Page 96 - Haematologica March 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):610-622
Red Cell Biology & its Disorders
PIEZO1 activation delays erythroid differentiation of normal and hereditary xerocytosis-derived human progenitor cells
Alexis Caulier,1,2* Nicolas Jankovsky,1* Yohann Demont,3 Hakim Ouled-Haddou,1 Julien Demagny,4 Corinne Guitton,5 Lavinia Merlusca,2 Delphine Lebon,1,2 Pascal Vong,1 Aurélien Aubry,1 Agnès Lahary,6 Christian Rose,7 Sandrine Gréaume,8 Emilie Cardon,1 Jessica Platon,1 Halima Ouadid-Ahidouch,9 Jacques Rochette,1,10 Jean-Pierre Marolleau,1,2 Véronique Picard11 and Loïc Garçon1,4,10
1EA4666 HEMATIM, Université Picardie Jules Verne, Amiens; 2Service des Maladies du Sang, CHU Amiens, Amiens; 3Unité de Thérapie Cellulaire, CHU Amiens, Amiens; 4Service d’Hématologie Biologique, CHU Amiens; 5Service de Pédiatrie Générale, CHU Bicêtre, AP- HP, Le Kremlin-Bicêtre; 6Laboratoire d’Hématologie, CHU Rouen, Rouen; 7Service d’Oncologie et d’Hématologie, Hôpital Saint Vincent de Paul, Lille; 8Etablissement Français du Sang (EFS) de Normandie, Bois-Guillaume; 9EA4667 Laboratoire de Physiologie Cellulaire et Moléculaire, Université Picardie Jules Verne, Amiens; 10Laboratoire de Génétique Moléculaire, CHU Amiens, Amiens and 11Laboratoire d’Hématologie, AP-HP, Le Kremlin-Bicêtre, France
*AC and NJ contributed equally to this work.
ABSTRACT
Hereditary xerocytosis is a dominantly inherited red cell membrane disorder caused in most cases by gain-of-function mutations in PIEZO1, encoding a mechanosensitive ion channel that translates a mechanic stimulus into calcium influx. We found that PIEZO1 was expressed early in erythroid progenitor cells, and investigated whether it could be involved in erythropoiesis, besides having a role in the homeostasis of mature red cell hydration. In UT7 cells, chemical PIEZO1 activation using YODA1 repressed glycophorin A expression by 75%. This effect was PIEZO1-dependent since it was reverted using specific short hairpin-RNA knockdown. The effect of PIEZO1 activation was confirmed in human pri- mary progenitor cells, maintaining cells at an immature stage for longer and modifying the transcriptional balance in favor of genes associated with early erythropoiesis, as shown by a high GATA2/GATA1 ratio and decreased α/β- globin expression. The cell proliferation rate was also reduced, with accumu- lation of cells in G0/G1 of the cell cycle. The PIEZO1-mediated effect on UT7 cells required calcium-dependent activation of the NFAT and ERK1/2 pathways. In primary erythroid cells, PIEZO1 activation synergized with erythropoietin to activate STAT5 and ERK, indicating that it may modulate signaling pathways downstream of erythropoietin receptor activation. Finally, we studied the in-vitro erythroid differentiation of primary cells obtained from 14 PIEZO1-mutated patients, from 11 families, carrying ten different mutations. We observed a delay in erythroid differentiation in all cases, ranging from mild (n=3) to marked (n=8). Overall, these data demon- strate a role for PIEZO1 during erythropoiesis, since activation of PIEZO1 - both chemically and through activating mutations - delays erythroid matu- ration, providing new insights into the pathophysiology of hereditary xero- cytosis.
Introduction
PIEZO proteins were identified as a family of mechanically activated transduc- tors, first described in neuronal cell lines, which convert mechanical forces into biological signals.1 PIEZO1 is a large, three-blade propeller-shaped protein dis- playing 38 transmembrane-helix domains, and is encoded by the broadly
Correspondence:
LOÏC GARÇON
garcon.loic@chu-amiens.fr
Received: February 11, 2019. Accepted: August 9, 2019. Pre-published: August 14, 2019.
doi:10.3324/haematol.2019.218503
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