King's College London

Rationale: Transplantation-accelerated arteriosclerosis is one of the major challenges for long-term survival of patients with solid organ transplantation. Although stem/progenitor cells (SPCs) have been implicated to participate in this process, the cells of origin and underlying mechanisms have not been fully defined.

Objective: The objective of our study was to investigate the role of c-Kit+ SPCs in allograft-induced neointima formation, and to explore the mechanisms underlying this process.

Method and Results: Using an inducible lineage tracing mouse model, we performed allograft transplantation between different donor and recipient mice, as well as bone marrow transplantation experiments, demonstrating that c-Kit+ cells are progenitors of neointimal smooth muscle cells (SMCs) and contribute to neointima formation in an allograft transplantation model. c-Kit-derived SMCs
originate from non-bone marrow tissues of recipient mice, but not donor mice, while bone marrowderived c-Kit+ cells mainly generate CD45+ leucocytes. ACK2, which specifically binds and blocks c-Kit function, ameliorates allograft-induced arteriosclerosis. Stem cell factor (SCF) and transforming growth factor β1 (TGF-β1) levels were significantly increased in blood and neointimal lesions after
allograft transplantation, by which SCF facilitated c-Kit+ SPC migration through the SCF/c-Kit axis and downstream activation of small GTPases, MEK/ERK/MLC and JNK/c-Jun signaling pathways, while TGF-β1 induces c-Kit+ SPC differentiation into SMCs via hexokinase1-dependent metabolic
reprogramming and a possible downstream O-GlcNAcylation of myocardin and serum response factor.

Conclusions: Our findings provide evidence that recipient non-bone marrow-derived c-Kit+ SPCs partially contribute to vascular remodeling in an allograft transplantation model, in which the SCF/c-Kit axis is responsible for stem cell migration and hexokinase1-dependent metabolic reprogramming for SMC differentiation.