Abstract
BackgroundThough accumulated evidence has demonstrated visceral organ involvement in acute graft-versus-host disease (aGVHD), how aGVHD influences the bone marrow (BM) niche and the reconstitution of hematopoiesis post-hematopoietic stem cell transplantation remains largely unknown.MethodsIn the current study, the cell morphology, immunophenotype, multi-differentiation capacity, self-renewal capacity, and hematopoiesis promotion of the MSCs from aGVHD and non-aGVHD patients were investigated. Additionally, the stemness and hematopoiesis-promoting property of healthy donor-derived MSCs were evaluated in the presence of BM supernatant from aGVHD patients. Mechanistically, antibodies targeting inflammatory cytokines involved in aGVHD were added into the MSC culture. Furthermore, a recombinant human tumor necrosis factor (TNF-α) receptor-Ig fusion protein (rhTNFR:Fc) was used to protect healthy donor-derived MSCs. Moreover, mRNA sequencing was performed to explore the underlying mechanisms.ResultsThe aGVHD MSCs exhibited morphological and immunophenotypic characteristics that were similar to those of the non-aGVHD MSCs. However, the osteogenic and adipogenic activities of the aGVHD MSCs significantly decreased. Additionally, the colony formation capacity and the expression of self-renewal-related genes remarkably decreased in aGVHD MSCs. Further, the hematopoiesis-supporting capacity of aGVHD MSCs significantly reduced. The antibody neutralization results showed that TNF-α contributed to the impairment of MSC properties. Moreover, rhTNFR:Fc exhibited notable protective effects on MSCs in the aGVHD BM supernatants. The mRNA sequencing results indicated that the TNF-α pathway and the Toll-like receptor pathway may be activated by TNF-α.ConclusionsThus, our data demonstrate MSCs as cellular targets of aGVHD and suggest a potential role of TNF-α blockage in maintaining the BM niche of aGVHD patients.
Highlights
For many years, allogeneic stem cell transplantation has been used for the treatment of hematological malignancies and nonmalignant hematologic disorders [1, 2]
Liver, and intestine are regarded as the principal target organs of life-threatening acute graft-versushost disease (aGVHD), increasing evidence has demonstrated that the bone marrow (BM) is a potential target tissue of aGVHD, which may contribute to long-term cytopenic conditions, immunodeficiency, bleeding, and infections in patients undergoing post-alloHSCT [5,6,7,8]
Results aGVHD mesenchymal stem cells (MSCs) share similar morphological and immunophenotypic characteristics with non-aGVHD MSCs In the current study, fibroblast-like MSCs were cultured from all BM samples
Summary
Allogeneic stem cell transplantation (alloHSCT) has been used for the treatment of hematological malignancies and nonmalignant hematologic disorders [1, 2]. The success of allo-HSCT is often limited by the development of acute graft-versus-host disease (aGVHD ). Liver, and intestine are regarded as the principal target organs of life-threatening aGVHD, increasing evidence has demonstrated that the bone marrow (BM) is a potential target tissue of aGVHD, which may contribute to long-term cytopenic conditions, immunodeficiency, bleeding, and infections in patients undergoing post-alloHSCT [5,6,7,8]. Numerous studies have demonstrated that aGVHD affects the restoration of almost all hematopoietic lineages post-allo-HSCT, including lymphopoiesis, myelopoiesis, and megakarypoiesis, by targeting HSCs. In addition, accumulated evidence indicates that aGVHD may damage the structure of the stromal niche in BM. Though accumulated evidence has demonstrated visceral organ involvement in acute graft-versushost disease (aGVHD), how aGVHD influences the bone marrow (BM) niche and the reconstitution of hematopoiesis post-hematopoietic stem cell transplantation remains largely unknown
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