Time-Course Analysis on the Differentiation of Bone Marrow-Derived Progenitor Cells Into Smooth Muscle Cells During Neointima Formation

Abstract

Objective-Bone marrow-derived progenitor cells have been implicated to contribute to neointima formation, but the time course and extent of their accumulation and differentiation into vascular cells and, most importantly, the long-term contribution of bone marrow-derived progenitor cells to the vascular lesion remain undefined. Methods and Results-Wire-induced injury of the femoral artery was performed on chimeric C57BL/6 mice transplanted with bone marrow from transgenic mice expressing enhanced green fluorescence protein, and vessels were harvested at 3 days, 1, 2, 3, 4, 6, and 16 weeks after dilatation (nϭ8 animals per time point). Using high-resolution microscopy, we unexpectedly found that the expression of smooth muscle cell or endothelial cell markers in enhanced green fluorescence protein positive cells was a very rare event. Indeed, most of the enhanced green fluorescence protein positive cells that accumulated during the acute inflammatory response were identified as monocytes/macrophages, and their number declined at later time points. In contrast, a substantial fraction of highly proliferative stem cell antigen-1 and CD34 ϩ but enhanced green fluorescence protein negative and thus locally derived cells were detected in the adventitia. Conclusion-These data provide evidence that the differentiation of bone marrow-derived progenitor cells into smooth muscle cell or endothelial cell lineages seems to be an exceedingly rare event. Moreover, the contribution of bone marrow-derived cells to the cellular compartment of the neointima is limited to a transient period of the inflammatory response. Key Words: progenitor cells Ⅲ smooth muscle cells Ⅲ vascular remodeling Ⅲ restenosis Ⅲ inflammation S mooth muscle cells (SMCs) play a decisive role in the pathogenesis of vascular diseases and its clinical manifestations. In addition to atherosclerosis, neointima (NI) formation is a major burden in vascular medicine and concerns patients after percutaneous coronary intervention, bypass operation, or graft vasculopathy. It had been widely accepted that intimal SMCs in proliferative vascular diseases are derived from resident medial SMCs or adventitial fibroblasts. 1,2 Several years ago, this theory was challenged by the suggested ability of bone marrow-derived progenitor cells (BMPCs) to differentiate into vascular cells during arterial remodeling. 3 However, until today, the differentiation capacity of BMPCs in vivo remains highly controversial. 4 In different mouse models of atherosclerotic plaque formation, it has been shown very recently that SMCs and endothelial cells (ECs) in atherosclerotic plaques are exclusively derived from the local vessel wall and not from the circulating blood. 5,6 See accompanying article on page 1877Although the homing of BM-derived cells on mechanically injured vessels has been clearly demonstrated in various animal models, the fraction of these cells expressing ␣-smooth muscle actin (␣-SMA) showed wide diversity, ranging from negligible to substantial numbers of all vascular SMCs. 3,...

Inhibition of Thrombin Receptor Signaling on α-Smooth Muscle Actin + CD34 + Progenitors Leads to Repair After Murine Immune Vascular Injury

“…31 These findings have remained controversial, in part because of the disputed ability of BM-derived cells to give rise to SMCs and because recent publications have directly contradicted the earlier data. 32,33 Recently, Iwata et al, working in 3 separate models of IH including TA, reported significant numbers of recipient ␣-SMA ϩ SM22␣ ϩ cells in the neointima, but these also expressed CD115, CD11b, F4/80, and Ly-6C, markers of the monocyte/macrophage lineage rather than established markers of differentiated SMCs such as smooth muscle myosin heavy chain or calponin. 8 The authors concluded that although BM-derived ␣-SMA ϩ cells were involved in vascular remodeling, they were myeloid cells and not true SMC progenitors.…”

A Novel IKK Inhibitor Prevents Progression of Restenosis After Arterial Injury in Mice

“…Furthermore, IMD-0354 inhibited in vitro mouse-derived VSMC proliferation induced by PDGF-BB, TNF-α, and IL-1β. Previous reports have suggested that there are fewer inflammatory cells in the neointima, 32) and that bone marrow-derived cells in the neointima lesion mainly differentiate into macrophage lineages. 33) Thus, the main role of these cells in the development of a neointimal lesion is to initiate inflammation and induce VSMC proliferation.…”

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

“…As was discussed in Chapter II, when we looked at mice which were slightly older, those around 17-19 weeks of age and compared them to our [10][11][12] week old mice, we saw a significant reduction in the eYFP+ contribution to the neointima in the PDGFRB SMC WT/WT mice. We then found through continuous BrdU infusion that PDGFRB SMC WT/WT mice 10-12 weeks of age had a higher growth fraction than those PDGFRB SMC WT/WT mice 17-19 weeks of age.…”

“…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, while a search of the literature reveals that the majority of studies rely on mouse experimental groups similar in age 11,129 ; there is a not-insignificant fraction of rat and mouse studies which rely on animals of similar body weights rather than similar ages. These studies are usually focused around either the carotid or femoral wire injury where, However, it's also possible that: 1) in the context of a chronic disease such a atherosclerosis, there is/are some factor or factors being secreted, environmental cues, etc which keep SMCs "primed" for phenotypic switching and thus in that setting SMCs do not lose the capability to undergo phenotypic switching; or 2) since he was studying young pigs for 30-60 days, perhaps the medial growth fraction was still high and would have decreased with age.…”