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The effect of intrauterine growth restriction on the developing pancreatic immune system

ABSTRACT: Immune cells in the pancreas are known to participate in organ development and homeostasis. However, the resident pancreatic immune system has yet to be fully defined. Immune cells also play a role in pathology and are implicated in diseases such as diabetes induced by intrauterine growth restriction (IUGR). We hypothesized that the resident immune system is established during neonatal development and disrupted by IUGR. Using single cell RNAseq and flow cytometry we identified many immune cell populations in the near term fetus (at embryologic day 22) and neonatal (postnatal day 1, 7, &14) rat islets and non-endocrine pancreas and in the spleen. Using flow cytometry, we observed the resident immune system is established during neonatal development in the pancreas and spleen. We identified 9 distinct immune populations in the endocrine pancreas and 8 distinct immune populations in the spleen by single cell RNAseq. There were no sex-specific differences in the relative proportion of immune cells in the pancreas or spleen. Finally, using the bilateral uterine artery ligation model, we tested if IUGR disrupted the neonatal immune system. We found significant changes to the percentage of CD11B+ HIS48- and CD8+ T cells in the islets and non-endocrine pancreas and in the spleen. IUGR-induced alterations were influenced by the tissue environment and the sex of the offspring. Interestingly, it that took longer for immune cells to reach percentages similar to controls in male than female IUGR offspring. In the female spleen, but not male, IUGR altered the percentage of several immune populations at e22, but the percentage was similar to controls post birth. Future research to define the role of these immune cells in pancreatic development may identify disrupted pathways that contribute to the development of diabetes following IUGR.

ORGANISM(S): Rattus

PROVIDER: GSE279616 | GEO | 2026/03/12

REPOSITORIES: GEO

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Project description:The lower glucose-responsiveness of neonatal beta cells is generally considered a sign of endocrine immaturity. We compared mRNA profiles of neonatal and 10-weeks old rat beta cells to see how their gene expression changes with functional maturation. Neonatal beta cells showed a lower glucose-inducible increment in insulin production than adult cells. This was in part explained by basal protein synthetic hyperactivity of neonatal cells: while at 2.5mM glucose 80% of neonatal beta cells were recruited into active protein synthesis, 10 mM glucose was required to achieve a similar fraction of active adult beta cells. Besides this progressive recruitment, glucose exerted in both age groups an additional amplifying effect in the recruited cells, but clearly more so in adult beta cells that showed a higher maximal synthetic capacity/cell. Neonatal beta cells balanced an advanced endocrine differentiation as judged by their mRNA expression of conserved beta cell marker genes, with higher expression of genes involved in cell cycle and development. One example, Delta-like 1 homolog (DLK1) was used to investigate if neonatal beta cells with basal hyperactivity corresponded to a more immature subset, as marked by high DLK1. Neonatal pancreas contained distinct subsets of DLK1high and DLK1low insulin-expressing cells, but both showed equal hyperactivity. We conclude that neonatal beta cells combine advanced endocrine maturation with traits of residual developmental immaturity. If DLK1 is used as marker for the latter, the basal hyperactivity which proved to be a cardinal feature of neonatal beta cells is not a direct reflection of their residual immaturity. A genome-wide view on postnatal maturation/differentiation of the rat beta cells The study compares Affymetrix RG230.20 expression profiles of 3 cell subsets: (1) HSSC: a population of cells isolated from post natal day 2-3 rat pancreas that is enriched (65-70%) in insulin cells (n=3), (2) LSSC: a population of cells isolated from postnatal day 2-3 rat pancreas that is mostly devoid of endocrine cells, and selected by its low side scatter (n=3); and (3) adult beta: a reference population of FACS-purified adult rat beta cells (>90% insulin+) freshly isolated from pancreas of 10 weeks-old rats (n=5). RNA was extracted from the cells immediately after isolation, without further treatment or culture. Details of the isolation procedure and extensive microscopic characterization of the preps are described in the accompanying scientific paper by Martens GA et al.

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The effect of intrauterine growth restriction on the developing pancreatic immune system

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