Circulating Bone Marrow Cells Can Contribute to Neointimal Formation

Abstract

To examine the source of smooth muscle-like cells during vascular healing, C57BL/6 (Ly 5.2) female mice underwent whole body irradiation followed by transfusion with 10⁶ nucleated bone marrow cells from congenic (Ly 5.1) male donors. Successful repopulation (88.4 ± 4.9%) by donor marrow was demonstrated in the female mice by flow cytometry with FITC-conjugated A20.1/Ly 5.1 monoclonal antibody after 4 weeks. The arteries of the female mice were then subjected to two types of insult: (1) The iliac artery was scratch-injured by 5 passes of a probe causing severe medial damage. After 4 weeks, the arterial lumen was obliterated by a cell-rich neointima, with cells containing α smooth muscle actin present around the residual lumen. Approximately half of these cells were of male donor origin, as evidenced by in situ hybridization with a Y-chromosome-specific probe. (2) In an organized arterial thrombus formed by inserting an 8-0 silk suture into the left common carotid artery, donor cells staining with α smooth muscle actin were found in those arteries sustaining serious damage but not in arteries with minimal damage. Our results suggest that bone marrow-derived cells are recruited in vascular healing as a complementary source of smooth muscle-like cells when the media is severely damaged and few resident smooth muscle cells are available to effect repair.

Crucial Role of Stromal Cell–Derived Factor-1α in Neointima Formation After Vascular Injury in Apolipoprotein E–Deficient Mice

“…Because a major part of neointimal SMCs can be derived from bone marrow cells, [11][12][13] and circulating SMC progenitors have been demonstrated in humans, 14 we investigated whether SDF-1␣ affects the percentage of peripheral blood Sca ϩ lin Ϫ progenitor cells after carotid injury. Arterial injury triggered the rapid expansion of PBPCs in the circulation after 1 day (Figure 5A), which was prevented by the administration of a blocking SDF-1␣ mAb (4.9Ϯ0.8% versus 1.7Ϯ0.3% of mononuclear cells, nϭ4, PϽ0.01; Figure 5A), with the percentage remaining at levels of uninjured mice (data not shown).…”

“…Application of a blocking SDF-1␣ mAb reduces neointimal area and neointimal SMC content, which indicates an important role during the progression of accelerated atherosclerosis. Because SDF-1␣ is important in the homeostasis of bone marrow homing and mobilization of progenitor cells, 7,19 and neointimal SMCs originate from a bone marrow source of progenitors, [13][14][15] we studied the effect of SDF-1␣ on progenitor cell mobilization and recruitment after carotid injury. We found that the expansion of PBPCs in the circulation and the accumulation of injected PBPCs in established neointimal lesions were mediated by SDF-1␣.…”

“…Furthermore, neutralization of SDF-1␣ after carotid injury in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice by application of a blocking antibody was evaluated for its effect on neointimal lesions. Bone marrowderived cells have been shown to contribute to neointimal SMC content, [13][14][15] and circulating SMC progenitors have been demonstrated in humans. 16 We therefore determined whether SDF-1␣ is involved in the mobilization of progenitor cells into the peripheral blood and whether these cells can be recruited to neointimal lesions and adopt an SMC phenotype.…”

Implications of Early Structural-Functional Changes in the Endothelium for Vascular Disease

“…These messages govern the plaque formation that includes clonal accumulation of SMCs within the intima. 49 Recent evidence indicates that besides migration of the existing SMCs from the vessel's media to the intima, circulating bone marrow cells 50 and the vascular progenitor cells present in the adventitia of all arteries, are other sources of intimal SMCs. 51 In coronary arteries, SMCs form a fibrous cap that, if afflicted by MMPs and IFN-␥, may lead to the plaque rupture.…”

The cell cycle: A critical therapeutic target to prevent vascular proliferative disease

“…Adventitial fibroblasts may also migrate to the intima, differentiate into myofibroblasts and contribute to neointima formation (27,28). Moreover, several groups have shown that bone marrow-derived vascular cells with some characteristics of VSMCs accumulate in the neointima of transplant vasculopathy and in a severe vascular injury animal model (29)(30)(31). Cell division involves two consecutive processes: interphase, ie, the time between two mitosis (M) periods, and the mitosis itself, ie, the process of cell division.…”