Obesity-Induced Methylation of Osteopontin Contributes to Adipogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells

Abstract

Obesity is a major risk factor for many chronic diseases, including diabetes, fatty livers, and cancer. Expansion of the adipose mass has been shown to be related to adipogenic differentiation of adipose-derived mesenchymal stem cells (ASCs). However, the underlying mechanism of this effect has yet to be elucidated. We found that osteopontin (OPN) is downregulated in ASCs and adipose tissues of obese mice and overweight human beings because of methylation on its promoter, indicating that OPN may affect the development of obesity. Silencing of OPN in wild-type ASCs promotes adipogenic differentiation, while reexpression of OPN reduced adipogenic differentiation in OPN−/− ASCs. The role of extracellular OPN in ASC differentiation was further demonstrated by supplementation and neutralization of OPN. Additionally, OPN suppresses adipogenic differentiation in ASCs through the C/EBP pathways. Consistent with these in vitro results, by intravenous injection of OPN-expressing adenovirus to the mice, we found OPN can delay the development of obesity and improve insulin sensitivity. Therefore, our study demonstrates an important role of OPN in regulating the development of obesity, indicating OPN might be a novel target to attenuate obesity and its complications.

Effective delivery of osteopontin small interference RNA using exosomes suppresses liver fibrosis via TGF-β1 signaling

“…Adipose tissue-derived MSCs (ASCs) represent a highly advantageous tool for stem cell-based therapy (Lou et al, 2015;Tang et al, 2019;Lou et al, 2020). Under specificdifferentiation conditions in vitro, ASCs can differentiate into adipocytes and osteoblasts depending on the presence of adipogenic and osteogenic factors (Tang et al, 2019). Positive staining of Alizarin Red S or Oil Red O was observed after osteogenic induction for 21 days or adipogenic induction for 7 days, respectively, as we previously reported (Figure 3A).…”

“…Adipose tissue-derived MSCs (ASCs) represent a highly advantageous tool for stem cell-based therapy (Lou et al, 2015;Tang et al, 2019;Lou et al, 2020). Under specificdifferentiation conditions in vitro, ASCs can differentiate into adipocytes and osteoblasts depending on the presence of adipogenic and osteogenic factors (Tang et al, 2019).…”

The Proliferation and Differentiation of Adipose-Derived Stem Cells in Neovascularization and Angiogenesis

“…Fully differentiated adipocytes require stimulation of precursor cells with different factors, for example the effects of biochemical cues of adipose specific extracellular matrix (ECM) not only enhance adipogenic differentiation but they also stimulate adipogenesis in ASCs [76,77]. Osteopontin (OPN) is downregulated in obese individuals and its silencing promotes ASCs adipogenic differentiation [78]. Precursors of adipocytes are able to differentiate into brown adipocytes when treated with norepinephrine, which increased lipolysis and Ucp1 mRNA expression [79].…”

Vascular Derived ECM Improves Therapeutic Index of BMP‐2 and Drives Vascularized Bone Regeneration

“…The effective reconstruction of large bone defects caused by trauma, tumor resection, or congenital malformation remains a major challenge in orthopedic surgery. [ 1,2 ] Vascularization represents one of the most crucial aspects of tacking this significant clinical problem due to the fact that bone is a highly vascularized tissue to support local tissue rescue, repairing, and survive. [ 3,4 ] In particular, neovascularization, also known as angiogenesis plays a pivotal role in bone formation, remodeling, and healing, as blood vessels supply oxygen, nutrients for cell survival, proliferation, and differentiation during these biological processes.…”