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
Affiliations
Vittorio Abbonante
Department of Molecular Medicine, University of Pavia, Italy;Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy
Christian Andrea Di Buduo
Department of Molecular Medicine, University of Pavia, Italy;Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy
Cristian Gruppi
Department of Molecular Medicine, University of Pavia, Italy;Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy
Carmelo De Maria
Interdepartmental Research Center “E. Piaggio”, University of Pisa, Italy
Elise Spedden
Department of Physics and Astronomy, Tufts University, Medford, MA, USA
Aurora De Acutis
Interdepartmental Research Center “E. Piaggio”, University of Pisa, Italy
Cristian Staii
Department of Physics and Astronomy, Tufts University, Medford, MA, USA
Mario Raspanti
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
Giovanni Vozzi
Interdepartmental Research Center “E. Piaggio”, University of Pisa, Italy
David L. Kaplan
Department of Biomedical Engineering, Tufts University, Medford, MA, USA
Francesco Moccia
Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, Italy
Katya Ravid
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA, USA
Alessandra Balduini
Department of Molecular Medicine, University of Pavia, Italy;Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy;Department of Biomedical Engineering, Tufts University, Medford, MA, USA
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.
