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Mesenchymal Stem Cells Cure Autoimmune Diseases Through IGF-2-altered Metabolism in Macrophages

Feb 18, 2019     Email"> PrintText Size

Mesenchymal stem cells (MSCs) are almost ubiquitous in the human body. They are easily accessible and can be expanded in culture dishes. Owing to their strong abilities to regulate immune responses, MSCs hold a great promise for the treatment of various immune disorders.

Previous studies have demonstrated that the immunoregulatory properties of MSCs are not intrinsic (Cell Stem Cell. 2008; 2:141-150), rather tightly regulated by local tissue environment (Nature Immunology. 2014; 15:1009-1016). MSCs in general are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation. However, how MSCs regulate tissue microenvironment and thereby exert therapeutic effects remains unknown.

In a recent study published in Cell Metabolism, a research group led by Prof. SHI Yufang and Prof. WANG Ying from Shanghai Institute of Nutrition and Health of Chinese Academy of Sciences revealed that a low oxygen culture condition could enhance the therapeutic effects of MSCs on autoimmune diseases by up-regulating the secretion of insulin like growth factor-2 (IGF-2).

They demonstrated the role of IGF-2 by genetic knockdown, specific antibody neutralization and direct administration of IGF-2 in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis.

IGF-2 was found to induce a population of PD-L1high macrophages, which in turn promote the differentiation of immunosuppressive Tregs. This effect of IGF-2 was found to be exerted through metabolically preprogramming maturing macrophages to commit oxidative phosphorylation (OXPHOS). Blockade of OXPHOS by oligomycin could diminish the therapeutic effect of IGF-2.

This study revealed an unappreciated mechanism of MSC-mediated therapy and provided a novel strategy for targeting macrophages in managing autoimmune disorders.

The study was supported by grants from the National Key R&D Program of China, Chinese Academy of Sciences, National Natural Science Foundation of China, Suzhou Science and Technology Program, and Department of Science and Technology of Jiangsu Province.

 

Figure: Low oxygen conditioned MSC metabolically reprogrammed maturing macrophages to highly express PD-L1 through production IGF-2. IGF-2-preprogrammed macrophages can promote Treg differentiation and notably inhibit autoimmune disease. (Image by Prof. SHI Yufang and Prof. WANG Ying's Group)

(Editor: LIU Jia)

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