A new path to platelet production through matrix sensing

Megakaryocytes in the bone marrow are immersed in a network of extracellular matrix (ECM) components that regulate 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 megakaryocyte 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 bone marrow matrix stiffness via collagen cross-linking. In vivo inhibition of LOX and consequent matrix softening lead to TRPV4 activation cascade, and increased platelet levels. Concurrently, in vitro proplatelet formation was reduced on a recombinant enzyme-mediated stiffer collagen. These results suggest a novel mechanism by which megakaryocytes, through TRPV4, sense ECM environmental rigidity and release platelets accordingly.