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

压电1 巨核细胞 骨髓 血小板 下调和上调 细胞生物学 生物 血小板生成素 骨髓纤维化 免疫学 造血 干细胞 遗传学 受体 机械敏感通道 基因 离子通道
作者
Vittorio Abbonante,Anastasia Iris Karkempetzaki,Catherine Léon,Anandi Krishnan,Nasi Huang,Christian A. Di Buduo,Daniele Cattaneo,Christina M. Ward,Shinobu Matsuura,Inès Guinard,Josiane Weber,Aurora De Acutis,Giovanni Vozzi,Alessandra Iurlo,Katya Ravid,Alessandra Balduini
出处
期刊:American Journal of Hematology [Wiley]
标识
DOI:10.1002/ajh.27184
摘要

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 Jak2 V617F PMF mice show significantly elevated PIEZO1 expression, compared to wild‐type controls. Accordingly, Mks isolated from bone marrow aspirates of JAK2 V617F 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 JAK2 V617F 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.
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