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

TY - JOUR

T1 - Phosphatidylinositol-3 kinase signaling controls survival and stemness of hematopoietic stem and progenitor cells

AU - Blokzijl-Franke, Sasja

AU - Ponsioen, Bas

AU - Schulte-Merker, Stefan

AU - Herbomel, Philippe

AU - Kissa, Karima

AU - Choorapoikayil, Suma

AU - den Hertog, Jeroen

PY - 2021/4

Y1 - 2021/4

N2 - 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.

AB - 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.

KW - Animals

KW - Female

KW - Hematopoietic Stem Cells/metabolism

KW - Humans

KW - Phosphatidylinositol 3-Kinases/metabolism

KW - Signal Transduction

KW - Stem Cells/metabolism

KW - Survival Analysis

KW - Zebrafish

U2 - 10.1038/s41388-021-01733-5

DO - 10.1038/s41388-021-01733-5

M3 - Article

C2 - 33714985

SN - 0950-9232

VL - 40

SP - 2741

EP - 2755

JO - Oncogene

JF - Oncogene

IS - 15

ER -