\u03b24GALT1 controls \u03b21 integrin function to govern thrombopoiesis and hematopoietic stem cell homeostasis

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

doi:10.1038/s41467-019-14178-y

Abstract

Glycosylation is critical to megakaryocyte (MK) and thrombopoiesis in the context of gene mutations that affect sialylation and galactosylation. Here, we identify the conserved B4galt1 gene as a critical regulator of thrombopoiesis in MKs. β4GalT1 deficiency increases the number of fully differentiated MKs. However, the resulting lack of glycosylation enhances β1 integrin signaling leading to dysplastic MKs with severely impaired demarcation system formation and thrombopoiesis. Platelets lacking β4GalT1 adhere avidly to β1 integrin ligands laminin, fibronectin, and collagen, while other platelet functions are normal. Impaired thrombopoiesis leads to increased plasma thrombopoietin (TPO) levels and perturbed hematopoietic stem cells (HSCs). Remarkably, β1 integrin deletion, specifically in MKs, restores thrombopoiesis. TPO and CXCL12 regulate β4GalT1 in the MK lineage. Thus, our findings establish a non-redundant role for β4GalT1 in the regulation of β1 integrin function and signaling during thrombopoiesis. Defective thrombopoiesis and lack of β4GalT1 further affect HSC homeostasis.

Highlights

Glycosylation is critical to megakaryocyte (MK) and thrombopoiesis in the context of gene mutations that affect sialylation and galactosylation
The underlying pathogenic mechanisms of low platelet count are categorized as: (1) defects in MK lineage commitment and differentiation; (2) defects in MK maturation; and (3) defect in platelet release
Optimized platelet release depends on the localization of MKs at bone marrow (BM) sinusoids and the organization of the MK demarcation membrane system (DMS), an essential precursor complex membranous structure for proplatelet formation before their release into the bloodstream[2]

Summary

Introduction

Glycosylation is critical to megakaryocyte (MK) and thrombopoiesis in the context of gene mutations that affect sialylation and galactosylation. Similar to the data obtained in transplanted NSG mice, ~50% of GFP+ B4galt1−/− MKs failed to localize at sinusoids compared to control MKs (31.2 ± 10.3% versus 62.6 ± 2.8%, respectively) (Fig. 3h). The GFP+ B4galt1−/− platelet count remained profoundly decreased (

Results

Conclusion