Analysis of the onset of ocular chronic graft versus host disease caused by donor-derived fibroblasts and the development of the new therapeutic intervention

为了确定供者来源的成纤维细胞是否来源于骨髓，我们使用了慢性移植物抗宿主病(CGVHD)的动物模型。(张勇，J免疫学，2002)为了研究慢性移植物抗宿主病(CGVHD)患者供体来源成纤维细胞的细胞来源，我们分析了间充质干细胞(MSC)(森川，S，J Exp Med)。和造血干细胞(HSC)(松崎Y，免疫2004年)。我们使用新鲜分离的供体MSCs和受体的HSC进行了前瞻性研究。这是一例单独的骨髓间充质干细胞不匹配移植。在不相合的MSC移植中，泪腺、肝脏和唾液腺的Mallory染色显示进行性纤维化，类似于全骨髓移植。相比之下，同基因骨髓间充质干细胞移植后3周和8周几乎没有发现过度纤维化的区域。以GFP B10.D2小鼠为供体，发现GFP MSCs存在于泪腺、皮肤、肠道等慢性移植物抗宿主病纤维化病变中。这些结果表明，供体MSCs是cGVHD纤维化组织中HSP47成纤维细胞的部分来源。此外，这些结果表明，仅供体MSCs就足以诱导cGVHD纤维化。

To determine whether donor-derived fibroblasts originate from bone marrow, we used an animal model of chronic graft versus host disease (cGVHD). (Zhang Y, J Immunol, 2002)To examine the cellular sources of donor-derived fibroblasts in cGVHD recipients, we analyzed mesenchymal stem cells (MSC) (Morikawa S, J Exp Med. 2009) and hematopoietic stem cells (HSC) (Matsuzaki Y, Immunity 2004) from bone marrow. We performed the prospective study using freshly isolated MSCs from donor and HSC from recipient. This is a MSC alone mismatched transplantation. In contrast, MSCs from recipients and HSCs from donor used as a syngeneic MSC transplantation.In mismatched MSC transplantation, mallory staining of lacrimal gland, liver and salivary gland revealed progressive fibrosis, similar to whole bone marrow transplantation. In contrast, excessive fibrotic areas were scarcely detected 3 and 8 weeks after syngeneic MSC transplantation. When GFP B10.D2 mice were used as donors, GFP+MSCs were found residing in cGVHD fibrotic lesion such as the lacrimal gland, skin and intestine. These results suggest that donor MSCs are partially a source of HSP47+fibroblasts in cGVHD fibrotic tissue. In addition, these results suggest that donor MSCs alone are sufficient to induce cGVHD fibrosis.