Recipient c-Kit Lineage Cells Repopulate Smooth Muscle Cells of Transplant Arteriosclerosis in Mouse Models: Stem Cells Repopulate Allograft Vessels

Zhichao Ni, Jiacheng Deng, Claire Marie Frances Potter, Witold Norbert Nowak, Wenduo Gu, Zhongyi Zhang, Ting Chen, Qishan Chen, Yanhua Hu, Bin Zhou, Qingbo Xu, Li Zhang

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51 Citations (Scopus)
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Abstract

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.
Original languageEnglish
Pages (from-to)223-241
Number of pages19
JournalCirculation Research
Volume125
Issue number2
Early online date13 May 2019
DOIs
Publication statusPublished - 5 Jul 2019

Keywords

  • arteriosclerosis
  • lineage tracing
  • metabolism
  • stem cells
  • transplantation

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