Aging and Metabolic Reprogramming of Adipose-Derived Stem Cells Affect Molecular Mechanisms Related to Cardiovascular Diseases

We performed a systematic search of the PubMed database for English-language articles related to the function of adipose-derived stem cells in the pathogenesis of cardiovascular diseases. In preclinical models, adipose-derived stem cells protected arteries and the heart from oxidative stress and inflammation and preserved angiogenesis. However, clinical trials did not reiterate successful treatments with these cells in preclinical models. The low success in patients may be due to aging and metabolic reprogramming associated with the loss of proliferation capacity and increased senescence of stem cells, loss of mitochondrial function, increased oxidative stress and inflammation, and adipogenesis with increased lipid deposition associated with the low potential to induce endothelial cell function and angiogenesis, cardiomyocyte survival, and restore heart function. Then, we identify noncoding RNAs that may be mechanistically related to these dysfunctions of human adipose-derived stem cells. In particular, a decrease in let-7, miR-17-92, miR-21, miR-145, and miR-221 led to the loss of their function with obesity, type 2 diabetes, oxidative stress, and inflammation. An increase in miR-34a, miR-486-5p, and mir-24-3p contributed to the loss of function, with a noteworthy increase in miR-34a with age. In contrast, miR-146a and miR-210 may protect stem cells. However, a systematic analysis of other noncoding RNAs in human adipose-derived stem cells is warranted. Overall, this review gives insight into modes to improve the functionality of human adipose-derived stem cells.


Introduction
Adipose-derived stem cells (ASCs) are easily acquired with high yields and, therefore, are an ideal stem cell source [1].The International Fat Applied Technology Society, renamed the International Federation for Adipose Therapeutics and Science, reached a consensus referring to adipose-derived stem cells for all plastic-adherent, multipotent cell populations isolated from adipose tissue, instead of referring to adipose stromal cells, adipose-derived adult stem cells, or adipose mesenchymal stem cells [2].ASCs are commonly isolated from the stromal vascular fraction (SVF) of adipose tissue.ASCs in white adipose tissue (WAT) have the potential to become preadipocytes, subsequently differentiating into mature adipocytes via adipogenesis involving the activation of peroxisome proliferator-activated receptor gamma (PPARγ).Anatomically separated WAT depots, namely subcutaneous WAT (S-WAT) and visceral WAT (V-WAT), are known to be functionally distinct.S-WAT expands to store excess lipids, thus preventing ectopic lipid disposition and organ damage, while the main function of V-WAT is to cushion and protect the visceral organs [3].However, apart from adipogenesis, ASCs can acquire properties of specialized cells or induce the differentiation of other cell types, among them endothelial cells (ECs) [4], vascular smooth muscle cells [5], and cardiomyocytes [6].In culture, ASCs retain markers in common with other mesenchymal stromal/stem cells, including CD90, CD73, CD105, and CD44, and remain negative for CD45 and CD31 [7][8][9][10].In addition, the immunological reactivity of ASCs is low because of the low expression of immunogenic surface antigens (CD40, CD40L, CD80, and CD86) and major histocompatibility complex II, allowing allogeneic use [11].Finally, ASCs exert paracrine function by producing cytokines and growth factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and insulin-like growth factor 1 (IGF-1) [12,13].
This review specifically aims at understanding mechanisms by which ASCs may inhibit atherosclerosis and improve heart function and thus protect against cardiovascular diseases.The initial step in atherosclerosis is endothelial dysfunction through mechanical shear stress and chemical stress induced by high glucose, high LDL and low HDL, high levels of reactive oxygen species (ROS) and oxidized LDL, and ANG-II.Injured endothelium attracts inflammatory cells, among them macrophages.Stress induces the polarization of macrophages from an anti-inflammatory M2 to an inflammatory M1 phenotype.M1 macrophages accumulate lipids and differentiate into foam cells.ROS and lipids induce cell death, thereby destabilizing atherosclerotic plaques.High oxidative stress also increases Th1/Th17 and decreases Th2/Treg cell immune response, further enhancing inflammation and cell death [14,15].
We particularly reviewed the role of ASCs exerting therapeutic effects that rely on paracrine secretion.Indeed, ASCs secrete several cytokines, growth factors, and chemokines that modulate oxidative stress, inflammation, immune responses, angiogenesis, and apoptosis in damaged vascular and heart cells [16].In the heart, the pericardium consists of a thin fibrous layer, nerves, a vascular network, and adipose mass.It also comprises mesenchymal cells, so-called formed cardiac colony-forming unit fibroblasts that give rise to all mesodermal lineages, including smooth muscle, bone, cartilage, adipose, endothelial, and heart muscle cells [17].Pericardial ASCs constituted intrinsic properties toward myogenesis and vessel formation and thus provided more potent structural repair, translating into functional amelioration after myocardial injury [18].
We discussed first the effect of ASCs in preclinical models, giving insight into underlying mechanisms.Then, we reviewed the clinical data.Because clinical trials did not reproduce successful treatments with ASCs in preclinical models, we tried to identify molecular explanations for the loss of function of ASCs, focusing on aging and metabolic reprogramming.We considered changes in the expression of noncoding RNAs in addition to changes in protein or lipid content because of their association with metabolic and cardiovascular diseases [19].
Currently, one aims to move from cell-based to cell-free therapy with extracellular exosomes of stem cell origin [20], further reducing the immunogenic response and thus improving the safety and increasing the stability upon storage and obtaining a better targeting of the cells and tissues to be treated [21].Previously, we showed the role of exosomemediated cell-to-cell communication in affecting pathways involved in the pathogenesis of cardiovascular diseases [22,23].Herein, we discussed particularly the role of exosomes secreted by ASCs.We searched the PubMed database for English-language articles related to adiposederived stem cells in mechanisms related to cardiovascular diseases.The search strategy encompassed a MESH search: ('Angiogenesis' [Mesh] OR 'Atherosclerosis' [Mesh] OR 'Myocardial Infarction' [Mesh] OR 'Cardiomyopathy' [Mesh]) OR 'Heart' [Mesh]) AND ('Adipose-derived stem cells' [Mesh]), identifying 1327 titles.The figure illustrates reasons for the exclusion of papers from this review paper: 552 papers reported only on in vitro experiments on the differentiation of stem cells including incubation with other cells or other components, such as growth factors and their interaction with scaffolds; 82 papers reported on in vivo experiments, for example, comparing fresh, uncultured cells with cells cultured under different conditions but without any mechanistic explanation for diverging results; 388 papers dealing with, in particular, angiogenesis in other diseases like wound healing, bot formation, and oncogenesis and referring to possible value for cardiovascular diseases; 15 papers published by the same authors in several journals but with basically the same content; 129 not reporting original experimental data like review papers, comments, and editorials.In addition, twenty-five papers were excluded because of flawed designs (too small a number of biological replicates or flawed statistics, for example, by not using consistent numbers of biological replicates) and thirty-six because full text was not available in English.The additional thirty-seven references give background information about the properties of ASCs and mechanisms in angiogenesis, atherosclerosis, and ischemia.

Adipose-Derived Stem Cells Preserve EC Function in Preclinical Models
Endothelial dysfunction links metabolic abnormalities, such as obesity, type 2 diabetes, and dyslipidemia, to cardiovascular diseases [24].ASCs may protect ECs and their functions by secreting paracrine factors rather than differentiating into mature ECs [25].Exosomes from ASCs inhibited the expression of miR-342-5p in ECs, thereby reverting their apoptosis [26] (Figure 2).), identifying 1327 titles.The figure illustrates reasons for the exclusion of papers from this review paper: 552 papers reported only on in vitro experiments on the differentiation of stem cells including incubation with other cells or other components, such as growth factors and their interaction with scaffolds; 82 papers reported on in vivo experiments, for example, comparing fresh, uncultured cells with cells cultured under different conditions but without any mechanistic explanation for diverging results; 388 papers dealing with, in particular, angiogenesis in other diseases like wound healing, bot formation, and oncogenesis and referring to possible value for cardiovascular diseases; 15 papers published by the same authors in several journals but with basically the same content; 129 not reporting original experimental data like review papers, comments, and editorials.In addition, twenty-five papers were excluded because of flawed designs (too small a number of biological replicates or flawed statistics, for example, by not using consistent numbers of biological replicates) and thirty-six because full text was not available in English.The additional thirty-seven references give background information about the properties of ASCs and mechanisms in angiogenesis, atherosclerosis, and ischemia.
Human ASCs overexpressing the high mobility group box 1 (HMGB1) protein increased post-ischemic angiogenesis more than control ASCs through increasing VEGF activity [32].Engrafted mouse ASCs also induced angiogenesis by activating the mechanistic target of the rapamycin kinase (mTOR) pathway, associated with reduced inflammatory neutrophil/macrophage infiltration, the secretion of pro-inflammatory IL-1β and TNF-α, and apoptosis [33].

Adipose-Derived Stem Cells Preserve Heart Function in Preclinical Models
Stromal cell-derived factor-1α (SDF-1α) and its receptor, C-X-C chemokine receptor type 4 (CXCR4), are critical for the recruitment, homing, and engraftment of transplanted ASCs into a myocardial infarction damage site.Activation of the SDF-1/CXCR4 axis by physical training potentiated stem cell therapy reduces vasoconstrictor and inflammatory responses [54].SDF-1 released by ASCs increased the number of circulating endothelial progenitor cells (EPCs) and capillary density and reduced hind limb ischemia [55].Periostin might increase these effects of ACSs, inducing integrin β1, PI3K/AKT, and eNOS [56] (Figure 4).
Ischemia-reperfusion (I/R) and hypoxia-reoxygenation (H/R) in a rat model triggered myocardial apoptosis through NF-κB, PUMA, and p53, downregulating BCL-2 and upregulating BAX and caspase 3. I/R-and H/R-induced heart damage was associated with fibrosis by inducing ETS-1, fibronectin, and collagen 3 [57].Intramuscular injection of ASCs or exosomes from ASCs reduced this heart damage and fibrosis by reducing BAX and increasing BCL-2 and cyclin D1.They also inhibited PUMA, ETS-1, fibronectin, and collagen [58].Of interest, rosuvastatin reinforced the action of ASCs [59].ASCs in which prolyl hydroxylase domain protein 2 (PHD2), a cellular oxygen sensor, was silenced reduced the myocardial infarct size and prevented loss of function in mice by preventing cardiomyocyte cell death [60].

Adipose-Derived Stem Cells Preserve Heart Function in Preclinical Models
Stromal cell-derived factor-1α (SDF-1α) and its receptor, C-X-C chemokine receptor type 4 (CXCR4), are critical for the recruitment, homing, and engraftment of transplanted ASCs into a myocardial infarction damage site.Activation of the SDF-1/CXCR4 axis by physical training potentiated stem cell therapy reduces vasoconstrictor and inflammatory responses [54].SDF-1 released by ASCs increased the number of circulating endothelial progenitor cells (EPCs) and capillary density and reduced hind limb ischemia [55].Periostin might increase these effects of ACSs, inducing integrin β1, PI3K/AKT, and eNOS [56] (Figure 4).Ischemia-reperfusion (I/R) and hypoxia-reoxygenation (H/R) in a rat model triggered myocardial apoptosis through NF-κB, PUMA, and p53, downregulating BCL-2 and upregulating BAX and caspase 3. I/R-and H/R-induced heart damage was associated with fibrosis by inducing ETS-1, fibronectin, and collagen 3 [57].Intramuscular injection of ASCs or exosomes from ASCs reduced this heart damage and fibrosis by reducing BAX and increasing BCL-2 and cyclin D1.They also inhibited PUMA, ETS-1, fibronectin, and collagen [58].Of interest, rosuvastatin reinforced the action of ASCs [59].ASCs in which prolyl hydroxylase domain protein 2 (PHD2), a cellular oxygen sensor, was silenced reduced the myocardial infarct size and prevented loss of function in mice by preventing cardiomyocyte cell death [60].
ASC-derived exosomes injected into the myocardium of I/R-treated mice significantly induced miR-221/222 and reduced levels of PUMA and ETS-1, which are associated with lower H2O2-induced apoptosis [61].MiR-210 in exosomes from hypoxia-exposed ASCs inhibited cardiomyocyte apoptosis by blocking the expression of protein tyrosine ASC-derived exosomes injected into the myocardium of I/R-treated mice significantly induced miR-221/222 and reduced levels of PUMA and ETS-1, which are associated with lower H 2 O 2 -induced apoptosis [61].MiR-210 in exosomes from hypoxia-exposed ASCs inhibited cardiomyocyte apoptosis by blocking the expression of protein tyrosine phosphatase 1B and death-associated protein kinase 1 [62].MiR-224-5p increased in exosomes derived from ASCs, downregulated TXNIP, and blocked apoptosis by sustaining the expression of BCL-2 [63], while miR-301 inhibited the apoptosis signal-regulating kinase 1 (ASK1), decreasing ROS release [64].Clathrin-mediated endocytosis of miR-214, enriched in the conditioned medium of ASCs, inhibited cardiomyocyte apoptosis [65].Circ_0001747, enriched in exosomes from ASCs, elevated the messenger RNA and protein levels of the MCL1 apoptosis regulator, the BCL-2 family member (MCL1), by sequestering miR-199b-3p and attenuating H/R-induced injury [66].

Adipose-Derived Stem Cells Are Less Efficient in the Human Clinical Setting Than in Preclinical Models
ASCs delivered to thirteen patients with ischemic heart failure and refractory angina who were not qualified for any form of direct revascularization did not improve LVEF and cardiac output at 12 months of follow-up [80].In a Danish multi-center double-blinded placebo-controlled phase II study, direct intramyocardial injections of allogeneic ASCs were safe but did not improve myocardial function, structure, or clinical symptoms [81].
The phase II, randomized, double-blinded, placebo-controlled MyStromalCell trial included patients with chronic ischemic heart disease.ASCs did not improve myocardial perfusion, LVEF, myocardial mass, stroke volume, left ventricle end-diastolic volume, end-systolic volume, and the amount of scar tissue [82].At 3 years follow-up, the bicycle exercise time and the exercise performance in watts were unchanged, but the performance measured in metabolic equivalents (METs) was slightly increased.In the same period, bicycle exercise time and exercise performance declined in the placebo group.Although angina was significantly reduced in the ASC group but not in the placebo group, there was no significant difference between the groups [83].Furthermore, the intramyocardial delivery of ASCs that were stimulated by VEGF-A 165 did not improve exercise ability compared to the placebo [84].In yet another study including thirty-one patients (seventeen treated with autologous ASCs, fourteen with placebo), ASCs increased the maximal oxygen consumption (MVO2) but not LVEF, left ventricle end-diastolic volume, and end-systolic volume [85].In the PRECISE Trial, a randomized, placebo-controlled, double-blind trial, transendocardial injections of ASCs preserved MRTs and MVO2s while they declined in the control group.The difference in the change in MVO2 from baseline to 6 and 18 months was significantly better in ASC-treated patients compared with the controls.The total left ventricular mass and wall motion score index improved in ASC-treated patients, and inducible ischemia was reduced after 18 months [86].In the Therapeutic Angiogenesis by Cell Transplantation using ASCs (TACT-ADRC), the ASC cohort improved rest pain and 6 min walking distance.Circulating CD34 + and CD133 + progenitor cell markers increased.The ratio of VEGF-A 165 b (an anti-angiogenic isoform of VEGF) to total VEGF-A in plasma significantly decreased, as did the TNF-α in macrophages [87].However, the goal of this study was to assess the effect of autologous ASCs on their ability to promote angiogenesis and suppress tissue inflammation more than their ability to improve heart function.
In conclusion, in contrast to the preclinical models in which ASCs could preserve heart function in patients, they had limited effects.Therefore, we searched for reasons to explain these differences.Comparing the preclinical models and human settings, two main differences emerged.One, most often animals were young and exposed to ischemia for a brief period, whereas heart dysfunction in patients developed over a much longer time.
Finally, the age-related metabolic risk factors that contribute to the development of human cardiovascular diseases are not reiterated in animal models.Therefore, in the last part, we looked at the effect of aging and metabolic reprogramming on the functionality of ASCs.

Aging and Metabolic Reprogramming Decrease the Number and Function of Human ASCs
Aging is associated with increased oxidative stress and mitochondrial dysfunctionassociated cellular damage, contributing to the decline in stemness.Nicotinamide adenine dinucleotide (NAD+), required for maintaining cellular homeostasis and stemness, decreases not only with age directly but also with age-related metabolic disorders.In addition, NAD+ mitigates the differentiation of ASCs to mature adipocytes, associated with an increase in mitochondrial activity and ROS release [88].The CD271-positive ASC subpopulation was reduced in the adipose tissues of diabetic patients, associated with decreased angiogenesis and the expression of the adipose stem cell marker SOX2 [89].Metformin may prevent the differentiation of ASCs to adipocytes and slow down ASC proliferation, preventing these cells from proliferation exhaustion by enhancing the expression of stemness signature genes encoding BMP7, dipeptidyl peptidase 4 (DPP4 or T-cell activation antigen CD26), SOX2, OCT3/4 (or POU class 5 homeobox 1, POU5F1), WNT2, CD90, and delta-like non-canonical Notch ligand 1 (DLK1) [90].Older ASCs had an inverse effect on T cell function by augmenting Th1 cells secreting IFN-γ and decreasing the percentage of anti-inflammatory Tregs [91].Type 2 diabetes may further enhance this age-dependent effect [92].Furthermore, age impaired the paracrine action of ASCs evidenced by reduced levels of SDF-1α, VEGF, and HGF [93].In addition, TGF-β1 and proliferative rates of ASCs decreased with donor age [94].However, another study revealed that a higher number of cell passages has a greater effect on the stemness of ASCs than donor age by itself; for example, by inducing the NF-κB signaling pathway closely related to harmful immune and inflammatory responses [95] (Figure 5).
induced oxidative stress and senescence in ASCs by the downregulation of stem cell markers c-Myc, OCT4, and Sca-1, and anti-oxidative HO-1 [112].MiR-145 was also decreased in obese and diabetic patients, most probably due to a lack of TGF-β1 [113].Restoring the expression of miR-145-5p in ASCs not only enhanced the expression of migration-associated protein FN1, the proliferation-associated proteins CCNA1 and CCND1, and the stem cell markers NANOG and OCT4 but also improved the functions of ECs and fibroblasts.In addition, miR-145 decreased the expression of senescence-associated protein p21 [114].Higher LDL and lower HDL levels in patients with metabolic syndrome were associated with more ROS by the induction of oxidative NOX4 and NOX5 and more inflammatory molecules like MCP-1, C-C motif chemokine ligand 3 (CCL3 or MIP1α), and IL-8 [115].In addition, obese-and particularly type 2 diabetes-derived ASCs released more inflammatory molecules due to the activation of NLRP3 inflammasome.Remarkably, the Higher LDL and lower HDL levels in patients with metabolic syndrome were associated with more ROS by the induction of oxidative NOX4 and NOX5 and more inflammatory molecules like MCP-1, C-C motif chemokine ligand 3 (CCL3 or MIP1α), and IL-8 [115].In addition, obese-and particularly type 2 diabetes-derived ASCs released more inflammatory molecules due to the activation of NLRP3 inflammasome.Remarkably, the immunosuppressive activities of ASCs derived from obese and T2D subjects were reduced and associated with the less effective suppression of lymphocyte proliferation, activation of M2 macrophages, and TGF-β1 secretion than lean-derived ASCs.Treatment of human ASCs from lean subjects with IL-1β mimicked the dysfunctional immune behavior of obese and T2D human ASCs [116].Exosomes isolated from ASCs enriched in miR-145 and mir-221 downregulated the pro-inflammatory markers IL-6 and NF-κB [44].However, IFN-γ suppressed miR-221 [117].In addition, exosomes enriched in miR-21 exerted an anti-inflammatory effect by blocking TLR4 and NF-kB signaling pathways [118].However, miR-21 was downregulated by high glucose in diabetic patients [119].In contrast, inflammatory IL-1β produced exosomes that transferred miR-146a to macrophages, protecting them against M1 polarization and reducing TNF-α and Il-6 by repressing NF-κB and AP-1 signaling [120].Other studies suggested that hypoxia, very small-sized air particles, high glucose, TNF-α, and apolipoprotein E induce miR-146a [121][122][123][124][125][126][127][128][129].
Hyperglycemia, oxidative stress, altered immune reactions, and inflammation associated with type 2 diabetes limited the promotion of angiogenesis by ASCs [113,130].Higher glycolysis may be responsible for their reduced angiogenic capacity because methylglyoxal (MGO), a highly reactive dicarbonyl primarily formed as a byproduct of glycolysis in chronic hyperglycemia and diabetes, inhibited VEGF and PDGF release.In addition, MGO induced the differentiation of ASCs to adipocytes, evidenced by the increased expression of PPARγ2 and increased Oil Red-O stainable lipids.

Conclusions
ASCs proved to protect arteries and the heart in preclinical models in which cardiovascular risks associated with obesity, high glucose, low HDL, and high LDL were kept low.When in patients, these risk factors were not controlled; loss of endothelial integrity, oxidative stress, and inflammation may be associated with metabolic reprogramming of ASCs, leading to loss of functionality.Noncoding RNAs were shown to regulate ASC function, and differences in their expression may explain differences in outcomes in preclinical models and patients.Table 1 shows that a decrease in let-7, miR-17-92, miR-21, miR-145, and miR-221 led to the loss of their function with obesity, type 2 diabetes, oxidative stress, and inflammation.An increase in miR-34a, miR-486-5p, and mir-24-3p contributed to the loss of function, with a noteworthy increase in miR-34a with age.In contrast, miR-146a and miR-210 may protect stem cells.However, a systematic analysis of other noncoding RNAs in human adipose-derived stem cells is warranted.Overall, this review gives insight into modes to improve the functionality of human adipose-derived stem cells.

Figure 1
Figure 1 illustrates the strategy and outcome of the literature search.

Figure 1 .
Figure 1.Strategy and outcome of the literature search.Figure 1. Strategy and outcome of the literature search.

Figure 1 .
Figure 1.Strategy and outcome of the literature search.Figure 1. Strategy and outcome of the literature search.

Cells 2023 ,
12, x FOR PEER REVIEW 4 of 19 We searched the PubMed database for English-language articles related to adiposederived stem cells in mechanisms related to cardiovascular diseases.The search strategy encompassed a MESH search: ('Angiogenesis' [Mesh] OR 'Atherosclerosis' [Mesh] OR 'Myocardial Infarction' [Mesh] OR 'Cardiomyopathy' [Mesh]) OR 'Heart' [Mesh]) AND ('Adipose-derived stem cells' [Mesh]

Figure 2 .
Figure 2. Adipose-derived stem cells improve EC function.The figure illustrates how adiposederived stem cells preserve EC repair, angiogenesis, and microtube formation, and how functional ECs preserve the viability and differentiation ability of adipose-derived stem cell differentiation.Increased regulators are in purple boxes and decreased ones are in pale blue boxes.Upregulated noncoding RNAs are in brown.Decreased ROS is in green.Arrowheads reflect activation; hammerheads reflect inhibition.

19 Figure 3 .
Figure 3. Adipose-derived stem cells prevent atherosclerosis.The figure illustrates how adiposederived stem cells preserve protective M2 macrophages and Treg cells associated with decreased oxidative stress and inflammation.Increased regulators are in purple boxes and decreased ones are in pale blue boxes.Upregulated noncoding RNAs are in brown and downregulated ones are in dark blue.Decreased ROS is in green.Arrowheads reflect activation; hammerheads reflect inhibition.

Figure 3 .
Figure 3. Adipose-derived stem cells prevent atherosclerosis.The figure illustrates how adiposederived stem cells preserve protective M2 macrophages and Treg cells associated with decreased oxidative stress and inflammation.Increased regulators are in purple boxes and decreased ones are in pale blue boxes.Upregulated noncoding RNAs are in brown and downregulated ones are in dark blue.Decreased ROS is in green.Arrowheads reflect activation; hammerheads reflect inhibition.

Figure 4 .
Figure 4. Adipose-derived stem cells preserve heart function.The figure illustrates how adiposederived stem cells protect against AMI, injury caused by ischemia-reperfusion and hypoxia-reoxygenation by retaining M2 macrophages, reducing oxidative stress, inflammation, and apoptosis, preventing vasoconstriction, and restoring angiogenesis.Increased regulators are in purple boxes and decreased ones are in pale blue boxes.Upregulated noncoding RNAs are in brown and downregulated ones are in dark blue.Decreased ROS is in green.Arrowheads reflect activation; hammerheads reflect inhibition.

Figure 4 .
Figure 4. Adipose-derived stem cells preserve heart function.The figure illustrates how adiposederived stem cells protect against AMI, injury caused by ischemia-reperfusion and hypoxiareoxygenation by retaining M2 macrophages, reducing oxidative stress, inflammation, and apoptosis, preventing vasoconstriction, and restoring angiogenesis.Increased regulators are in purple boxes and decreased ones are in pale blue boxes.Upregulated noncoding RNAs are in brown and downregulated ones are in dark blue.Decreased ROS is in green.Arrowheads reflect activation; hammerheads reflect inhibition.

Figure 5 .
Figure 5. Aging and metabolic reprogramming decrease the number and function of human adipose-derived stem cells.The figure illustrates how aging, obesity, type 2 diabetes, and hyperlipidemia reduce stemness and induce senescence in ASCs associated with loss of function in association with oxidative stress, inflammation, apoptosis, and loss of angiogenesis.Increased regulators are in purple boxes and decreased ones are in pale blue boxes.Upregulated noncoding RNAs are in brown and downregulated ones are in dark blue.Increased ROS is in red.Arrowheads reflect activation; hammerheads reflect inhibition.

Figure 5 .
Figure 5. Aging and metabolic reprogramming decrease the number and function of human adiposederived stem cells.The figure illustrates how aging, obesity, type 2 diabetes, and hyperlipidemia reduce stemness and induce senescence in ASCs associated with loss of function in association with oxidative stress, inflammation, apoptosis, and loss of angiogenesis.Increased regulators are in purple boxes and decreased ones are in pale blue boxes.Upregulated noncoding RNAs are in brown and downregulated ones are in dark blue.Increased ROS is in red.Arrowheads reflect activation; hammerheads reflect inhibition.

Table 1 .
Overview of critical miRs in human adipose-derived stem cells and their regulation by aging and metabolic reprogramming.