PDF(Pubmed)
Abstract：
Fibrosis is a prominent feature of chronic allograft rejection, caused by an excessive production of matrix proteins, including collagen-1. Several cell types produce collagen-1, including mesenchymal fibroblasts and cells of hematopoietic origin. Here, we sought to determine whether tissue-resident donor-derived cells or allograft-infiltrating recipient-derived cells are responsible for allograft fibrosis, and whether hematopoietic cells contribute to collagen production. A fully MHC-mismatched mouse heterotopic heart transplantation model was used, with transient depletion of CD4+ T cells to prevent acute rejection. Collagen-1 was selectively knocked out in recipients or donors. In addition, collagen-1 was specifically deleted in hematopoietic cells. Tissue-resident macrophages were depleted using anti-CSF1R antibody. Allograft fibrosis and inflammation were quantified 20 days post-transplantation. Selective collagen-1 knock-out in recipients or donors showed that tissue-resident cells from donor hearts, but not infiltrating recipient-derived cells, are responsible for production of collagen-1 in allografts. Cell-type-specific knock-out experiments showed that hematopoietic tissue-resident cells in donor hearts substantially contributed to graft fibrosis. Tissue resident macrophages, however, were not responsible for collagen-production, as their deletion worsened allograft fibrosis. Donor-derived cells including those of hematopoietic origin determine allograft fibrosis, making them attractive targets for organ preconditioning to improve long-term transplantation outcomes.
摘要：
纤维化是慢性同种异体移植排斥反应的一个突出特征，由基质蛋白的过量产生引起的，包括胶原蛋白-1。几种细胞类型产生胶原-1,包括间充质成纤维细胞和造血来源的细胞。这里,我们试图确定组织驻留供体来源的细胞或同种异体移植浸润受体来源的细胞是否负责同种异体移植纤维化。以及造血细胞是否有助于胶原蛋白的产生。使用完全MHC错配的小鼠异位心脏移植模型，与瞬时消耗CD4+T细胞，以防止急性排斥反应。在受体或供体中选择性敲除胶原蛋白-1。此外,胶原-1在造血细胞中特异性缺失。使用抗CSF1R抗体耗尽组织驻留的巨噬细胞。移植后20天定量同种异体移植物纤维化和炎症。受体或供体中的选择性胶原-1敲除表明来自供体心脏的组织驻留细胞,但不浸润受者来源的细胞，负责同种异体移植物中胶原蛋白1的产生。细胞类型特异性敲除实验表明，供体心脏中的造血组织驻留细胞对移植物纤维化有很大贡献。组织驻留巨噬细胞，然而,不负责胶原蛋白的产生，因为它们的缺失恶化了同种异体移植纤维化。供体来源的细胞，包括造血来源的细胞决定同种异体移植物纤维化，使它们成为器官预处理的有吸引力的目标，以改善长期移植结果。
