Abstract
Crohn’s disease (CD) is a chronic inflammatory bowel disease that is difficult to treat. However, previous preclinical and clinical studies have shown that mesenchymal stromal cells (MSCs) are a promising therapeutic approach, whereas the exact underlying molecular mechanisms of MSCs in treating CD remain unclear. Furthermore, the heterogeneity of MSCs, as well as the in vivo microenvironments may influence the therapeutic efficacy. In our previous study, we found that a subpopulation of mouse MSCs with a high expression of matrix Gla protein (MGP), one of the members of vitamin K-dependent protein family, possessed better immunoregulatory properties. Therefore, in this study we investigate whether the abundant MSCs-derived MGP participate in the therapeutic mechanisms for MSCs treating CD. Obvious suppression of cell proliferation and cytokine production in T cells were observed in vitro through MSCs-derived MGP. Moreover, MGP alleviated the clinical and histopathological severity of colonic inflammation in mouse experimental colitis models to a remarkable degree. Our results indicate that MGP might be a novel important mediator of MSCs-mediated immunomodulation in treating CD.
Highlights
Crohn’s disease (CD) is a multifactorial chronic relapsing disease of the colon and small intestine, triggered by a loss of balance between pro-inflammatory T cells and regulatory T lymphocytes, which results in the production of various pro-inflammatory cytokines and lymphocytes infiltrating the gut[1,2,3,4]
We detected the expressions of VKDPs using quantitative polymerase chain reaction and confirmed that matrix Gla protein (MGP) was the most highly expressed member in mesenchymal stromal cells (MSCs)
The expression of other VKDPs members, including protein S (PS), growth arrest-specific protein 6 (Gas6), osteocalcin (OC), and periostin (POSTN) were lower compared with MGP, and the expressions of prothrombin, factor VIII (F VIII), FIX, FX, protein Z, and protein C (PC) were extremely weak (Fig. 1b)
Summary
Crohn’s disease (CD) is a multifactorial chronic relapsing disease of the colon and small intestine, triggered by a loss of balance between pro-inflammatory T cells and regulatory T lymphocytes, which results in the production of various pro-inflammatory cytokines and lymphocytes infiltrating the gut[1,2,3,4]. In our study[7], it was noticed that one of our mouse bone marrow MSCs subpopulations possessed a higher immunosuppressive ability and express high levels of VKDPs-related genes, which are a group of Official journal of the Cell Death Differentiation Association. The coagulation factors are the most well-known VKDPs, there are many others with important physiologic roles related to bone mineralization, arterial calcification, apoptosis, phagocytosis, growth control, chemotaxis, and signal transduction[14]. In the previous study[7], we reported that MSC4, one of the subpopulations in the MSC family, possesses trilineage differentiation abilities, exhibits superior immunomodulation ability, and expresses the highest levels of matrix Gla protein (MGP) in the VKDPs family
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