Circulating progenitor cells contribute to neointimal formation in nonirradiated chimeric mice

Abstract

Recent evidence suggests that bone marrow-derived cells may contribute to repair and lesion formation following vascular injury. In most studies, bone marrow-derived cells were tracked by transplanting exogenous cells into bone marrow that had been compromised by irradiation. It remains to be determined whether endogenous circulating progenitors actually contribute to arterial remodeling under physiological conditions. Here, we established a parabiotic model in which two mice were conjoined subcutaneously without any vascular anastomosis. When wild-type mice were joined with transgenic mice that expressed green fluorescent protein (GFP) in all tissues, GFP-positive cells were detected not only in the peripheral blood but also in the bone marrow of the wild-type mice. The femoral arteries of the wild-type mice were mechanically injured by insertion of a large wire. At 4 wk, there was neointima hyperplasia that mainly consisted of alpha-smooth muscle actin-positive cells. GFP-positive cells were readily detected in the neointima (14.8+/-4.5%) and media (31.1+/-8.8%) of the injured artery. Some GFP-positive cells expressed alpha-smooth muscle actin or an endothelial cell marker. These results indicate that circulating progenitors contribute to re-endothelialization and neointimal formation after mechanical vascular injury even in nonirradiated mice.

Origin of Cells That Contribute to Neointima Growth

“…6 Although it has been assumed that medial SMCs transdifferentiate into macrophage-like cells, 6 recent reports suggested that some synthetic SMCs with characteristics of macrophages might derive from circulating blood cells rather than from medial SMCs. 7,8 Evidence in support of this hypothesis was provided in several models of vascular diseases. By taking advantage of genetically modified mice, it was directly demonstrated that bone marrow cells home in on the damaged vessels and contribute to both vascular repair and pathological remodeling.…”

“…14 In this regard, high-resolution confocal microscopy with z-axis analysis has been used to convincingly demonstrate that bone marrowderived cells express ␣-smooth muscle actin (␣-SMA) in neointima after wire-mediated vascular injury. 8 To rigorously identify GFP-positive cells, these studies used a plastic embedding technique to preserve the GFP fluorescence signal and to avoid the use of anti-GFP antibodies that could potentially increase the risk of false signals by nonspecific antibody binding. 7,8,16,17 Moreover, an ultrahigh-resolution immunoelectron microscopic observational study confirmed that ␣-SMA and GFP could be located within a cell.…”

“…8 To rigorously identify GFP-positive cells, these studies used a plastic embedding technique to preserve the GFP fluorescence signal and to avoid the use of anti-GFP antibodies that could potentially increase the risk of false signals by nonspecific antibody binding. 7,8,16,17 Moreover, an ultrahigh-resolution immunoelectron microscopic observational study confirmed that ␣-SMA and GFP could be located within a cell. 8 Thus, it appears certain that bone marrow-derived cells expressing ␣-SMA can be detected in the neointima.…”

Radiosensitive Smooth Muscle Cells Populate Neointimal Lesions Through a Platelet Derived Growth Factor Receptor Beta Dependent Mechanism

“…Further, multiple genes originally thought to be SMC-specific have now been identified as being expressed in alternative cell types including bone marrow cells 11,[20][21][22][23] , adventitial cells [24][25][26] , endothelial cells 27 , and more 28,29 , with the only gene currently thought to be specific to SMCs (and pericytes, a perivascular cell similar to SMCs in the microvasculature) being Myh11 17 . Indeed this ambiguity led to several papers 23,30,31 suggesting additional de novo sources of SMCs being derived from cells other than SMCs.…”

“…Indeed this ambiguity led to several papers 23,30,31 suggesting additional de novo sources of SMCs being derived from cells other than SMCs.…”