Piezo1 Mechanosensor Expression in Rare Hematopoietic Cells Controls Systemic Inflammatory Response in Mice

Mutations in the Piezo1 mechanosensor are associated with blood cell anomalies. The objective of our study was to explore the role of Piezo1 in the development and function of the megakaryocyte (MK) lineage. To this end, PF4-Cre mice, bearing Cre recombinase under the control of the Pf4 gene promoter-which drives expression to hematopoietic progenitors and to the MK/platelet lineage-were crossbred with Piezo1-floxed mice to generate Piezo1 knockout (KO) mice. In our results, the hematopoietic stem cell (HSC) count-including Multipotent Progenitors 2 (MPP2) progenitors that give rise to MKs-tended to be augmented in KO mice, while the level of MPP3 progenitors that give rise to white blood cells (WBCs) tended to be reduced, as compared to matching controls. The level of circulating WBCs was significantly reduced in the KO mice compared to controls. In addition, while platelet count was modestly elevated, platelet activation response was reduced in Piezo1 KO mice compared to controls. MK levels and ploidy were similar in both groups. Baseline serum pro-and anti-inflammatory cytokine profiles were also similar in the two experimental groups. However, upon LPS challenge, there was a significant reduction in IL-6 and INF-γ levels in the sera of Piezo1 KO mice compared to controls. Our findings point to an immunoregulatory and thrombotic potential of Piezo1 in relatively rare bone marrow cells, along with an ability to modulate WBC count.