Macrophages in the murine pancreas and their involvement in fetal endocrine development in vitro

Abstract

Macrophages are a heterogeneous population of cells that belong to the mononuclear phagocyte system. They play an important role in tissue homeostasis and remodeling and are also potent immune regulators. Pancreatic macrophages are critically involved in the development and pathogenesis of autoimmune diabetes. To elucidate the ontogeny of pancreatic macrophages, we characterized in this study the macrophages present in the adult and developing fetal pancreas of normal mice. We additionally examined the presence of local macrophage precursors and the involvement of macrophages in the growth of endocrine tissue in the fetal pancreas. We identified two phenotypically distinct macrophage subsets in the adult pancreas. The majority of macrophages was CD45(+)ER-MP23(+)MOMA-1(+). Under noninflammatory conditions, only a minority ( approximately 5%) of the pancreatic macrophages additionally expressed the macrophage marker F4/80. In contrast, in the fetal pancreas, phenotypically, mature macrophages were identified exclusively by their expression of F4/80 and lacked detectable staining with ER-MP23 and MOMA-1 antibodies. In fetal pancreas organ cultures, we could show that macrophages develop from pre-existing precursors, which are present in the fetal pancreas at embryonic age 12.5. Moreover, the number of macrophages increased significantly when macrophage-colony stimulating factor was added to these cultures. It is important that this increase of F4/80-positive cells was paralleled by an increase in the number of insulin-producing cells, suggesting that macrophages support the growth of these endocrine cells.

Lineage tracing and resulting phenotype of haemopoietic-derived cells in the pancreas during beta cell regeneration

“…Such cells were predominantly distributed within the microvasculature in and around larger islets. Approximately 5% of pancreatic haemopoietic lineage cells expressed macrophage lineage markers, although only a proportion of macrophages resident in adult mouse pancreas were shown to express F4/80 [29]. A contribution of macrophages to normal islet development has been demonstrated and reviewed by Homo-Delarche and Drexhage [30].…”

“…A contribution of macrophages to normal islet development has been demonstrated and reviewed by Homo-Delarche and Drexhage [30]. Macrophages expressing F4/80 first appear in the developing mouse pancreas on day e14.5 [29], and the culture of pancreatic rudiments with macrophage colony-stimulating factor increased the number of insulin-immunoreactive cells, suggesting that an increase in macrophage number potentiated beta cell replication. In the macrophage colony-stimulating factor 1-deficient gene knockout mouse (op/op), animals develop osteopetrosis as adults, but young animals suffer from abnormal islet morphogenesis, a much reduced beta cell mass and deficiencies in beta cell replication [31].…”

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

“…In organs, such as the skin and brain, local precursors for macrophages and Langerhans cells have been detected [9][10][11]. We earlier described the presence of local precursors for macrophages in the fetal pancreas of C57BL/6 mice [12]. However, little is known about the origin of the DCs that accumulate in the pre-diabetic NOD pancreas and the factors driving this accumulation.…”

Macrophages and CSF-1

“…72 MMP9 is produced by the mesenchyme, and when blocked using an anti-MMP9 Ab a decrease in ureteric bud branching in metanephric organ cultures Macrophages in the developing murine pancreas are located principally at the duct-islet interface 105 in close apposition to insulin-producing islet cells. 43 These F4/80 + cells are reported to display a stellate morphology. 106 Similarly in the human, macrophages cluster around developing ducts, recruited via local CSF-1 expression, and provide a supportive developmental microenvironment.…”

“…As potent effector cells, macrophages produce a range of mediators including plateletderived growth factors (PDGFs), 37 transforming growth factors (TGFs), 38 insulin-like growth factor (IGF)-1 39 and Wnts. [40][41][42] Macrophage-derived factors mediate cell fate decisions, as observed in β cell differentiation in the developing pancreas 43 and hepatic progenitor differentiation during liver regeneration. 40 Macrophages also contribute to development through angiogenic regulation.…”