A new path to platelet production through matrix sensing

Vittorio Abbonante, Christian Andrea di Buduo, Cristian Gruppi, Carmelo De Maria, Elise Spedden, Aurora de Acutis, Cristian Staii, Mario Raspanti, Giovanni Vozzi, David L. Kaplan, Francesco Moccia, Katya Ravid, Alessandra Balduini

Research output: Contribution to journalArticlepeer-review

Abstract

Megakaryocytes (MK) in the bone marrow (BM) are immersed in a network of extracellular matrix components that regulates platelet release into the circulation. Combining biological and bioengineering approaches, we found that the activation of transient receptor potential cation channel subfamily V member 4 (TRPV4), a mechano-sensitive ion channel, is induced upon MK adhesion on softer matrices. This response promoted platelet production by triggering a cascade of events that lead to calcium influx, β1 integrin activation and internalization, and Akt phosphorylation, responses not found on stiffer matrices. Lysyl oxidase (LOX) is a physiological modulator of BM matrix stiffness via collagen crosslinking. In vivo inhibition of LOX and consequent matrix softening lead to TRPV4 activation cascade and increased platelet levels. At the same time, in vitro proplatelet formation was reduced on a recombinant enzyme-mediated stiffer collagen. These results suggest a novel mechanism by which MKs, through TRPV4, sense extracellular matrix environmental rigidity and release platelets accordingly.

Original languageEnglish
Pages (from-to)1150-1160
Number of pages11
JournalHaematologica
Volume102
Issue number7
DOIs
Publication statusPublished - Jun 26 2017

ASJC Scopus subject areas

  • Hematology

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