Correction: Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor belonging to the Per-Arnt-Sim (PAS) family of proteins. The AHR is involved in hematopoietic stem cell (HSC) functions including self-renewal, proliferation, quiescence, and differentiation. We hypothesize that AHR impacts HSC functions by influencing genes that have roles in HSC maintenance and function and that this may occur through regulation of bone marrow (BM) niche cells. We examined BM and niche cells harvested from 8-week-old AHR null-allele (KO) mice in which exon 3 was deleted in theAhrgene and compared these data to cells from B6 control mice; young and old (10 months) animals were also compared. We report changes in HSCs and peripheral blood cells in mice lacking AHR. Serial transplantation assays revealed a significant increase in long term HSCs. There was a significant increase in mesenchymal stem cells constituting the endosteal BM niche. Gene expression analyses of HSCs revealed an increase in expression of genes involved in proliferation and maintenance of quiescence. Our studies infer that loss of AHR results in increased proliferation and self-renewal of long term HSCs, in part, by influencing the microenvironment in the niche regulating the balance between quiescence and proliferation in HSCs.

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IP3 3-Kinase B Controls Hematopoietic Stem Cell Homeostasis and Prevents Lethal Hematopoietic Failure in Mice

Blood ◽

10.1182/blood.v124.21.250.250 ◽

2014 ◽

Vol 124 (21) ◽

pp. 250-250

Author(s):

Karsten Sauer

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Conflicts Of Interest ◽

Cell Activity ◽

Hematopoietic Stem ◽

Stem And Progenitor Cells ◽

Phosphoinositide 3 Kinase ◽

And Function

Tight regulation of hematopoietic stem cell (HSC) homeostasis ensures life-long hematopoiesis and prevents blood cancers. The mechanisms balancing HSC quiescence with expansion and differentiation into hematopoietic progenitors are incompletely understood. Here, we identify inositoltrisphosphate (IP3) 3-kinase B (Itpkb) as a novel essential regulator of HSC quiescence and function. Young Itpkb-/- mice accumulated phenotypic HSC which were less quiescent and proliferated more than wildtype controls. Itpkb-/- HSC downregulated quiescence and stemness associated mRNAs, but upregulated activation, oxidative metabolism, protein synthesis and lineage associated transcripts. Although they showed no significant homing defects and had normal to elevated viability, Itpkb-/- HSC had a severely reduced competitive long-term repopulating potential. Aging Itpkb-/- mice lost hematopoietic stem and progenitor cells and died with severe anemia. Wildtype HSC normally repopulated Itpkb-/- hosts, indicating a HSC-intrinsic Itpkb requirement. In vitro, Itpkb-/- HSC had reduced cobblestone-area forming cell activity and showed increased stem cell factor activation of the phosphoinositide 3-kinase (PI3K) effector Akt. This was reversed by exogenous provision of the Itpkb product IP4, a known PI3K/Akt antagonist. Itpkb-/- HSC also showed transcriptome changes consistent with hyperactive Akt/mTOR signaling. Thus, we propose that Itpkb ensures HSC quiescence and function in part by limiting cytokine-induced PI3K signaling in HSC. Disclosures No relevant conflicts of interest to declare.

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