CXCL2 Impairs Functions of Bone Marrow Mesenchymal Stem Cells and Can Serve as a Serum Marker in High-Fat Diet-Fed Rats.

Jianhai Bi,Xia Liu,Li Yan,Qian Wang,Tao Lv,Zhigang Yang,Xin Fu,Ran Xiao,Qiuchen Li,Lei Cai,Xun Yang

doi:10.3389/fcell.2021.687942

Abstract

In modern society excessive consumption of a high-fat diet (HFD) is a significant risk factor for many diseases such as diabetes, osteoarthritis and certain cancers. Resolving cellular and molecular mechanisms underlying HFD-associated disorders is of great importance to human health. Mesenchymal stem cells (MSCs) are key players in tissue homeostasis and adversely affected by prolonged HFD feeding. Low-grade systemic inflammation induced by HFD is characterized by increased levels of pro-inflammatory cytokines and alters homeostasis in many organs. However, whether, which and how HFD associated inflammatory cytokines impair MSCs remain unclear. Here we demonstrated that HFD induced serum cytokines disturbances, especially a continuous elevation of serum CXCL2 level in rats. Coincidentally, the differentially expressed genes (DEGs) of bone marrow MSCs (BMSCs) which functions were impaired in HFD rats were enriched in cytokine signaling. Further mechanism analysis revealed that CXCL2 treatment in vitro suppresses the adipogenic potential of BMSCs via Rac1 activation, and promoted BMSC migration and senescence by inducing over-production of ELMO1 and reactive oxygen species (ROS) respectively. Moreover, we found that although glycolipid metabolism indicators can be corrected, the CXCL2 elevation and BMSC dysfunctions cannot be fully rescued by diet correction and anti-inflammatory aspirin treatment, indicating the long-lasting deleterious effects of HFD on serum CXCL2 levels and BMSC functions. Altogether, our findings identify CXCL2 as an important regulator in BMSCs functions and may serve as a serum marker to indicate the BMSC dysfunctions induced by HFD. In addition, our findings underscore the intricate link among high-fat intake, chronic inflammation and BMSC dysfunction which may facilitate development of protective strategies for HFD associated diseases.

Highlights

In recent years, overnutrition like excessive consumption of a high-fat diet (HFD) has been viewed as a significant risk factor for the obesity and obesity-associated metabolic disorders such as insulin resistance, type 2 diabetes, fatty liver disease, osteoarthritis and cancers (Stemmer et al, 2012; Kyrou et al, 2018)
We show that the continuously elevated serum CXCL2 level is closely correlated with the dysfunction of bone marrow-derived mesenchymal stem cells (MSC) (BMSCs) in HFD-fed rats in vivo and CXCL2 treatment can directly contribute to the dysfunction of BMSCs through ELMO/Rac1-mediated signaling in vitro
Glycolipid metabolism indicators can be corrected, the CXCL2 elevation and BMSC dysfunctions cannot be fully rescued by diet correction and anti-inflammatory aspirin treatment, indicating the long-lasting deleterious effects of HFD on serum CXCL2 levels and BMSC functions

Summary

Introduction

Overnutrition like excessive consumption of a high-fat diet (HFD) has been viewed as a significant risk factor for the obesity and obesity-associated metabolic disorders such as insulin resistance, type 2 diabetes, fatty liver disease, osteoarthritis and cancers (Stemmer et al, 2012; Kyrou et al, 2018). Certain cytokine may account for alterations in body composition in chronic diseases associated with HFD. Effects of TNFα and IL-6 on the development of kidney dysfunction was further demonstrated in HFD-fed Apo E−/− mice (TomiyamaHanayama et al, 2009). These studies reveal the role for cytokines in tissue homeostasis and function. It remains unclear how the HFD-driven disturbance of cytokines impacts on tissue composition and function

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