Lineage Tracing Analysis Of Non-bone Marrow C-Kit+ Stem/progenitor Cells Participate In Pathological Hyperplasia Of Allograft Vessels

Background:Transplantation-accelerated arteriosclerosis is one of the major limitations for long-term survival of patients with solid organ transplantation.More than 50%transplant patients encounter angiographically visible transplantation arteriosclerosis within 10 years of transplantation.Transplantation arteriosclerosis is a chronic vascular proliferation disease characterized by diffuse intimal hyperplasia,which is characterized by the accumulation of white blood cells and vascular smooth muscle cells in the artery,resulting in vascular stenosis,tissue ischemia and subsequent graft failure.Although stem/progenitor cells(SPCs)have been implicated to participate in this process,yet the cells of origin and underlying mechanisms have not been fully defined.Therefore,we performed this lineage tracing study using an animal arterial graft model to reveal the pathophysiological progress in which c-Kit+stem/progenitor cells participate in arteriosclerosis after transplantation.Objective:The object of our study was to investigate the role of c-Kit+ stem/progenitor cells SPCs in allograft-induced neointima formation,and to trace the involvement of c-Kit+SPCs in the pathological hyperplasia,differentiation and vascular remodeling of allograft vessels by using an allograft transplantation mouse model.Methods and Results:c-Kit+ SPCs are detected in allograft-induced neointima lesions by immunostaining.By using an inducible lineage tracing mouse model,we showed that c-Kit+ SPCs are important source of neointimal smooth muscle cells(SMCs)and contribute 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 SMCs 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)levels are significantly increased in blood and neointimal lesions after allograft transplantation.Conclusion:Our findings provide evidence that recipient non-bone marrow-derived c-Kit+SPCs migrate to neointimal lesions,differentiate into SMCs and contribute to vascular remodeling in an allograft transplantation model.