Newly identified roles for PIEZO1 mechanosensor in controlling normal megakaryocyte development and in primary myelofibrosis

Abstract

Mechanisms through which mature megakaryocytes (Mks) and their progenitors sense the bone marrow extracellular matrix to promote lineage differentiation in health and disease are still partially understood. We found PIEZO1, a mechanosensitive cation channel, to be expressed in mouse and human Mks. Human mutations in PIEZO1 have been described to be associated with blood cell disorders. Yet, a role for PIEZO1 in megakaryopoiesis and proplatelet formation has never been investigated. Here, we show that activation of PIEZO1 increases the number of immature Mks in mice, while the number of mature Mks and Mk ploidy level are reduced. Piezo1/2 knockout mice show an increase in Mk size and platelet count, both at basal state and upon marrow regeneration. Similarly, in human samples, PIEZO1 is expressed during megakaryopoiesis. Its activation reduces Mk size, ploidy, maturation, and proplatelet extension. Resulting effects of PIEZO1 activation on Mks resemble the profile in Primary Myelofibrosis (PMF). Intriguingly, Mks derived from Jak2V617F PMF mice show significantly elevated PIEZO1 expression, compared to wild‐type controls. Accordingly, Mks isolated from bone marrow aspirates of JAK2V617F PMF patients show increased PIEZO1 expression compared to Essential Thrombocythemia. Most importantly, PIEZO1 expression in bone marrow Mks is inversely correlated with patient platelet count. The ploidy, maturation, and proplatelet formation of Mks from JAK2V617F PMF patients are rescued upon PIEZO1 inhibition. Together, our data suggest that PIEZO1 places a brake on Mk maturation and platelet formation in physiology, and its upregulation in PMF Mks might contribute to aggravating some hallmarks of the disease.

Piezo1 and Its Function in Different Blood Cell Lineages

“…Shear stress is implicated in Piezo1 upregulation in various cell types such as in endothelial and vascular cells in the context of pulmonary hypertension [ 34 , 35 ], in endothelial cells via adrenomedullin [ 36 ] and in megakaryocytes (MKs) and platelets with the activation of integrins [ 37 ]. Stiffness sensation by Piezo1 was found to be associated with upregulation of the expression of the channel in MKs, as proven by culturing these cells in a 3D culture medium of different stiffness and by its enhanced MK expression in the case of primary myelofibrosis (PMF), a disease characterized by bone marrow fibrosis and augmented stiffness of the extracellular matrix (ECM) [ 38 ]. Stiffness created by kidney fibrosis was also shown to cause Piezo1 upregulation and to be associated with the progression of the disease [ 39 ].…”

“…Moreover, the Piezo1 agonist Yoda-1 seemed to induce Ca 2+ influx by 170%, indicating that this channel is implicated in shear stress responses and Ca 2+ influx in human platelets and Meg-01 cells [ 37 ]. A recent study using primary bone marrow cells showed that Piezo1 acts as a brake for MK maturation and platelet production in vitro, as well as an attenuator of these processes in vivo in mice, as shown by the deletion of Piezo1/2 in the megakaryocytic lineage [ 38 ]. Elevated expression of the Piezo1 protein was observed in MKs isolated from the bone marrow of mice or patients affected by JAK2V617F-induced primary myelofibrosis, a clonal hematological neoplasia characterized by a stiff ECM in the bone marrow microenvironment [ 38 ].…”