Recipient c-Kit Lineage Cells Repopulate Smooth Muscle Cells of Transplant Arteriosclerosis in Mouse Models.

Abstract

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.