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

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 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.

miR-214-3p-Sufu-GLI1 is a novel regulatory axis controlling inflammatory smooth muscle cell differentiation from stem cells and neointimal hyperplasia

“…Smooth muscle cell (SMC) accumulation and phenotypic transition are critical steps for vascular remodelling in response to vascular injury. Although recent ground-breaking efforts, using SMC-restricted lineage-tracking techniques, have provided definitive evidence to support the conventional concept that medium SMCs are the main cellular origins of (neo)intimal SMCs upon injury [ 1 – 3 ], other studies also show that vascular stem/progenitor cells (SPCs), particularly SPCs located in the adventitial layer (namely AdSPCs), represent an additional source of the (neo)intimal SMCs in the atheroma [ 4 , 5 ]. There is compelling evidence to show that the blood vessel walls contain resident SPCs, such as smooth muscle progenitor cells that can migrate into the intima, where they differentiate into SMCs and contribute to atherosclerotic/neointima lesion formation and plaque stabilisation [ 6 – 12 ].…”

PLK1 Inhibition alleviates transplant-associated obliterative bronchiolitis by suppressing myofibroblast differentiation

“…During transplant rejection, metabolic reprogramming has been shown to occur in multiple cell types [22][23][24], particularly myofibroblasts, which are known to contribute to transplant-associated OB. Furthermore, TGF-β1 promotes myofibroblast differentiation via both Smad and non-Smad pathways [25,26].…”

A histone deacetylase 7-derived peptide promotes vascular regeneration via facilitating 14-3-3γ phosphorylation

“…The cells were expanded and subjected to Sca‐1 + cell purification using anti‐Sca‐1 immunomagnetic microbeads Miltenyi Biotec (Bergisch Gladbach, Germany). The purity of isolated Sca‐1 + cells was confirmed to around 85% using flow cytometry . The Sca‐1 + ‐VPCs were maintained in stem cell culture medium and split every other day.…”