Yao Yonghua, Song Xianmin, Cheng Hui, Tang Gusheng, Hu Xiaoxia, Zhou Hong, Wang Jianmin
Department of Hematology, Institute of Hematology, Changhai Hospital, Shanghai, China.
PLoS One. 2014 Aug 13;9(8):e104607. doi: 10.1371/journal.pone.0104607. eCollection 2014.
Acute graft-versus-host disease (aGvHD) is the most common complication of allogeneic hematopoietic stem cell transplantation (HSCT), which is often accompanied by impaired hematopoietic reconstitution. Sinusoidal endothelial cells (SECs) constitute bone marrow (BM) vascular niche that plays an important role in supporting self-renewal capacity and maintaining the stability of HSC pool. Here we provide evidences that vascular niche is a target of aGvHD in a major histocompatibility complex (MHC)-haploidentical matched murine HSCT model. The results demonstrated that hematopoietic cells derived from GvHD mice had the capacity to reconstitute hematopoiesis in healthy recipient mice. However, hematopoietic cells from healthy donor mice failed to reconstitute hematopoiesis in GvHD recipient mice, indicating that the BM niche was impaired by aGvHD in this model. We further demonstrated that SECs were markedly reduced in the BM of aGvHD mice. High level of Fas and caspase-3 expression and high rate of apoptosis were identified in SECs, indicating that SECs were destroyed by aGvHD in this murine HSCT model. Furthermore, high Fas ligand expression on engrafted donor CD4(+), but not CD8(+) T cells, and high level MHC-II but not MHC-I expression on SECs, suggested that SECs apoptosis was mediated by CD4(+) donor T cells through the Fas/FasL pathway.
急性移植物抗宿主病（aGvHD）是异基因造血干细胞移植（HSCT）最常见的并发症，常伴有造血重建受损。窦状内皮细胞（SECs）构成骨髓（BM）血管微环境，在支持造血干细胞自我更新能力和维持造血干细胞池稳定性方面发挥重要作用。在此，我们提供证据表明，在主要组织相容性复合体（MHC）单倍体匹配的小鼠HSCT模型中，血管微环境是aGvHD的一个靶点。结果表明，来自移植物抗宿主病小鼠的造血细胞有能力在健康受体小鼠中重建造血功能。然而，来自健康供体小鼠的造血细胞在移植物抗宿主病受体小鼠中未能重建造血功能，这表明在该模型中骨髓微环境受到了aGvHD的损害。我们进一步证明，移植物抗宿主病小鼠骨髓中的SECs明显减少。在SECs中鉴定出高水平的Fas和caspase-3表达以及高凋亡率，表明在该小鼠HSCT模型中SECs被aGvHD破坏。此外，移植的供体CD4(+)而非CD8(+) T细胞上Fas配体的高表达，以及SECs上高水平的MHC-II而非MHC-I表达，提示SECs凋亡是由CD4(+)供体T细胞通过Fas/FasL途径介导的。
