PI3K alpha and delta promote hematopoietic stem cell activation

Hemmati, Shayda; Sinclair, Taneisha; Tong, Mingwei; Bartholdy, Boris; Okabe, Rachel; Ames, Kristina; Ostrodka, Leanne; Haque, Tamanna; Kaur, Imit; Mills, Taylor; Agarwal, Anupriya; Pietras, Eric M.; Zhao, Jean J.; Roberts, Thomas M.; Gritsman, Kira

doi:10.1172/jci.insight.125832

Cited by 31 publications

(14 citation statements)

References 43 publications

(54 reference statements)

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“…The activating versus suppressive functions of the IL-1/PU.1 axis may at first appear paradoxical. Indeed, previous reports indicate that acute IL-1 administration in vivo triggers cell cycle activity in the SLAM compartment (Hemmati et al, 2019;Pietras et al, 2016;Weisser et al, 2016), which we recapitulate here. On the other hand, our H2B-GFP and cell cycle analyses show that only a limited fraction of phenotypic HSC LT enter the cell cycle following IL-1 challenge in vivo, particularly relative to the larger SLAM compartment, which is known to contain HSC-like CD41 hi SLAM cells that can rapidly enter the cell cycle in response to acute inflammatory stress (Haas et al, 2015).…”

Section: Discussionsupporting

confidence: 83%

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

Chavez

Rabe

Loeffler

et al. 2021

Journal of Experimental Medicine

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Hematopoietic stem cells (HSCs) are capable of entering the cell cycle to replenish the blood system in response to inflammatory cues; however, excessive proliferation in response to chronic inflammation can lead to either HSC attrition or expansion. The mechanism(s) that limit HSC proliferation and expansion triggered by inflammatory signals are poorly defined. Here, we show that long-term HSCs (HSCLT) rapidly repress protein synthesis and cell cycle genes following treatment with the proinflammatory cytokine interleukin (IL)-1. This gene program is associated with activation of the transcription factor PU.1 and direct PU.1 binding at repressed target genes. Notably, PU.1 is required to repress cell cycle and protein synthesis genes, and IL-1 exposure triggers aberrant protein synthesis and cell cycle activity in PU.1-deficient HSCs. These features are associated with expansion of phenotypic PU.1-deficient HSCs. Thus, we identify a PU.1-dependent mechanism triggered by innate immune stimulation that limits HSC proliferation and pool size. These findings provide insight into how HSCs maintain homeostasis during inflammatory stress.

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Section: Discussionsupporting

confidence: 83%

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

Chavez

Rabe

Loeffler

et al. 2021

Journal of Experimental Medicine

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show abstract

“…The activating versus suppressive functions of the IL-1/PU.1 axis may at first appear paradoxical. Indeed, previous reports indicate that acute IL-1 triggers HSC cell cycle activity (Hemmati et al, 2019;Pietras et al, 2016;Weisser et al, 2016). Here, we show that IL-1 does not trigger cell cycle activity in PU.1-sufficient HSC LT , even in the context of acute stimulation.…”

Section: Discussionsupporting

confidence: 40%

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

Rabe

Loeffler

Higa

et al. 2020

Preprint

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Loss of hematopoietic stem cell (HSC) quiescence and resulting clonal expansion are common initiating events in the development of hematological malignancy. Likewise, chronic inflammation related to aging, disease and/or tissue damage is associated with leukemia progression, though its role in oncogenesis is not clearly defined. Here, we show that PU.1-dependent repression of protein synthesis and cell cycle genes in HSC enforces homeostatic protein synthesis levels and HSC quiescence in response to IL-1 stimulation. These genes are constitutively de-repressed in PU.1-deficient HSC, leading to activation of protein synthesis, loss of quiescence and aberrant expansion of HSC. Taken together, our data identify a mechanism whereby HSC regulate their cell cycle activity and pool size in response to chronic inflammatory stress.

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“…Moreover, although β‐catenin alone will ultimately result in HSC exhaustion, it has been shown to promote HSC expansion when in combination with active Akt signaling 28 . Conversely, inflammation‐induced HSC proliferation is often accompanied by PI3K/Akt activation 29‐31 . Therefore, we evaluated the expression of phosphorylated β‐catenin (Ser552) and Akt (Thr308) in BM HSCs with and without LPS.…”

Section: Resultsmentioning

confidence: 99%

Cell-Intrinsic WNT4 Promotes Hematopoietic Stem and Progenitor Cell Self-Renewal

et al. 2021

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Although intracellular Wnt signaling pathways need to be tightly regulated to promote hematopoietic stem cell self-renewal, the source and identity of important Wnt ligands in the bone marrow is still largely unknown. The noncanonical ligand Wnt4 is expressed in the bone marrow as well as in the stroma, and its overexpression in fetal liver cells facilitates thymic recovery; however, its impact on adult hematopoietic stem cell function remains unclear. Here, we report that the deletion of Wnt4 from hematopoietic cells in mice (Wnt4Δ/Δ) resulted in decreased lymphopoiesis at steady state. This was likely at least in part due to the increased proinflammatory environment present in the bone marrow of Wnt4Δ/Δ mice. Wnt4Δ/Δ hematopoietic stem cells displayed reduced reconstitution capacity in serial transplants, thus demonstrating defective self-renewal, and they expanded poorly in response to lipopolysaccharide stimulation. This appeared to be the result of the absence of Wnt4 in stem/progenitor cells, as myeloid-restricted Wnt4 deletion had no notable effect. Finally, we observed that Wnt4Δ/Δ stem/progenitor cells were more quiescent, presenting enhanced levels of stress-associated JNK phosphorylation and p16INK4a expression, likely contributing to the reduced expansion observed in transplants. In conclusion, our results identify a new, largely autocrine role for Wnt4 in hematopoietic stem cell self-renewal, suggesting that regulation of Wnt signaling in hematopoiesis may not need Wnt secretion and could be independent of morphogen gradients.

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PI3K alpha and delta promote hematopoietic stem cell activation

Cited by 31 publications

References 43 publications

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

Cell-Intrinsic WNT4 Promotes Hematopoietic Stem and Progenitor Cell Self-Renewal

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