Transplantation of adipose tissue and stem cells: role in metabolism and disease

Abstract

Humans and other mammals have three main adipose tissue depots: visceral white adipose tissue, subcutaneous white adipose tissue and brown adipose tissue, each of which possesses unique cell-autonomous properties. In contrast to visceral adipose tissue, which can induce detrimental metabolic effects, subcutaneous white adipose tissue and brown adipose tissue have the potential to benefit metabolism by improving glucose homeostasis and increasing energy consumption. In addition, adipose tissue contains adipose-derived stem cells, which possess the ability to differentiate into multiple lineages, a property that might be of value for the repair or replacement of various damaged cell types. Adipose tissue transplantation has primarily been used as a tool to study physiology and for human reconstructive surgery. Transplantation of adipose tissue is, however, now being explored as a possible tool to promote the beneficial metabolic effects of subcutaneous white adipose tissue and brown adipose tissue, as well as adipose-derived stem cells. Ultimately, the clinical applicability of adipose tissue transplantation for the treatment of obesity and metabolic disorders will reside in the achievable level of safety, reliability and efficacy compared with other treatments.

Figure 1. Adipose tissue in human

Visceral white adipose tissue is associated with increased risk of several metabolic conditions, diseases, and mortality, whereas subcutaneous and brown fat is associated with improved metabolism. Visceral fat secretes higher levels of the adipokines, resistin and retinol binding protein (RBP) 4, which are associated with insulin resistance, whereas subcutaneous fat secretes higher levels of high molecular (MW) adiponectin which is associated with improved metabolism. The developmental gene T-box 15 is more highly expressed in visceral fat of lean individuals, whereas glypican-4 is more highly expressed in the subcutaneous fat of lean individuals. Gene expression of the uncoupling protein 1 (UCP1) is specific to brown fat. miRNA-145 is more highly expressed in the visceral fat of individuals with type 2 diabetes, whereas several miRNAs in the subcutaneous fat are associated with smaller adipocyte size. Visceral fat has higher levels of inflammatory cells and cytokines. Subcutaneous fat is more responsive to the insulin-sensitizing drugs, such as thiazolidinediones (TZDs), than visceral fat.

Figure 2. Fat depots and transplantation of subcutaneous fat in mice

A. The subcutaneous fat depots, visceral fat depots, and brown fat depots are shown in a mouse model, as reprinted from Murano et al¹⁵⁹ and Cinti S. ¹⁶⁰ (used with permission). B. Transplantation of subcutaneous flank fat into the visceral cavity of mice induced several beneficial metabolic effects such as decreased body weight, decreased fat mass and improved insulin sensitivity. These beneficial effects were not mediated by inflammation, adiponectin, or leptin, but might be mediated by decreased levels of resistin.

Figure 3. Differentiation of human adipose-derived stem cells (ASCs) into various phenotypes for clinical applications

The multipotent ASCs have high self-renewal capacity and can differentiate into several cell lineages, such as white and brown adipocytes, osteocytes, chondrocytes, myocytes, leukocytes and endothelial cells from the mesoderm layer; neurons and epithelial cells from the ectoderm layer; as well as hepatocytes, pancreatic cells and epithelial cells from the endoderm layer. This multipotent potential of ASCs may contribute to tissue repair, maintenance, and/or enhancement of various tissues.

Figure 4. Potential Effects of Transplantation of Adipose-Derived Cells Expressing Properties of Subcutaneous White Adipocytes and Brown Adipocytes

Several steps are to be considered as ASCs are engineered to induce beneficial metabolic effects in vivo I. Optimal sources of isolated ASCs are young, healthy, low passaged cells with high potential for proliferation and differentiation without tumorigenesis. II. ASCs are engineered to express regulators of brown fat differentiation or beneficial properties of subcutaneous fat, with the help of inhibitors of nontarget lineages, by various methods such as those involving adenoviral vectors in animals or microbubbles containing plasmid DNA that are triggered to release into specific tissues by ultrasound in humans. III. Scaffolds, growth factors, and inhibitors can be used to promote the growth of engineered ASCs that are delivered in vivo by transplantation during surgery, subcutaneous injections or intravenous injections. IV. The ASCs proliferate, differentiate, and become vascularized and innervated to form functional fat grafts. V. The fat grafts derived from engineered ASCs may then induce potential beneficial metabolic benefits. Abbreviations: BMP7: bone morphogenetic protein; FGF: fibroblast growth factor; HGF: hepatic growth factor; IL: interleukin; MMP: matrix metalloproteinase; PDGF: platelet-derived growth factor; PLGA: (poly(lactic-co-glycolic acid)); PPARγ: peroxisome proliferator-activated receptor; PRDM16: PR domain containing 16; TGF: transforming growth factor; UCP1: uncoupling protein 1;VEGF: vascular endothelial growth factor.