Bone marrow‐derived CX₃CR1 progenitors contribute to neointimal smooth muscle cellsviafractalkine CX₃CR1 interaction

Abstract

Smooth muscle cells play a major role in numerous vascular diseases that contribute to remodeling, repair after injury, and arteriogenesis, and the source of these cells is thought to lie within the vessel wall and the circulating blood. Currently, the precise origin and mechanism of differentiation of extravascular smooth muscle progenitor cells (SPCs) is unclear. We show here that the CX(3)CR1 mononuclear cell population of murine bone marrow provides a source of SPCs that contributes to smooth muscle cells within the neointimal plaque after vascular injury. Moreover, CX(3)CR1-fractalkine (FKN) interaction in vivo is essential for smooth muscle cell differentiation of bone marrow-derived progenitor cells at the vessel wall level. Functional competence of bone marrow-derived CX(3)CR1 positive cells to interact with FKN is also crucial in part for neointima formation following vascular injury. Finally, in a pure preparation of bone marrow-derived CX(3)CR1 positive cells, we show that in vitro smooth muscle cell differentiation increases markedly in the presence of FKN. Our data highlight a novel functional relationship between the myeloid and vascular systems and in the context of vascular injury and repair underscores a key chemokine-receptor pathway that may regulate cell fate when smooth muscle cell differentiation is required.

Nuclear Factor of Activated T Cells c1 Mediates p21-activated Kinase 1 Activation in the Modulation of Chemokine-induced Human Aortic Smooth Muscle Cell F-actin Stress Fiber Formation, Migration, and Proliferation and Injury-induced Vascular Wall Remodeling

“…In recent years, many reports showed that besides resident VSMCs, progenitor cell recruitment to and homing at the site of vascular injury also plays a role in neointima formation, at least in rodent animal models (3,4). Among the many theories put forth in explaining the abnormal multiplication of these cells, their dedifferentiation gained momentum (5,6).…”

Role of Vessel Wall and Bone Marrow Syndecan-4 in Neointimal Hyperplasia

“…These data are important as they underscore what a number of other recent studies 5,6 have hinted at, namely, a complex interplay among vessel wall cell surface molecules, ECMbound factors, and cells resident in BM during the vascular response to injury. Moreover, although controversy still exists on the precise role of BM cells in SMC differentiation and proliferation following injury, Ikesue et al's study 4 provides supportive evidence for a functional role of BMderived Syn4 in promoting neointimal hyperplasia and vascular progenitor cell (VPC) mobilization.…”

“…It appears increasingly evident that the majority of SMC in the neointima derive from the local vessel wall but that a small number, representing Ϸ1% to 5% of plaque cells, come from outside the local vascular niche. This study and others 5,6 are beginning to address the potential functional significance of such extravascular sources of SMC. The nature of these progenitors is still unclear and ranges from myeloid cells to more undifferentiated lineages.…”

“…The nature of these progenitors is still unclear and ranges from myeloid cells to more undifferentiated lineages. For instance, Kumar et al 5 recently showed that although BM-derived CX3C chemokine receptor 1-positive smooth muscle progenitor cells represented only Ϸ5% of neointimal cells, deficiency in BM CX 3 CR1 function reduced neointimal area by 40%. This is consistent with in vitro work suggesting that smooth muscle progenitors express much higher levels of ECM 7 compared with normal SMC.…”

Hypoxia-induced endothelial CX3CL1 triggers lung smooth muscle cell phenotypic switching and proliferative expansion

“…CX3CL1 modulates CX3CR1 ϩ cells such as bone marrowderived cells, lymphocytes, fibroblasts, and SMC (27,43,61). Circulating mesenchymal precursors and fibroblasts contribute to remodeling of lung artery adventitia in neonatal rat and calf models of hypoxic PH (16,21,48).…”