Details

Autor(en) / Beteiligte

• Ni, Zhichao
• Deng, Jiacheng
• Potter, Claire M.F
• Nowak, Witold N
• Gu, Wenduo
• Zhang, Zhongyi
• Chen, Ting
• Chen, Qishan
• Hu, Yanhua
• Zhou, Bin
• Xu, Qingbo
• Zhang, Li

Titel

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

Ist Teil von

• Circulation research, 2019-07, Vol.125 (2), p.223-241

Ort / Verlag

United States: American Heart Association, Inc

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• RATIONALE: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. OBJECTIVE: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. METHODS AND RESULTS: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. CONCLUSIONS: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.