Hofbauer cells of M2a, M2b and M2c polarization may regulate feto-placental angiogenesis

Abstract

The human placenta comprises a special type of tissue macrophages, the Hofbauer cells (HBC), which exhibit M2 macrophage phenotype. Several subtypes of M2-polarized macrophages (M2a, M2b and M2c) exist in almost all tissues. Macrophage polarization depends on the way of macrophage activation and leads to the expression of specific cell surface markers and the acquisition of specific functions, including tissue remodeling and the promotion of angiogenesis. The placenta is a highly vascularized and rapidly growing organ, suggesting a role of HBC in feto-placental angiogenesis. We here aimed to characterize the specific polarization and phenotype of HBC and investigated the role of HBC in feto-placental angiogenesis. Therefore, HBC were isolated from third trimester placentas and their phenotype was determined by the presence of cell surface markers (FACS analysis) and secretion of cytokines (ELISA). HBC conditioned medium (CM) was analyzed for pro-angiogenic factors, and the effect of HBC CM on angiogenesis, proliferation and chemoattraction of isolated primary feto-placental endothelial cells (fpEC) was determined in vitro Our results revealed that isolated HBC possess an M2 polarization, with M2a, M2b and M2c characteristics. HBC secreted the pro-angiogenic molecules VEGF and FGF2. Furthermore, HBC CM stimulated the in vitro angiogenesis of fpEC. However, compared with control medium, chemoattraction of fpEC toward HBC CM was reduced. Proliferation of fpEC was not affected by HBC CM. These findings demonstrate a paracrine regulation of feto-placental angiogenesis by HBC in vitro Based on our collective results, we propose that the changes in HBC number or phenotype may affect feto-placental angiogenesis.

Human Placental Hofbauer Cells Maintain an Anti-inflammatory M2 Phenotype despite the Presence of Gestational Diabetes Mellitus

“…M2c macrophages particularly play a role in tissue remodeling processes which is assumed as a central function of HBC. Recent results published by our group suggest that HBC regulate placental vascular growth (25). In this study, an assay of endothelial cell activation by macrophage-derived factors was carried out.…”

“…They differ in expression of surface molecules and cytokines, and functions. We have previously described that HBC constitute a mixture of M2a, M2b, and M2c macrophages (25). The observed changes in surface molecules and secreted cytokines would, therefore, indicate a shift toward an increase in M2a population (reflected by enlarged CD206 + together with CD209 + populations) as well as an increase in M2b populations (reflected by a trend toward increased CD86 + population and elevated—though not significant—secretion of IL-1β and IL-6).…”

“…Also the pleiotropic functions of HBCs are still somewhat enigmatic (40); it has been suggested by various studies that one function of HBCs is to regulate placental vasculo- and angiogenesis (23–25). In GDM, often placental hypervascularization is observed (62, 63), resulting in excessive nutrient transport to the fetus and fetal macrosomia.…”

“…Our group recently showed that HBCs are capable of inducing placental endothelial cell migration and tube formation (25) thereby contributing to placental angiogenesis. This is in line with other researchers who found that only M2, but not M1, macrophages are pro-angiogenic (52, 64).…”

“…Furthermore, DNA methylation profiling of HBCs indicated a programmed M2 phenotype (22). HBCs are implicated in placental vasculogenesis and angiogenesis (23, 24) and we recently demonstrated a regulation of placental endothelial cells by HBC in vitro (25). Moreover, HBC are thought to play a role in maternal immunological tolerance against the fetus (26).…”