Transplantation of fat tissues and iPSC-derived energy expenditure adipocytes to counteract obesity-driven metabolic disorders: Current strategies and future perspectives

Abstract

Several therapeutic options have been developed to address the obesity epidemic and treat associated metabolic diseases. Despite the beneficial effects of surgery and drugs, effective therapeutic solutions have been held back by the poor long-term efficiency and detrimental side effects. The development of alternative approaches is thus urgently required. Fat transplantation is common practice in many surgical procedures, including aesthetic and reconstructive surgery, and is a budding future direction for treating obesity-related metabolic defects. This review focuses on adipose tissue transplantation and the recent development of cell-based therapies to boost the mass of energy-expenditure cells. Brown adipocyte transplantation is a promising novel therapy to manage obesity and associated metabolic disorders, but the need to have an abundant and relevant source of brown fat tissue or brown adipocytes for transplantation is a major hurdle to overcome. Current studies have focused on the rodent model to obtain a proof of concept of a tissue-transplantation strategy able to achieve effective long-term effects to reverse metabolic defects in obese patients. Future perspectives and opportunities to develop innovative human fat tissue models and 3D engineered hiPSC-adipocytes are discussed.

Keywords: Adipose tissues; Metabolic disorders; Obesity; Transplantation; iPSC-derived adipocytes.

Fig. 1

Sources of energy expenditure adipocytes and expected effects of their transplantation on metabolic health. Left part: iPSCs can be generated from patients. An iPSC colony and an iPSC-derived 3D vascularized adiposphere expressing perilipin 1 (red), UCP1 (green), and CD31 (white) are shown. Right part: A biopsy of subcutaneous white adipose tissue can be converted ex vivo in beige adipose tissue expressing UCP1 (green). Lipid droplets were staining with Oil Red O. Images showed in the figure originate from projects developed in Dani’s group

Fig. 2

Generation of prevascularized hiPSC-3D adipospheres. Adipose progenitors were derived from hiPSCs and induced to differentiate in 3D adipospheres in the presence of endothelial cells. 3D adipospheres were stained for CD31 endothelial cells (white), and UCP1 (green) and then transparized as described by Yao Xi and Dani Christian (Methods in Molecular Biology, iPS cells: Methods and Protocols, in press). Images were acquired on a LSM780 confocal microscope and the 3D reconstruction was generated by the Imaris software. The scale bar is 50 μm

Fig. 3

Comparison of the extra cellular matrix profile of hiPSC-3D adipospheres and human adipose tissue. 3D adipospheres and human adipose tissue were fixed and stained for lipid droplets (red) and proteins of the extra cellular matrix indicated