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

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.

Fishing Innate Immune System Properties through the Transcriptomic Single-Cell Data of Teleostei

“…The properties of the hematopoietic stem and progenitor cells could be extensively studied using the data from seven experiments: GSE92542 (larvae) [116], GSE158099 (embryo, larvae) [117], GSE166900 (larvae) [118], GSE167787 (larvae) [119], GSE186423 (larvae) and GSE186427 (embryo) [120], GSE186565 [121]. Four of the seven experiments contain clusters of neutrophils, and three of them contain macrophage clusters.…”

Stem cell homing in periodontal tissue regeneration

“…Stem cell homing was originally defined as the process of endothelialization through blood vessels and migration of hematopoietic stem cells (HSCs) after transplantation, and finally, HSCs colonize in the bone marrow and restart hematopoiesis, in which many cytokines and chemokines are involved ( Ji et al, 2015 ; Zhu et al, 2015 ). Blood lineages are considered to be risen from hematopoietic stem and progenitor cells (HSPCs), which then migrate to the bone marrow niche through homing for further proliferation and differentiation ( Li et al, 2018a ; Blokzijl-Franke et al, 2021 ; Ranzoni et al, 2021 ). The homing mechanism of HSPCs is relevant to stem cell transplantation therapy and has been investigated by many researchers ( Morrison and Scadden, 2014 ; Li et al, 2018a ; Liesveld et al, 2020 ), though the specific mechanism of HSPCs homing was not elucidated.…”

Recent Advances in Developmental Hematopoiesis: Diving Deeper With New Technologies

“…Bulk RNA-seq, scRNA-seq and microarray analyses have then been performed to analyze the intrinsic regulation (e.g. by transcription factors) of HSPC formation by sequencing phenotypically enriched populations for arterial endothelial cells, HE cells, cells undergoing EHT, pre-HSCs and/or HSCs sorted from mouse, chicken, human and/or zebrafish embryos (78,86,97,(112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123). Overall, these studies highlighted important features.…”