Insulin cell mass is altered inCsf1op/Csf1opmacrophage-deficient mice

Abstract

Macrophages play an important role in organ development, tissue homeostasis, and remodeling. Thus, we monitored the presence of F4/80-positive macrophages in the pancreas of wild-type mice, and some developmental features of this complex tissue were compared throughout life in wild-type and macrophage-deficient Csf1op/Csf1op (op/op) mice. The combined use of immunohistochemistry, morphometry, and cell quantification allows us to evaluate insulin and glucagon cell mass, total and insulin cell proliferation, and apoptosis in fetuses (E18.5), weanings (postnatal day 21), nonpregnant adults, and adults in late pregnancy (18.5 days). F4/80-positive macrophages were found in pancreases recovered from Csf1op/Csf1+ (op/+) mice but were extremely scarce or absent in pancreas recovered from op/op ones at all studied time-points. The macrophage-deficient op/op phenotype was clearly associated with a major insulin mass deficit in fetuses and adults, abnormal postnatal islet morphogenesis, and impaired pancreatic cell proliferation at weaning and late pregnancy. We also obtained indirect evidence of increased neogenesis in this model at time-points when pancreatic remodeling does occur. The demonstration of the colony-stimulating factor 1-dependent macrophage involvement in life-time pancreas development/remodeling allows us to pinpoint the tissue-modeling and remodeling functions of this leukocyte lineage.

Islet Microenvironment, Modulated by Vascular Endothelial Growth Factor-A Signaling, Promotes β Cell Regeneration

“…Transcriptome analysis showed that MΦs recruited to βVEGF-A islets express high levels of M2 markers along with MMPs associated with tissue restoration and remodeling, and lower levels of M1 markers, indicating that these MΦs likely have a unique regenerative phenotype (Ricardo et al, 2008; Sica and Mantovani, 2012). Very little is known about the role of MΦs in adult β cell maintenance, but during late stages of pancreatic development, mice with severe MΦ deficiency had reduced β cell proliferation, β cell mass, and impaired islet morphogenesis (Banaei-Bouchareb et al, 2004). …”

Macrophages and CSF-1

“…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. 107 In the Csf1 op/op mouse, macrophages are scarce and insulin mass is reduced due to reduced β cell proliferation and abnormal islet morphology.…”

“…107 In the Csf1 op/op mouse, macrophages are scarce and insulin mass is reduced due to reduced β cell proliferation and abnormal islet morphology. 106 In the eye, macrophages contribute to remodelling with macrophage-derived nerve growth factor (NGF) contributing to normal neuronal apoptosis. 108 Macrophages also contribute to angiogenesis of the eye.…”

The kidney regulates regeneration, but don’t upset the balance

“…Osteopetrotic (Csf1 op /Csf1 op ) mice which have spontaneous mutation within the Csf-1 gene are characterized by multiple organ growth deficiencies. Additionally, they exhibit growth restriction and developmental abnormalities of the bones, brain, and reproductive and endocrine organs [12][13][14][15]. Complementation experiments by injecting exogenous CSF-1 or insertion of a Csf-1 transgene rescue this phenotype [16][17][18].…”