Biology subjects

Perino, A.

Publications and source records attributed to Perino, A..

3 recordsLinked to original sources

bioRxiv2023

The bile acid receptor TGR5 regulates the hematopoietic support capacity of the bone marrow niche

The gut is an emerging regulator of bone marrow (BM) hematopoiesis, with several signaling molecules involved in this communication. Among them, bile acids (BAs) act as a relay between the microbiota and the rest of the body through the activation of specific receptors, including Takeda G protein-coupled receptor 5 (TGR5). TGR5 has potent regulatory effects in immune cells, but its role in the BM as a primary immune organ remains unknown. Here, we demonstrate that TGR5 is expressed in hematopoietic progenitors and BM stromal progenitors. TGR5 deficiency did not affect steady-state hematopoiesis but led to impaired short-term progenitor reconstitution and reduced regulated bone marrow adipose tissue (BMAT) in young male mice, but not in female mice. The reduction in BMAT was accompanied by an enrichment in BM adipocyte progenitors and was associated with enhanced hematopoietic recovery upon BM transplantation into Tgr5-/- recipients. Moreover, its reduction was associated with lower myeloid-to-lymphoid progenitor ratios in obese and in aged Tgr5-/- male mice, resembling more those of lean or young controls. Our results indicate that TGR5 is essential for maintaining a balanced BM microenvironment in a sex-dependent manner and open the possibility of modulating stromal hematopoietic support by acting on TGR5 signaling. Impact statementTGR5 loss-of-function reduced regulated bone marrow adipose tissue in male mice, without affecting that of females at homeostasis, and accelerated myeloid recovery upon bone marrow transplantation. These data highlight TGR5 as a new player in the bone marrow microenvironment.

cell biology↗

bioRxiv2023

Genetic and dietary modulators of the inflammatory response in the gastro-intestinal tract of the BXD mouse genetic reference population

Inflammatory gut disorders, including inflammatory bowel disease (IBD), can be impacted by dietary, environmental and genetic factors. While the incidence of IBD is increasing worldwide, we still lack a complete understanding of the gene-by-environment interactions underlying inflammation and IBD. Here, we profiled the colon transcriptome of 52 BXD mouse strains fed with a chow or high-fat diet (HFD) and identified a subset of BXD strains that exhibit an IBD-like transcriptome signature on HFD, indicating that an interplay of genetics and diet can significantly affect intestinal inflammation. Using gene co-expression analyses, we identified modules that are enriched for IBD-dysregulated genes and found that these IBD-related modules share cis-regulatory elements that are responsive to the STAT2, SMAD3, and REL transcription factors. We used module quantitative trait locus (ModQTL) analyses to identify genetic loci associated with the expression of these modules. Through a prioritization scheme involving systems genetics in the mouse and integration with external human datasets, we identified Muc4 and Epha6 as the top candidates mediating differences in HFD-driven intestinal inflammation. This work provides insights into the contribution of genetics and diet to IBD risk and identifies two candidate genes, MUC4 and EPHA6, that may mediate IBD susceptibility in humans.

systems biology↗

bioRxiv2022

Hepatic lipid overload potentiates biliary epithelial cell activation via E2Fs

During severe or chronic hepatic injury, biliary epithelial cells (BECs), also known as cholangiocytes, undergo rapid reprogramming and proliferation, a process known as ductular reaction (DR), and allow liver regeneration by differentiating into both functional cholangiocytes and hepatocytes. While DR is a hallmark of chronic liver diseases, including advanced stages of non-alcoholic fatty liver disease (NAFLD), the early events underlying BEC activation are largely unknown. Here, we demonstrate that BECs readily accumulate lipids upon fatty acid (FA) treatment in BEC-derived organoids, and during high-fat diet feeding in mice. Lipid overload induces a metabolic rewiring to support the conversion of adult cholangiocytes into active BECs. Mechanistically, we found that lipid overload unleashes the activation of the E2F transcription factors in BECs, which drives cell cycle progression while promoting glycolytic metabolism. These findings demonstrate that fat overload is sufficient to initiate a DR, without epithelial damage, and provide new insights into the mechanistic basis of BEC activation, revealing unexpected connections between lipid metabolism, stemness, and regeneration.

cell biology↗