Aims Graft vascular disease (GVD), a clinically important and highly complex vascular occlusive disease, arises from the interplay of multiple cellular and molecular pathways. While occlusive intimal lesions are composed predominantly of smooth-muscle-like cells (SMLCs), the origin of these cells and the stimuli leading to their accumulation in GVD are uncertain. Macrophages have recently been identified as both potential drivers of intimal hyperplasia and precursors that undergo transdifferentiation to become SMLCs in non-transplant settings. Colony-stimulating factor-1 (CSF1) is a well-known regulator of macrophage development and differentiation, and prior preclinical studies have shown that lack of CSF1 limits GVD. We sought to identify the origins of SMLCs and of cells expressing the CSF1 receptor (CSF1R) in GVD, and to test the hypothesis that pharmacologic inhibition of CSF1 signalling would curtail both macrophage and SMLC activities and decrease vascular occlusion. Methods and results We used genetically modified mice and a vascular transplant model with minor antigen mismatch to assess cell origins. We found that neointimal SMLCs derive from both donor and recipient, and that transdifferentiation of macrophages to SMLC phenotype is minimal in this model. Cells expressing CSF1R in grafts were identified as recipient-derived myeloid cells of Cx3cr1 lineage, and these cells rarely expressed smooth muscle marker proteins. Blockade of CSF1R activity using the tyrosine kinase inhibitor PLX3397 limited the expression of genes associated with innate immunity and decreased levels of circulating monocytes and intimal macrophages. Importantly, PLX3397 attenuated the development of GVD in arterial allografts. Conclusion These studies provide proof of concept for pharmacologic inhibition of the CSF1/CSF1R signalling pathway as a therapeutic strategy in GVD. Further preclinical testing of this pathway in GVD is warranted.

中文翻译：

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PLX3397，一种 CSF1 受体抑制剂，限制同种异体移植诱导的血管重塑

目的 移植血管疾病 (GVD) 是一种临床上重要且高度复杂的血管闭塞性疾病，由多种细胞和分子途径的相互作用引起。虽然闭塞性内膜病变主要由平滑肌样细胞 (SMLC) 组成，但这些细胞的来源和导致它们在 GVD 中积聚的刺激因素尚不确定。巨噬细胞最近被确定为内膜增生的潜在驱动因素和在非移植环境中经历转分化成为 SMLC 的前体。集落刺激因子 1 (CSF1) 是众所周知的巨噬细胞发育和分化调节剂，之前的临床前研究表明，缺乏 CSF1 会限制 GVD。我们试图确定 SMLC 和在 GVD 中表达 CSF1 受体 (CSF1R) 的细胞的起源，并检验 CSF1 信号的药物抑制会减少巨噬细胞和 SMLC 活性并减少血管闭塞的假设。方法和结果 我们使用转基因小鼠和具有轻微抗原错配的血管移植模型来评估细胞来源。我们发现新内膜 SMLC 来源于供体和受体，并且巨噬细胞向 SMLC 表型的转分化在该模型中是最小的。移植物中表达 CSF1R 的细胞被鉴定为 Cx3cr1 谱系的受体来源的骨髓细胞，这些细胞很少表达平滑肌标记蛋白。使用酪氨酸激酶抑制剂 PLX3397 阻断 CSF1R 活性会限制与先天免疫相关的基因表达，并降低循环单核细胞和内膜巨噬细胞的水平。重要的，PLX3397 减弱了动脉同种异体移植物中 GVD 的发展。结论 这些研究提供了药物抑制 CSF1/CSF1R 信号通路作为 GVD 治疗策略的概念证据。有必要对该途径在 GVD 中进行进一步的临床前测试。