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

Silvia Giannini (), Melissa M. Lee-Sundlov, Leonardo Rivadeneyra, Christian A. Di Buduo, Robert Burns, Joseph T. Lau, Hervé Falet, Alessandra Balduini and Karin M. Hoffmeister ()
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Silvia Giannini: Harvard Medical School
Melissa M. Lee-Sundlov: Harvard Medical School
Leonardo Rivadeneyra: Versiti
Christian A. Di Buduo: University of Pavia
Robert Burns: Versiti
Joseph T. Lau: Roswell Park Cancer Institute
Hervé Falet: Harvard Medical School
Alessandra Balduini: University of Pavia
Karin M. Hoffmeister: Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14178-y

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