Wnt/β-catenin signaling mediates the abnormal osteogenic and adipogenic capabilities of bone marrow mesenchymal stem cells from chronic graft-versus-host disease patients

Authors：Qi, Han-zhou; Ye, Yi-ling; Suo, Yuan; Qu, Hong; Zhang, Hai-yan; Yang, Kai-bo; Fan, Zhi-ping; Huang, Fen; Xuan, Li; Chen, Yan-qiu; Jin, Hua^*; Liu, Qi-fa^*

Source：Cell Death & Disease, 2021, 12(4): 308.

DOI：10.1038/s41419-021-03570-6

Chronic graft-versus-host disease (cGVHD) is the main cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mesenchymal stem cells (MSCs) in bone marrow (BM) remain unclear in the pathophysiology of cGVHD. In this study, we analyzed BM-MSCs from 66 patients after allo-HSCT, including 33 with active cGVHD and 33 without cGVHD. BM-MSCs showed similar morphology, frequency, phenotype, and proliferation in patients with or without cGVHD. MSCs from the active cGVHD group showed a decreased apoptosis rate (P<0.01). Osteogenic capacity was increased while adipogenic capacity was decreased in the active cGVHD MSCs compared with no-cGVHD MSCs. The expressions of osteogenic gene RUNX2 and COL1A1 were higher (P<0.001) while adipogenic gene PPAR-gamma and FABP4 were lower (P<0.001) in the active cGVHD MSCs than no-cGVHD MSCs. These changes were associated with the severity of cGVHD (P<0.0001; r=0.534, r=0.476, r=-0.796, and r=-0.747, respectively in RUNX2, COL1A1, PPAR-gamma, and FABP4). The expression of Wnt/beta -catenin pathway ligand Wnt3a was increased in cGVHD-MSCs. The dysfunction of cGVHD-MSCs could be reversed by Dickkopf related protein 1(DKK1) to inhibit the binding of Wnt3a. In summary, the differentiation of BM-MSCs was abnormal in active cGVHD, and its underlying mechanism is the upregulated of Wnt3a through Wnt/beta -catenin signaling pathway of MSCs.

• Institution
  南方医科大学