Bone Marrow-Derived NGFR-Positive Dendritic Cells Regulate Arterial Remodeling
It has been proposed that bone marrow contributes to the pathogenesis of arteriosclerosis. Nerve growth factor receptor (NGFR) is expressed in bone marrow stromal cells; it is also present in peripheral blood and ischemic coronary arteries. We hypothesized that bone marrow-derived NGFR-positive (NGFR+) cells regulate arterial remodeling. We found that human NGFR+ mononuclear cells (MNCs) in peripheral blood expressed markers for plasmacytoid dendritic cells (DCs) and were susceptible to apoptosis in response to proNGF secreted by activated arterial smooth muscle cells (SMCs). Bone marrow-specific depletion of NGFR+ cells increased neointimal formation following arterial ligation in mice. Bone marrow-derived NGFR+ cells accumulated in the neointima and underwent apoptosis. In contrast, in a bone marrow-specific NGFR-knockout model, SMCs occupied the neointima with augmented proliferation. NGFR+ cells in the neointima promoted mannose receptor C-type 1-positive antiinflammatory macrophage accumulation and secreted antiinflammatory IL-10, thereby inhibiting SMC proliferation in the neointima. In patients with acute coronary syndrome (ACS), NGFR+ peripheral MNCs increased after ACS onset. Multiple linear regression analysis showed that an insufficient increase in NGFR+ peripheral MNCs in ACS was an adjusted independent risk factor for 9-month intimal progression of a nontargeted lesion. Taken together, these observations imply that bone marrow-derived NGFR+ DCs are suppressors of arteriosclerosis. Overall design: To explore the cellular characteristics of NGFR+ peripheral MNCs derived from bone marrow, human NGFR+ MNCs were isolated from three healthy volunteers. NGFR+ and NGFR-negative (NGFR-) MNCs were sorted using fluorescence-activated cell sorting. Comparative gene expression analysis of NGFR+, NGFR- MNCs, or unsorted MNCs was performed using data from RNA-seq.