Abstract 275: Identification of Smooth Muscle Derived Macrophages as a Novel Potential Source of Tissue Resident Macrophages

Abstract

Smooth muscle cells (SMC) are not terminally differentiated but display remarkable plasticity to differentiate into other cell types in response to injury or chronic disease states such as atherosclerosis. Of major significance, we previously demonstrated that nearly a third of the macrophage marker positive cells within advanced mouse and human atherosclerotic plaques are of SMC not myeloid origin. These transitions in SMC phenotype are dependent on the stem cell pluripotency gene Klf4 and play a critical role in overall lesion pathogenesis. Since atherosclerosis happens well beyond our reproductive ages, we hypothesized that transitions of SMC to a macrophage-like state also occur in normal mice and play some protective role that is likely to be evolutionarily conserved. To test this hypothesis, we performed flow cytometric evaluations of transitions of SMC to a macrophage-like state within various microvascular tissue beds of our Myh11ERT2Cre eYFP SMC-specific lineage tracing mice. Remarkably, we found that 15-20% of eYFP+ cells within the stromovascular fraction of epidydimal and mesenteric fat depots were CD45+ of which >90% were also positive for the macrophage markers CD11b, F4/80, and Lgals3. Similar SMC derived macrophage-like cells were also observed in skeletal muscle and subcutaneous fat, but at much reduced levels. The percentage of SMC-derived macrophages in pathological fat depots increased about 2-fold upon four-weeks of diet-induced obesity (DIO). Interestingly, these macrophages appear to exhibit an M2-like polarization in that they were CD206+ but CD86-. We are currently ascertaining if the frequency or function of these SMC derived macrophage like cells within pathological fat depots is altered by SMC specific conditional knockout of Klf4, and/or if this is associated with alterations in insulin sensitivity or glycemia. In summary, we have discovered a novel source of tissue resident macrophages which we postulate play a protective role in regulating the inflammatory and metabolic properties of pathological adipose tissue depots.