Phosphatidylinositol-3 kinase signaling controls survival and stemness of hematopoietic stem and progenitor cells
- Blokzijl-Franke, S., Ponsioen, B., Schulte-Merker, S., Herbomel, P., Kissa, K., Choorapoikayil, S., den Hertog, J.
- Oncogene 40(15): 2741-2755 (Journal)
- Registered Authors
- den Hertog, Jeroen, Herbomel, Philippe, Schulte-Merker, Stefan
- MeSH Terms
- Hematopoietic Stem Cells/metabolism*
- Phosphatidylinositol 3-Kinases/metabolism*
- Signal Transduction
- Stem Cells/metabolism*
- Survival Analysis
- 33714985 Full text @ Oncogene
Blokzijl-Franke, S., Ponsioen, B., Schulte-Merker, S., Herbomel, P., Kissa, K., Choorapoikayil, S., den Hertog, J. (2021) Phosphatidylinositol-3 kinase signaling controls survival and stemness of hematopoietic stem and progenitor cells. Oncogene. 40(15):2741-2755.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes