Abstract
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-γ 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-γ, and FABP4). The expression of Wnt/β-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/β-catenin signaling pathway of MSCs.
Highlights
Allogeneic hematopoietic stem cell transplantation is widely used in the treatment of hematopoietic and non-hematopoietic diseases
Since upregulation of Wnt/β-catenin signaling was found in active Chronic graftversus-host disease (cGVHD)-Mesenchymal stem cells (MSCs), we evaluated the effects of inhibiting the Wnt/β-catenin pathway by Dickkopf related protein 1 (DKK1) on the differentiation capacities of active cGVHD-MSCs in vitro
Immunomodulation of active cGVHD-MSCs was comparable to no cGVHD-MSCs and healthy donors (HD)-MSCs To further investigated the immunomodulatory function of BM-MSCs in active cGVHD patients, we evaluate the cytokine infiltration in the bone marrow serum of active cGVHD patients
Summary
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of hematopoietic and non-hematopoietic diseases. Qi et al Cell Death and Disease (2021)12:308 induction of Tregs[18]. Emerging evidence has demonstrated that MSCs participate in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS)[19,20,21]. In regard to the relationship between MSCs and the pathogenesis of GVHD, a few studies reported that the number of MSCs were decreased and differentiation was abnormal in aGVHD patients[22,23]. It is rarely reported whether MSCs were abnormal in cGVHD patients
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