Metabolic Rescue of Obese Adipose-Derived Stem Cells by Lin28/Let7 Pathway

Abstract

Adipose-derived stem cells (ASCs) are promising candidates for autologous cell-based regeneration therapies by virtue of their multilineage differentiation potential and immunogenicity; however, relatively little is known about their role in adipose tissue physiology and dysfunction. Here we evaluated whether ASCs isolated from nonobese and obese tissue differed in their metabolic characteristics and differentiation potential. During differentiation to mature adipocytes, mouse and human ASCs derived from nonobese tissues both increased their insulin sensitivity and inhibition of lipolysis, whereas obese-derived ASCs were insulin-resistant, showing impaired insulin-stimulated glucose uptake and resistance to the antilipolytic effect of insulin. Furthermore, obese-derived ASCs showed enhanced release of proinflammatory cytokines and impaired production of adiponectin. Interestingly, the delivery of cytosol from control ASCs into obese-derived ASCs using a lipid-based, protein-capture methodology restored insulin sensitivity on glucose and lipid metabolism and reversed the proinflammatory cytokine profile, in part due to the restoration of Lin28 protein levels. In conclusion, glucose and lipid metabolism as well as maturation of ASCs is truncated in an obese environment. The reversal of the altered pathways in obese cells by delivery of normal subcellular fractions offers a potential new tool for cell therapy.

Obesity Determines the Immunophenotypic Profile and Functional Characteristics of Human Mesenchymal Stem Cells From Adipose Tissue

“…We have defined hASCs according to these criteria [20][21][22]. Other methods have been frequently used to identify, isolate, and characterize human and murine ASCs from adipose tissue [23,38]. Thus, previous studies have reported that human and murine WAT is a rich reservoir of CD45 -CD34 + ASCs, with a high basal migration capacity in lean-derived, but not obese-derived, ASCs [23,39].…”

“…Previous results demonstrated that the metabolic phenotype of CD34 + MSCs isolated from obese adipose tissue significantly differed from equivalent cells isolated from lean adipose tissue [23]. To question whether an obese environment might similarly affect the plasticity of isolated hASCs, we evaluated proliferation, migration, and differentiation capacity of hASCs obtained from lean and obese individuals.…”

LIN28: roles and regulation in development and beyond

“…Additionally, LIN28 regulates glucose metabolism; its overexpression increases the ability of muscle cells to take up glucose (Zhu et al, 2010), while its loss results in insulin resistance Zhu et al, 2011). Furthermore, sensitivity to insulin can be restored in obese adipose stem cells with the introduction of LIN28 (Perez et al, 2013). Finally, LIN28 overexpression increases regeneration during digit repair, epidermal hair regrowth and pinnal tissue regrowth in the mouse (Shyh- Chang et al, 2013).…”

“…Initial investigations have revealed roles for LIN28 in glucose uptake and tolerance, diabetes, sickle cell anemia and cancer (de Vasconcellos et al, 2014;Perez et al, 2013;Shinoda et al, 2013;Shyh-Chang et al, 2013;Zhu et al, 2011), suggesting that the modulation of LIN28 activity might be an attractive therapeutic approach. For example, the expression of LIN28 in cultured, sickle-shaped erythrocytes resulted in a significant decrease in their sickle morphology compared with control erythrocytes (de Vasconcellos et al, 2014).…”

miRNAs link metabolic reprogramming to oncogenesis

“…These phenomena occurred in part through let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway [60]. Furthermore, it was recently shown that Lin28 restores glucose metabolism in obese adipocyte stem cells through repression of let-7 expression [61]. MiR-29a…”