PIEZO1 activation delays erythroid differentiation of normal and hereditary xerocytosis-derived human progenitor cells - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Haematologica Année : 2020

PIEZO1 activation delays erythroid differentiation of normal and hereditary xerocytosis-derived human progenitor cells

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Yohann Demont
  • Fonction : Auteur
  • PersonId : 1151783
  • IdRef : 125012322
Julien Demagny
Agnes Lahary
  • Fonction : Auteur

Résumé

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 primary 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/GATAI ratio and decreased alpha/beta-globin expression. The cell proliferation rate was also reduced, with accumulation 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 STATS 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 demonstrate a role for PIEZO1 during erythropoiesis, since activation of PIEZO1 both chemically and through activating mutations - delays erythroid maturation, providing new insights into the pathophysiology of hereditary xerocytosis.

Dates et versions

hal-03604942 , version 1 (10-03-2022)

Identifiants

Citer

Alexis Caulier, Nicolas Jankovsky, Yohann Demont, Hakim Ouled-Haddou, Julien Demagny, et al.. PIEZO1 activation delays erythroid differentiation of normal and hereditary xerocytosis-derived human progenitor cells. Haematologica, 2020, 105 (3), pp.610-622. ⟨10.3324/haematol.2019.218503⟩. ⟨hal-03604942⟩
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