Abstract
Rationale: Transplantation-accelerated arteriosclerosis is one of the major challenges for long-term survival of patients with solid organ transplantation. Though stem/progenitor cells (SPCs) have been implicated to participate in this process, the origin of these SPCs and the underlying mechanisms behind their contribution to disease have not been fully defined.Objective: The objective of our study was to investigate the role of c-Kit+ SPCs in allograft-induced lesion formation, and to explore the underlying mechanisms.
Methods and Results: c-Kit+ SPCs were detected in allograft-induced neointima lesions using immunostaining. By using an inducible lineage tracing mouse model, we showed that c-Kit+ SPCs are an important source of neointimal smooth muscle cells (SMCs) and endothelial cells (ECs), contributing to neointima formation in an aortic allograft transplantation model. We performed allograft transplantation between different donor and recipient mice, as well as bone marrow transplantation experiments, demonstrating that c-Kit+ SPCs-derived cells originate from non-bone marrow tissues of recipient mice, but not donor mice. ACK2, which specifically binds and blocks c-Kit function, ameliorates allograft-induced arteriosclerosis. Stem cell factor (SCF) and vascular endothelial growth factor (VEGF) levels were significantly increased in blood and neointimal lesions after allograft transplantation. C-Kit+ SPCs were harvested from grafts to investigate underlying mechanisms in vitro. Mechanistically, SCF facilitated cell migration through SCF/c-Kit axis and downstream activation of small GTPases, MEK/ERK/MLC and JNK/c-Jun signalling pathways, while VEGF induced c-Kit+ SPCs migration via AKT/FAK signalling.
Conclusions: Our findings provide evidence that recipient non-bone marrow-derived c-Kit+ SPCs migrate to allograft lesions, differentiate into SMCs and ECs contributing to vascular remodelling in an allograft transplantation model. Mechanisms involving cell migration may provide insights into pathogenesis and treatment of vascular diseases.
| Date of Award | 2018 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Yanhua Hu (Supervisor) & Qingbo Xu (Supervisor) |