Dataset Information

Developmental programming of Kupffer cells by maternal obesity causes fatty liver disease in the offspring [snMultiome sequencing]

ABSTRACT: Kupffer cells (KCs) are tissue-resident macrophages which colonize the liver early during embryogenesis. KCs start to acquire a tissue-specific transcriptional signature immediately after colonizing the liver, mature together with the tissue, and adapt to the tissue’s functions. Throughout development and adulthood, KCs have distinct core functions that are essential for liver and organismal homeostasis, such as supporting fetal erythropoiesis as well as postnatal erythrocyte recycling and liver metabolism. However, whether perturbations of macrophage core functions during development contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a mouse model of maternal obesity to perturb KC functions during gestation. We show that offspring exposed to maternal obesity develop fatty liver disease, driven by aberrant developmental programming of KCs that persists into adulthood. Programmed KCs mediate lipid uptake by hepatocytes through apolipoprotein secretion. KC depletion in neonates born to obese mothers, followed by replenishment with exogenous monocytes, rescues the fatty liver disease. The transcriptional programming of KCs and the fatty liver disease phenotype are also rescued by genetic depletion of hypoxia-inducible factor alpha (Hif1a) in macrophages during gestation. These results establish developmental perturbation of KC functions as a cause for the development of fatty liver disease in adult life and, thereby, place fetal-derived macrophages as intergenerational messengers within the concept of developmental origins of health and diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE283082 | GEO | 2024/12/04

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:There is an evident, unmet need to develop a commercially available in vitro system that can model inflammatory states of the liver and predict immune-mediated hepatotoxicity of drugs and xenobiotics taken under inflamed conditions. Hepatocyte-Kupffer cell co-cultures can model inflammation-mediated hepatotoxicity; however, Kupffer cell (KC) source remains an important bottleneck for the development of such models. Primary human Kupffer cells (PHKCs) are costly, limited in availability and exhibit donor variability. An alternative cell source for KCs has not been reported. Important paradigm shift from the classical dogma of adult blood-circulating monocyte-derived macrophages to intrahepatic precursor/fetal monocyte-derived macrophages has shed new light into the origin of KCs in vivo. Based on these recent findings, we report here, a novel method to generate human KCs in vitro from stem cells (hPSC-KCs) via fetal monocytes. hPSC-KCs expressed macrophage markers, CD11, CD14, CD68, CD163 and CD32 at gene and protein level and exhibited functional properties such as phagocytosis and Interleukin-6 and Tumor Necrosis Factor-4alpha production upon activation. Importantly, molecular signature, liver-macrophage specific CLEC-4F expression and cytokines production levels of hPSC-KCs were similar to PHKCs but different from non-liver macrophages. We used an inflammatory liver co-culture model to demonstrate that activated hPSC-KCs, but not non-liver macrophages, were able to recapitulate effects of PHKCs when stimulated with paradigm hepatotoxicants. hPSC-KCs developed in this study offer a renewable human cell source for liver-specific macrophages which can be used to develop in vitro systems for modelling the inflammatory state of the liver. Gene expression profiles of 9 samples were determined using Human Gene 2.0 ST Array. These 9 samples included three replicates each of PHKCs (primary human Kupffer cells), human pluripotent stem cell-dervied Kupffer cells (hPSC-KCs) and non-liver macrophages (NL-Mφ).

Dataset Information

Developmental programming of Kupffer cells by maternal obesity causes fatty liver disease in the offspring [snMultiome sequencing]

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets