Epstein–Barr virus-induced gene 3 commits human mesenchymal stem cells to differentiate into chondrocytes via endoplasmic reticulum stress sensor

• Published in: PloS one Vol. 17; no. 12; p. e0279584
• Main Authors: Zhang, Tong, Yamagata, Kaoru, Iwata, Shigeru, Sonomoto, Koshiro, Trimova, Gulzhan, Nguyen, Anh Phuong, Hao, He, Shan, Yu, Nguyen, Mai-Phuong, Nakayamada, Shingo, Tanaka, Yoshiya
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.12.2022; Public Library of Science (PLoS)
• Subjects: Accumulation; Analysis; Antibodies; Arthritis; Biology and Life Sciences; Bone marrow; Cartilage; Cell cycle; Cell differentiation; Cell Differentiation - genetics; Chondrocytes; Chondrocytes - cytology; Chondrogenesis; Chondrogenesis - genetics; Control; Cytokines; Differentiation; EBI3 protein; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Endoribonucleases - genetics; Endoribonucleases - metabolism; Epstein-Barr virus; Health aspects; Humans; Identification and classification; IL-1β; Inositol; Inositols; Interleukin 27; Interleukins; Interleukins - genetics; Interleukins - physiology; Kinases; Medicine and Health Sciences; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Minor Histocompatibility Antigens - genetics; Minor Histocompatibility Antigens - physiology; Phenylbutyric acid; Prevention; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Research and Analysis Methods; Rheumatoid arthritis; Risk factors; Sensors; Stem cells; Stress; Stress (Physiology); Tumor necrosis factor-α; Viruses; Japan; United States > US; Chicago Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0279584

Mesenchymal stem cells (MSC) can differentiate into chondrocytes. Epstein–Barr virus-induced gene 3 (EBI3) is differentially expressed during chondrogenic differentiation and can be produced by MSC. EBI3 is also a subunit of interleukin (IL)-27 and IL-35, and it accumulates in the endoplasmic reticulum (ER) when its partners, such as IL-27 p28 and IL-35 p35, are insufficient. ER stress induced by protein accumulation is responsible for chondrogenic differentiation. However, the role of EBI3 and its relevance to the ER stress in chondrogenic differentiation of MSC have never been addressed. Here, we demonstrate that EBI3 protein is expressed in the early stage of chondrogenic differentiation of MSC. Additionally, knockdown, overexpression, or induction of EBI3 through IL-1β inhibits chondrogenesis. We show that EBI3 localizes and accumulates in the ER of MSC after overexpression or induction by IL-1β and TNF-α, whereas ER stress inhibitor 4-phenylbutyric acid decreases its accumulation in MSC. Moreover, EBI3 modulates ER stress sensor inositol-requiring enzyme 1 α (IRE1α) after induced by IL-1β, and MSC-like cells coexpress EBI3 and IRE1α in rheumatoid arthritis (RA) synovial tissue. Altogether, these data demonstrate that intracellular EBI3 commits to chondrogenic differentiation by regulating ER stress sensor IRE1α.