Phosphatidylinositol-3 kinase signaling controls survival and stemness of hematopoietic stem and progenitor cells

Sasja Blokzijl-Franke,Philippe Herbomel,Stefan Schulte-Merker,Jeroen Den Hertog,Bas Ponsioen,Suma Choorapoikayil,Karima Kissa

doi:10.1038/s41388-021-01733-5

Abstract

Hematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to all blood lineages during life. HSPCs emerge from the ventral wall of the dorsal aorta (VDA) during a specific timespan in embryonic development through endothelial hematopoietic transition (EHT). We investigated the ontogeny of HSPCs in mutant zebrafish embryos lacking functional pten, an important tumor suppressor with a central role in cell signaling. Through in vivo live imaging, we discovered that in pten mutant embryos a proportion of the HSPCs died upon emergence from the VDA, an effect rescued by inhibition of phosphatidylinositol-3 kinase (PI3K). Surprisingly, inhibition of PI3K in wild-type embryos also induced HSPC death. Surviving HSPCs colonized the caudal hematopoietic tissue (CHT) normally and committed to all blood lineages. Single-cell RNA sequencing indicated that inhibition of PI3K enhanced survival of multipotent progenitors, whereas the number of HSPCs with more stem-like properties was reduced. At the end of the definitive wave, loss of Pten caused a shift to more restricted progenitors at the expense of HSPCs. We conclude that PI3K signaling tightly controls HSPCs survival and both up- and downregulation of PI3K signaling reduces stemness of HSPCs.

Highlights

Stem cells define a particular type of cells that maintain selfrenewal capacity and may differentiate into multiple cell types at the same time
We found that ptena−/−ptenb−/− mutant embryos expressed runx1 and c-myb along the ventral wall of the dorsal aorta (VDA) during the period that Hematopoietic stem and progenitor cells (HSPCs) emerge just like their siblings (Fig. S1), indicating that loss of Pten does not affect the number of hemogenic endothelial cells
Ptenb−/− mutant embryos led to the unexpected finding that half of the HSPCs undergo apoptosis upon emergence from the VDA during endothelial hematopoietic transition (EHT) at the onset of the definitive wave (Fig. 1)

Summary

Introduction

Stem cells define a particular type of cells that maintain selfrenewal capacity and may differentiate into multiple cell types at the same time. Hematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to all blood lineages during life [1,2,3]. An initial primitive wave of hematopoiesis occurs in the embryo, giving rise to primitive erythrocytes and myeloid cells.

Methods

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Conclusion