**9. Smooth Muscle Progenitor Cells (SMPCs)**

Studies have identified circulating SM progenitor cells (SMPCs) and EPCs that can acquire SMC-like or EC-like phenotypes in mouse and human: [11, 13, 108]. These cell types share similar surface markers and functions with myeloid cells [109, 110] and SMCs and ECs, although their origin, identity, and physiological and pathological functions remain unclear. Many studies have identified BM-derived cells that express SMC or EC-specific genes within vascular lesions.

SMPCs, identified as circulating BM-derived cells, enter blood vessels and acquire phenotypes expressing SMC marker genes, particularly SMα-actin [13, 19, 111, 112]. Atherosclerotic vessels in patients who received sex-mismatched BM transplantation contain donor-derived smooth muscle-like cells, suggesting the possible involvement of circulating SMPCs in the lesion development [24]. Functions of SMPCs in the process of atherogenesis, however, remain obscure. SMPCs may promote inflammation and plaque instability by producing cytokines and MMPs [113]. SMPCs may participate in pathological angiogenesis [109]. In contrast, atheroprotective effects of SMPCs remain unknown. Further studies are needed to understand the role of SMPCs in the vascular disease.

Challenges in identification of SMC lineage are in part caused by their outstanding plasticity during the development and pathological processes. Non-SMCs also express SMC differen‐ tiation markers other than SM-MHC. For instance, ECs, fibroblasts/myofibroblasts, and macrophages express SMα-actin in certain conditions [2]. Iwata et al. used multiple SMC differentiation markers to analyze BM-derived smooth muscle-like cells [14]. BM-derived SMα-actin-immunopositive cells in vascular lesions in mice did not express the definitive SMC lineage marker, SM-MHC [14]. As mentioned, SM-MHC expression reduces in intimal SMCs after vascular injury and increases over time [27, 38] (Figure 1). Twelve months after vascular injury in mouse arteries, when resident SMCs had fully recovered SM-MHC expression, BMderived cells did not express SM-MHC. Instead, the BM-derived SMα-actin-positive cells expressed markers of monocytes/macrophages. Moreover, we found that adoptively transfer‐ red CD11b+Ly-6C+ BM monocytes expressed SMα-actin in the injured artery (Figure 4). Interestingly, increased expression of inflammatory genes and MMPs in these BM-derived SMα-actin+ cells indicated their potential role in the remodeling processes [14]. These results suggest that an activated monocyte population can become SM-like cells in atherosclerotic lesions, which may promote plaque instability. Future investigations will further evaluate the origin and functionality of SMC and macrophage lineages in vascular lesions [114].
