From the School of Cardiovascular Medicine and Sciences, King's College London, BHF Centre, United Kingdom (Z.N., J.D., C.M.F.P., W.N.N., W.G., Z.Z., Y.H., Q.X.).
Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (T.C., Q.C., Q.X., L.Z.).
Circ Res. 2019 Jul 5;125(2):223-241. doi: 10.1161/CIRCRESAHA.119.314855. Epub 2019 May 13.
Transplantation-accelerated arteriosclerosis is one of the major challenges for long-term survival of patients with solid organ transplantation. Although stem/progenitor cells have been implicated to participate in this process, the cells of origin and underlying mechanisms have not been fully defined.
The objective of our study was to investigate the role of c-Kit lineage cells in allograft-induced neointima formation and to explore the mechanisms underlying this process.
Using an inducible lineage tracing Kit-CreER;Rosa26-tdTomato mouse model, we observed that c-Kit is expressed in multiple cell types in the blood vessels, rather than a specific stem/progenitor cell marker. We performed allograft transplantation between different donor and recipient mice, as well as bone marrow transplantation experiments, demonstrating that recipient c-Kit cells repopulate neointimal smooth muscle cells (SMCs) and leukocytes, and contribute to neointima formation in an allograft transplantation model. c-Kit-derived SMCs originate from nonbone marrow tissues, whereas bone marrow-derived c-Kit cells mainly generate CD45 leukocytes. However, the exact identity of c-Kit lineage cells contributing to neointimal SMCs remains unclear. ACK2 (anti-c-Kit antibody), which specifically binds and blocks c-Kit function, ameliorates allograft-induced arteriosclerosis. Stem cell factor and TGF (transforming growth factor)-β1 levels were significantly increased in blood and neointimal lesions after allograft transplantation, by which stem cell factor facilitated c-Kit cell migration through the stem cell factor/c-Kit axis and downstream activation of small GTPases, MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase)/MLC (myosin light chain), and JNK (c-Jun N-terminal kinase)/c-Jun signaling pathways, whereas TGF-β1 induces c-Kit cell differentiation into SMCs via HK (hexokinase)-1-dependent metabolic reprogramming and a possible downstream O-GlcNAcylation of myocardin and serum response factor.
Our findings provide evidence that recipient c-Kit lineage cells contribute to vascular remodeling in an allograft transplantation model, in which the stem cell factor/c-Kit axis is responsible for cell migration and HK-1-dependent metabolic reprogramming for SMC differentiation.
移植加速性动脉硬化是实体器官移植患者长期存活的主要挑战之一。虽然干细胞/祖细胞被认为参与了这一过程，但细胞起源和潜在机制尚未完全确定。
本研究旨在探讨 c-Kit 谱系细胞在同种异体移植诱导的新生内膜形成中的作用，并探讨其潜在机制。
利用诱导型谱系追踪 Kit-CreER;Rosa26-tdTomato 小鼠模型，我们观察到 c-Kit 在血管中的多种细胞类型中表达，而不是特定的干细胞/祖细胞标志物。我们进行了不同供体和受体小鼠之间的同种异体移植以及骨髓移植实验，证明受体 c-Kit 细胞重新填充新生内膜平滑肌细胞（SMC）和白细胞，并有助于同种异体移植模型中的新生内膜形成。c-Kit 衍生的 SMC 起源于非骨髓组织，而骨髓衍生的 c-Kit 细胞主要产生 CD45 白细胞。然而，导致新生内膜 SMC 形成的确切 c-Kit 谱系细胞身份仍不清楚。ACK2（抗 c-Kit 抗体）特异性结合并阻断 c-Kit 功能，可改善同种异体移植诱导的动脉硬化。同种异体移植后，血液和新生内膜病变中干细胞因子和 TGF-β1（转化生长因子）水平显著升高，其中干细胞因子通过干细胞因子/c-Kit 轴促进 c-Kit 细胞迁移，并激活下游小 GTPases、MEK（丝裂原激活蛋白激酶激酶）/ERK（细胞外信号调节激酶）/MLC（肌球蛋白轻链）和 JNK（c-Jun N 末端激酶）/c-Jun 信号通路，而 TGF-β1 通过 HK（己糖激酶）-1 依赖性代谢重编程和肌球蛋白和血清反应因子的 O-GlcNAc 化的可能下游作用诱导 c-Kit 细胞分化为 SMC。
本研究结果表明，受体 c-Kit 谱系细胞有助于同种异体移植模型中的血管重塑，其中干细胞因子/c-Kit 轴负责细胞迁移和 HK-1 依赖性代谢重编程以促进 SMC 分化。
