Stromal Cell–Derived Factor-1 and CXCR4 Interaction Is Critical for Development of Transplant Arteriosclerosis

Abstract

Background-Posttransplant chronic allograft deterioration associated with development of transplant arteriosclerosis (TA) remains an unresolved problem. Recent studies suggest that the smooth muscle cells (SMCs) constituting the neointima are derived from recipient hematopoietic stem cells (HSCs). However, the underlying mechanisms of the process are not yet fully elucidated. Methods and Results-We examined the genes expressed in allografts at different stages of TA development using a mice aortic transplantation model. Genes were analyzed by a differential mRNA display technique. We show that stromal cell-derived factor-1␣ (SDF-1␣) is a critical molecular target for the treatment of TA. During the course of TA, intragraft SDF-1␣ expression was upregulated with time, and the circulating HSCs expressing its counterreceptor CXCR4 increased in the recipients receiving allografts. CXCR4-positive HSCs, derived from transplant recipients, migrated into allografts via microvessels in the adventitia and then toward the luminal side. The HSCs differentiated into SMC-like cells, contributing to the in situ formation of the neointima. In support of a functional role for these molecules, in vivo neutralization of SDF-1␣ inhibited HSC mobilization and significantly attenuated neointimal formation. Conclusions-Interaction between SDF-1␣ and CXCR4 plays a key role in TA development. Blockade of SDF-1␣ may become a new therapeutic modality for TA.

Stem cell homing and angiomyogenesis in transplanted hearts are enhanced by combined intramyocardial SDF-1α delivery and endogenous cytokine signaling

“…Thus, injection of SDF-1␣-overexpressing MSCs in the ischemic myocardium provides a novel strategy whereby the recruitment of CXCR4-positive progenitor cells may be enhanced so as to facilitate repair of the injured myocardium. However, long-term overexpression of SDF-1␣ has been reported to cause chronic allograft deterioration associated with the development of transplant arteriosclerosis (23). Accordingly, further study on the duality of SDF-1␣ action is clearly needed.…”

Activation of endothelial nitric oxide synthase is critical for erythropoietin-induced mobilization of progenitor cells

“…In addition to representing hematopoietic stem cells, c-Kit + /Sca-1 + /Lin-1 − (KSL) cells in circulating blood have also been considered vascular progenitor cells derived from bone marrow [21,22,24]. CD34 + cells (hematopoietic progenitors) are population of cells enriched with EPCs [4,18], and CD34 + /Flk-1 + cells participate in therapeutic neovascularization [20].…”

“…Nevertheless, it has been suggested that cells expressing CD34 + /Flk-1 + participate in therapeutic neovascularization [20]. It is also important to note that, hematopoietic stem cells, characterized by co-expression of stem cell antigen-1 (Sca-1) and receptor for stem cell factor, c-kit [21,22,24], posses the ability to differentiate into nonhematopoietic tissues, including cardiac myocytes [19].…”

Protective Role of CXC Receptor 4/CXC Ligand 12 Unveils the Importance of Neutrophils in Atherosclerosis

“…12,13 An upregulation of Cxcl12 has been observed in transplant arteriopathy or in hypoxia, and blocking Cxcl12 or Cxcr4 reduced neointima formation and SMC progenitor recruitment in transplant arteriosclerosis or during neovascularization of ischemic tissues. 10,11,14 The expression of CXCL12 is also detectable in primary atherosclerotic plaques, 15 and reduced CXCL12 plasma levels have been associated with unstable coronary artery disease, suggesting antiinflammatory or plaque-stabilizing properties of CXCL12. 16 Owing to the embryonic lethality after genetic deletion, a role of Cxcl12/Cxcr4 in the development, stability, and cellular homeostasis of primary atherosclerosis has not yet been studied in vivo.…”