β4GALT1 controls β1 integrin function to govern thrombopoiesis and hematopoietic stem cell homeostasis

Giannini, Silvia; Lee‐Sundlov, Melissa M.; Rivadeneyra, Leonardo; Buduo, Christian A. Di; Burns, Robert T.; Lau, Joseph T.Y.; Falet, Hervé; Balduini, Alessandra; Hoffmeister, Karin M.

doi:10.1038/s41467-019-14178-y

Cited by 40 publications

(35 citation statements)

References 69 publications

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“…Disrupted tight junction signaling in mucosa could possibly explain a response to the breakdown of the integrity of epithelial tight junctions (50). Notably, the current study indicated that MF diet reduced the expression of genes involved in key pathways (epithelial adherens junction, integrin, and ILK signaling) that regulate tight junctions in IL (51,52). Several pathogens invade hosts by taking advantage of the dysregulation of tight junctions in mucosal cells (53).…”

Section: Discussionmentioning

confidence: 64%

Formula Diet Alters the Ileal Metagenome and Transcriptome at Weaning and during the Postweaning Period in a Porcine Model

et al. 2020

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Exclusive breastfeeding impacts the intestinal microbiome and is associated with a better immune function than is seen with milk formula (MF) feeding in infants and yet with mechanisms poorly defined. The porcine model was used to evaluate the impact of MF on ileum microbial communities and gene expression relative to human milk (HM)-fed piglets. Fifty-two Dutch Landrace male piglets were fed an isocaloric diet of either HM (n = 26) or MF (n = 26) from day 2 through day 21 of age and weaned to a solid diet until day 51. Eleven piglets from each group were euthanized at day 21, while the remaining piglets (HM, n = 15; MF, n = 15) were euthanized at day 51 to collect ileal epithelium (EP) scrapings and ileal (IL) tissues. The epithelial mucosa was subjected to shotgun metagenome sequencing, and EP and IL tissues were used for transcriptome analysis. On day 21, transcriptome data revealed that the levels of pathways involved in inflammation and apoptosis were significantly higher in MF piglets than in HM piglets, whereas the levels of tight junctions and pathogen detection systems were lower in MF piglets than in HM piglets. The MF impacts on the small intestine were maintained over the postweaning period (day 51) as indicated by higher levels of Dialister invisus bacteria and higher levels of expression of genes associated with inflammation and apoptosis pathways relative to HM group. The current study demonstrated that MF might impact local intestinal inflammation, apoptosis, and tight junctions and might suppress pathogen recognition in the small intestine compared with HM. IMPORTANCE Exclusive human milk (HM) breastfeeding for the first 6 months of age in infants is recommended to improve health outcomes during early life and beyond. When women are unable to provide sufficient HM, milk formula (MF) is often recommended as a complementary or alternative source of nutrition. Previous studies in piglets demonstrated that MF alters the gut microbiome and induces inflammatory cytokine production. The links between MF feeding, gut microbiome, and inflammation status are unclear due to challenges associated with the collection of intestinal samples from human infants. The current report provides the first insight into MF-microbiome-inflammation connections in the small intestine compared with HM feeding using a porcine model. The present results showed that, compared with HM, MF might impact immune function through the induction of ileal inflammation, apoptosis, and tight junction disruptions and likely compromised immune defense against pathogen detection in the small intestine relative to piglets that were fed HM.

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Section: Discussionmentioning

confidence: 64%

Formula Diet Alters the Ileal Metagenome and Transcriptome at Weaning and during the Postweaning Period in a Porcine Model

et al. 2020

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“…We observed variability of the RCA/FSC ratio in our population. We found various single nucleotide polymorphisms (database AWESOME) 45 in 3 genes involved in platelet glycosylation/sialylation: SLC35A1 , GNE and B4GALT1 46 . This analysis demonstrated that the variability observed could be explained by a genetic variation.…”

Section: Discussionmentioning

confidence: 70%

Measuring beta‐galactose exposure on platelets: Standardization and healthy reference values

Lasne

Pascreau

Darame

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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Background Correct diagnosis of the cause of thrombocytopenia is crucial for the appropriate management of patients. Hyposialylation/desialylation (characterized by abnormally high β‐galactose exposure) accelerates platelet clearance and can lead to thrombocytopenia. However, the reference range for β‐galactose exposure in healthy individuals has not been defined previously. Objective The objective of the present study was to develop a standardized assay of platelet β‐galactose exposure for implementation in a clinical laboratory. Methods β‐Galactose exposure was measured in platelet‐rich plasma by using flow cytometry and Ricinus communis agglutinin (RCA). A population of 120 healthy adults was recruited to study variability. Results We determined an optimal RCA concentration of 12.5 μg/mL. The measure was stable for up to 4 hours (mean fluorescence intensity [MFI]‐RCA: 1233 ± 329 at 0 hour and 1480 ± 410 at 4 hours). The platelet count did not induce a variation of RCA and the measure of RCA was stable when tested up to 24 hours after blood collection (MFI‐RCA: 1252 ± 434 at day 0 and 1140 ± 297 24 hours after blood sampling). To take into account the platelet size, results should be expressed as RCA/forward scatter ratio. We used the assay to study variability in 120 healthy adults, and we found that the ratio is independent of sex and blood group. Conclusion We defined a normal range in a healthy population and several preanalytical and analytical variables were evaluated, together with positive and negative controls. This assay may assist in the diagnosis of thrombocytopenic diseases linked to changes in β‐galactose exposure.

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“…While alterations in the activity of some of the β4GalT subfamily members have been associated with various diseases, 8,9 our recent data shows that deletion of the B4GALT1 leads to severe thrombocytopenia and impaired HSC homeostasis. 10 Additionally, in megakaryocytes B4GALT1 expression is regulated via the JAK signaling to control glycan expression on proteins. 10,11 Thus, galactosylation regulated by JAK plays an important role in megakaryopoiesis.…”

Section: Introductionmentioning

confidence: 99%

Increased B4GALT1 expression is associated with platelet surface galactosylation and thrombopoietin plasma levels in MPNs

Buduo

Giannini

Abbonante

et al. 2021

Blood

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Aberrant megakaryopoiesis is a hallmark of the myeloproliferative neoplasms (MPNs), a group of clonal haematological malignancies originating from haematopoietic stem cells, leading to an increase in mature blood cells in the peripheral blood. Sialylated derivatives of the glycan structure β4-N-acetyllactosamine (Galβ1,4GlcNAc or type-2 LacNAc, thereafter referred to as LacNAc) regulate platelet lifespan, hepatic Thrombopoietin production, and thrombopoiesis. We found increased Thrombopoietin plasma levels in MPNs with high allele burden of the mutated clones. Remarkably, platelets isolated from MPNs had a significant increase in LacNAc expression that correlated with the high allele burden regardless of the underlying identified mutation. Megakaryocytes derived in vitro from these patients showed an increased expression of the B4GALT1 gene encoding β-1,4-galactosyltransferase1 (β4GalT1). Consistently, megakaryocytes from MPN showed increased LacNAc expression relative to healthy controls, which was counteracted by the treatment with a Janus Kinase 1/2 inhibitor. Altered expression of B4GALT1 in mutant megakaryocytes can lead to the production of platelets with aberrant galactosylation which in turn promote hepatic Thrombopoietin synthesis regardless of platelet mass. Our findings provide a new paradigm for understanding aberrant megakaryopoiesis in MPNs and identify β4GalT1 as a potential actionable target for therapy.

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β4GALT1 controls β1 integrin function to govern thrombopoiesis and hematopoietic stem cell homeostasis

Cited by 40 publications

References 69 publications

Formula Diet Alters the Ileal Metagenome and Transcriptome at Weaning and during the Postweaning Period in a Porcine Model

Formula Diet Alters the Ileal Metagenome and Transcriptome at Weaning and during the Postweaning Period in a Porcine Model

Measuring beta‐galactose exposure on platelets: Standardization and healthy reference values

Increased B4GALT1 expression is associated with platelet surface galactosylation and thrombopoietin plasma levels in MPNs

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