUTE MI), have chronic ischemic heart disease (PRECISE, MyStromalCell, ATHENA, and ATHENA II), or nonischemic cardiomyopathy (ADI-ME-CHF-002). Of these, the APOLLO124, PRECISE,125 and MyStromalCell126 trials have been completed. These studies showed that the use of ADSCs is safe and feasible. In addition, the results indicated that ADSC use preserves cardiac function, improves cardiac perfusion, and even reduces scar tissue size, thereby reinforcing the findings of the previous preclinical trials.