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 -