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.

Glucose intolerance in adults born with intrauterine growth retardation (IUGR) may involve peripheral insulin resistance and/or abnormal endocrine pancreas development during fetal life. We quantified insulincontaining cells in deceased human fetuses with IUGR (<10th percentile, n ‫؍‬ 21) or normal growth (control fetuses, n ‫؍‬ 15). Paraffin-embedded pancreatic tissues from fetuses older than 32 weeks were obtained from two fetopathology departments. Mean gestational age was 36 weeks in both groups. Tissues with lysis and those fetuses with defects, aneuploidy, or genetic abnormalities were excluded. For each subject, six pancreatic sections spaced evenly throughout the organ were immunostained with anti-insulin antibody. Total tissue and insulin-positive areas were measured by computer-assisted quantitative morphometry. Results were expressed in percentages. To evaluate islet morphogenesis, the percentages of ␤-cells inside and outside islets were determined. Islet density was similar in the two groups (P ‫؍‬ 0.86). The percentage of pancreatic area occupied by ␤-cells (␤-cell fraction) was not correlated with gestational age (r ‫؍‬ 0.06 and P ‫؍‬ 0.97 in IUGR fetuses; r ‫؍‬ 0.12 and P ‫؍‬ 0.67 in control fetuses) or body weight (r ‫؍‬ 0.16 and P ‫؍‬ 0.47 in IUGR fetuses; r ‫؍‬ 0.24 and P ‫؍‬ 0.39 in control fetuses). Mean ␤-cell fraction was 2.53% in the IUGR fetuses and 2.86% in the control fetuses (P ‫؍‬ 0.47). The percentage of ␤-cells located within islets was identical in the two groups (mean 35%). Our data militate against a primary developmental pancreatic abnormality in human IUGR, leaving peripheral insulin resistance as the most likely mechanism of glucose intolerance in adults born with IUGR. Diabetes 51:385-391, 2002