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

为了确定供体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）动物模型。为了研究cGVHD受者供体来源成纤维细胞的细胞来源，我们分析了骨髓间充质干细胞（MSC） （Morikawa S, J Exp Med. 2009）和造血干细胞（Matsuzaki Y, Immunity . 2004）。我们使用来自供体的新鲜分离的MSCs和来自受体的HSC进行了前瞻性研究。这是一个单独的MSC错配移植。相比之下，来自受体的间充质干细胞和来自供体的造血干细胞被用作同基因间充质干细胞移植。错配间充质干细胞移植中，泪腺、肝脏和唾液腺的mallory染色显示进行性纤维化，与全骨髓移植相似。相比之下，在同基因间充质干细胞移植后3周和8周，几乎没有发现过多的纤维化区域。当GFP B10。D2小鼠作为供体，GFP+MSCs存在于cGVHD纤维化病变如泪腺、皮肤和肠中。这些结果表明，供体间充质干细胞是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，仅供体间充质干细胞就足以诱导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.