Using adipose-derived mesenchymal stem cells to fight the metabolic complications of obesity: Where do we stand?

Abstract

Obesity is a critical risk factor for the development of metabolic diseases, and its prevalence is increasing worldwide. Stem cell-based therapies have become a promising tool for therapeutic intervention. Among them are adipose-derived mesenchymal stem cells (ADMSCs), secreting numerous bioactive molecules, like growth factors, cytokines, and chemokines. Their unique features, including immunosuppressive and immunomodulatory properties, make them an ideal candidates for clinical applications. Numerous experimental studies have shown that ADMSCs can improve pancreatic islet cell viability and function, ameliorate hyperglycemia, improve insulin sensitivity, restore liver function, counteract dyslipidemia, lower pro-inflammatory cytokines, and reduce oxidative stress in the animal models. These results prompted scientists to use ADMSCs clinically. However, up to date, there have been few clinical studies or ongoing trails using ADMSCs to treat metabolic disorders such as type 2 diabetes mellitus (T2DM) or liver cirrhosis. Most human studies have implemented autologous ADMSCs with minimal risk of cellular rejection. Because the functionality of ADMSCs is significantly reduced in subjects with obesity and/or metabolic syndrome, their efficacy is questioned. ADMSCs transplantation may offer a potential therapeutic approach for the treatment of metabolic complications of obesity, but randomized controlled trials are required to establish their safety and efficacy in humans prior to routine clinical use.

Keywords: ADMSCs; adipose tissue; metabolic syndrome; obesity.

FIGURE 1

Paracrine functions of ADMSCs. It is now believed that the therapeutic effects of ADMSCs are due to their ability to secrete a wide range of bioactive molecules, including cytokines, chemokines, antioxidant factors, and growth factors. The paracrine mechanism plays a major role in immunomodulation, limitation of apoptosis, and stimulation of local angiogenesis. The immunomodulatory activity of ADMSCs consists of inhibition of dendritic cells (DCs) differentiation, suppression of immunoglobulin synthesis, inhibition of the CD8+ and CD4+ T lymphocytes and natural killer (NK) cells proliferation, and promotion of M2 macrophage polarization and regulatory T cells (Treg) proliferation. Abbreviations: ADMSCs, adipose‐derived mesenchymal stem cells; ANG1, angiopoietin‐1; CCL2, chemokine (C‐C motif) ligand 2; CCL20, chemokine (C‐C motif) ligand 20; CCL26, chemokine (C‐C motif) ligand 26; CCL3, chemokine (C‐C motif) ligand 3; CCL4, chemokine (C‐C motif) ligand 4; CCL5, chemokine (C‐C motif) ligand 5; CCL6, chemokine (C‐C motif) ligand 6; CX3CL1, chemokine (C‐X3‐C motif) ligand 1; CXCL1, chemokine (C‐X‐C motif) ligand 1; CXCL10, chemokine (C‐X‐C motif) ligand 10; CXCL11, chemokine (C‐X‐C motif) ligand 11; CXCL12, chemokine (C‐X‐C motif) ligand 12; CXCL2, chemokine (C‐X‐C motif) ligand 2; CXCL5, chemokine (C‐X‐C motif) ligand 5; CXCL8, chemokine (C‐X‐C motif) ligand 8; FGF, fibroblast growth factor; GM‐CSF, granulocyte macrophage colony‐stimulating factor; HGF, hepatocyte growth factor; HIF, hypoxia inducible factor; IDO, indoleamine 2,3‐dioxygenase; IGF‐1, insulin‐like growth factor 1; IL‐10, interleukin 10; IL‐6, interleukin 6; LIF, leukemia inhibitory factor; MCP‐1, monocyte chemoattractant protein 1; NK, natural killer cells; NO, nitric oxide; PGE2, prostaglandin 2; TGF‐β, tumor growth factor β; VEGF, vascular endothelial growth factor

FIGURE 2

Mechanisms of ADMSCs actions on glucose homeostasis and liver functions. ADMSCs therapy is effective in restoring glycemic status i.e. promotes insulin production and improves insulin sensitivity. Additionally, transplantation of ADMSCs reverses liver steatosis, through reduced inflammation, reduced apoptosis, and improved hepatocyte regeneration. Abbreviations: ADMSCs, adipose‐derived mesenchymal stem cells; AKT, serine/threonine kinase 1; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GLUT4, glucose transporter 4; G6Pase, glucose‐6‐phosphatase; HLCs, hepatocyte‐like cells; HO‐1, heme oxygenase‐1; IL‐1β, interleukin 1β; IL‐6, interleukin 6; IL‐8, interleukin 8; IPCs, insulin producing cells; IRS‐1, insulin receptor substrate 1; LDH, lactate dehydrogenase; MCP‐1, aka CCL2, monocyte chemoattractant protein 1; NQO1, NAD(P)H quinone oxidoreductase 1; PEPCK, phosphoenolpyruvate carboxykinase; PPAR‐γ, peroxisome proliferator‐activated receptor gamma; SOD, superoxide dismutase; TBIL, total bilirubin level; TNF‐α, tumor necrosis factor α

FIGURE 3

Mechanisms underlying the effects of ADMSCs in improving serum lipid profile, reducing atherosclerosis, and restoring ovarian function. Abbreviations: ADMSCs, adipose‐derived mesenchymal stem cells; FGF, fibroblast growth factor; HDL, high‐density lipoprotein; IGF‐1, insulin‐like growth factor 1; LDL, low‐density lipoprotein; TC, total cholesterol; TG, triglycerides; VEGF, vascular endothelial growth factor

FIGURE 4

Potential therapeutic application of ADMSCs in the treatment of obesity and related comorbidities such as diabetes, insulin resistance, vascular disorders, infertility, and NAFLD. Abbreviations: ADMSCs, adipose‐derived mesenchymal stem cells; NAFLD, nonalcoholic fatty liver disease