Tumor necrosis factor α in aGVHD patients contributed to the impairment of recipient bone marrow MSC stemness and deficiency of their hematopoiesis-promotion capacity

• Published in: Stem cell research & therapy 2020-03, Vol.11 (1), p.119-14, Article 119
• Main Authors: Ding, Li, Ning, Hong-Mei, Li, Pei-Lin, Yan, Hong-Min, Han, Dong-Mei, Zheng, Xiao-Li, Liu, Jing, Zhu, Ling, Xue, Mei, Mao, Ning, Guo, Zi-Kuan, Zhu, Heng, Wang, Heng-Xiang
• Format: Article
• Language: English
• Subjects: Acute graft versus host disease; Antibodies; Blood; Bone Marrow; Bone Marrow Cells; Bone marrow niche; Cell growth; Cell self-renewal; Cytokines; Graft vs Host Disease; Hematopoiesis; Hematopoietic stem cells; Humans; Hypotheses; Immunoglobulins; Medical research; Medicine, Experimental; Mesenchymal stem cell; Mesenchymal Stem Cells; Necrosis; Physical characteristics; RNA; RNA sequencing; Stem cells; Stemness; Studies; Toll-like receptors; Transplantation; Tumor necrosis factor; Tumor Necrosis Factor-alpha - genetics; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Tumors; Viral antibodies
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-020-01615-9

Though 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. In 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. The 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. Thus, 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.