Role of colony stimulating factor 1 receptor (CSF1R) in graft vascular disease

项目概要 实体器官移植是终末期器官衰竭的常见且有效的治疗方法。 尽管免疫抑制治疗已成功预防急性移植排斥反应， 实体器官移植物的长期存活受到称为移植物血管的状况的影响 疾病（GVD），移植物内的脉管系统被闭塞。 GVD 是 由细胞外基质、平滑肌样细胞 (SMLC) 和免疫细胞的沉积组成 细胞积聚形成阻塞性新内膜病变。目前尚无治疗方法 防止或逆转新内膜积聚；一旦GVD导致移植失败，最终 解决办法就是重新移植。此外，以前用于研究 GVD 的动物模型已经 产生的 GVD 与临床样本中观察到的不同，这反映了需要 更好地理解模型的局限性。 该领域的一些悬而未决的问题包括 1) 来源是什么（捐赠者与接受者）以及 导致新内膜损伤的细胞类型，以及 2) 驱动新内膜损伤的早期事件是什么 GVD 中细胞的增殖和迁移最终成为新生内膜 SMLC。 研究人员试图通过鼠血管移植来回答这些问题 主要组织相容性复合物 (MHC) 不匹配的 GVD 模型，但最近的工作 表明这些模型与临床 GVD 有很大不同——在这些小鼠模型中， 新内膜细胞可能来自受体，而在临床心脏移植中，GVD 新生内膜细胞大多来自移植物。 最近描述的基于H-Y抗原驱动的GVD血管移植模型 不兼容可能会解决此问题。在此模型中，组织不相容性较轻微 （H-Y 抗原提供较小的组织相容性不匹配）允许供体内侧细胞存活， 与临床 GVD 发病机制中的观察结果相似。虽然这一观察结果对 新模型的相关性，目前还不清楚内侧平滑肌细胞是否来自 正如其他模型所示，供体组织参与血管闭塞 血管损伤。该提案将解决本研究中的一些基本发病机制问题。 模型，特别关注供体与受体的新内膜病变起源，其程度 来自移植血管系统的分化成熟平滑肌细胞有助于新生内膜 SMLC，以及先前确定的集落刺激因子 1 (CSF1)/的要求 该 GVD 模型中的集落刺激因子 1 受体 (CSF1R) 信号通路。

Project Summary Solid organ transplantation is a common and effective treatment of end-stage organ failure. Although immunosuppressive treatment has been successful in preventing acute graft rejection, the long-term survival of solid organ transplants is affected by a condition termed graft vascular disease (GVD), through which the vasculature within the graft becomes occluded. GVD is composed of deposition of extracellular matrix, smooth muscle-like cells (SMLCs) and immune cells that accumulate to form obstructive neointimal lesions. Currently there is no treatment to either prevent or reverse neointimal accumulation; once GVD leads to graft failure, the ultimate solution is to retransplant. Furthermore, animal models previously used to study GVD have produced GVD that differs from what is observed in clinical samples, which reflects on the need to better understand the limitations of the models. Some of the open questions in the field include 1) what are the origins (donor vs recipient) and cell types that contribute to neointimal lesions, and 2) what are the early events that drive the proliferation and migration of cells that eventually become neointimal SMLCs in GVD. Investigators have attempted to answer these questions using murine vascular transplant models of GVD with Major Histocompatibility Complex (MHC) mismatches but recent work suggests that these models differ importantly from clinical GVD — in these mouse models, neointimal cells may arise from the recipient, whereas in clinical heart transplantation, GVD neointimal cells are mostly graft derived. A recently described vascular transplant model of GVD based on H-Y antigen-driven incompatibility may provide a remedy to this problem. In this model, milder tissue incompatibility (H-Y antigens provide minor histocompatibility mismatch) allows survival of donor medial cells, similar to observations in clinical GVD pathogenesis. While this observation is promising for the relevance of the new model, it is still not clear whether medial smooth muscle cells from the donor tissue are participating in vascular occlusion, as has been shown in other models of vascular injury. This proposal will address some of these basic pathogenetic questions in this model, specifically looking at donor vs recipient origin of neointimal lesions, the extent to which differentiated mature smooth muscle cells from the graft vasculature contribute to neointimal SMLCs, and the requirement for the previously identified colony stimulating factor 1 (CSF1)/ colony stimulating factor 1 receptor (CSF1R) signaling pathway in this model of GVD.