CD34 and EPCR coordinately enrich functional murine hematopoietic stem cells under normal and inflammatory conditions

Rabe, Jennifer L.; Hernández, Giovanni; Mills, Taylor; Nerlov, Claus; Pietras, Eric M.

doi:10.1016/j.exphem.2019.12.003

Cited by 39 publications

(68 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To investigate how IL-1 represses cell cycle and protein synthesis genes in HSC LT , we reanalyzed our IPA data and noticed it had identified SPI1 (PU.1) pathway activation in IL-1-exposed SLAM cells ( Fig. 1D), consistent with our prior published findings (Pietras et al, 2016;Rabe et al, 2020).…”

Section: Il-1 Induced Gene Repression Is Associated With Increased Pusupporting

confidence: 84%

“…This is particularly true under inflammatory stress conditions, where increased proliferative activity can lead to overproduction of blood cells, rapid HSC attrition and BM failure (Essers et al, 2009;King et al, 2011;Matatall et al, 2016;Pietras, 2017;Pietras et al, 2014;Takizawa et al, 2017). Highly enriched HSC fractions can maintain a quiescent phenotype and long-term engraftment capacity even under a variety of inflammatory stress conditions (Bujanover et al, 2018;Hernandez et al, 2020;Pietras et al, 2014;Pietras et al, 2016;Rabe et al, 2020;Wilson et al, 2008;Zhao et al, 2019), implying the existence of mechanism(s) that prevent spurious HSC cell cycle entry.…”

Section: Discussionmentioning

confidence: 99%

“…0.5 µg of IL-1 or PBS/BSA alone was injected intraperitoneally (i.p.) in a 100 µl bolus once per day for either one or 20 days, as previously described (Pietras et al, 2016;Rabe et al, 2020). In vivo puromycin labeling assays were performed as previously described (Chapple et al, 2018), with 500 µg of puromycin (Life Technologies) injected i.p.…”

Section: Methodsmentioning

confidence: 99%

“…Flow cytometry: Analysis of BM cell populations was performed using a similar protocol as previously described (Pietras et al, 2016;Rabe et al, 2020). Bone marrow was flushed from femurs and tibiae of mice using staining media (SM; Hanks Buffered Saline Solution + 2% FBS) and a syringe equipped with a 21G needle.…”

Section: Methodsmentioning

confidence: 99%

“…Cell sorting: For HSC isolation by cell sorting, arm, leg, pelvic bones and spines were isolated from mice as previously described (Pietras et al, 2016;Rabe et al, 2020). Bones were crushed in SM using a mortar and pestle and depleted of erythrocytes using 1x ACK.…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

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

Rabe

Loeffler

Higa

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Il-1 Induced Gene Repression Is Associated With Increased Pusupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

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

Rabe

Loeffler

Higa

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Current Concepts on Endothelial Stem Cells Definition, Location, and Markers

Chambers

Pathak

Pedrini

et al. 2021

Stem Cells Translational Medicine

View full text Add to dashboard Cite

Ischemic vascular disease is a major cause of mortality and morbidity worldwide, and regeneration of blood vessels in perfusion-deficient tissues is a worthwhile therapeutic goal. The idea of delivering endothelial stem/progenitor cells to repair damaged vasculature, reperfuse hypoxic tissue, prevent cell death, and consequently diminish tissue inflammation and fibrosis has a strong scientific basis and clinical value. Various labs have proposed endothelial stem/progenitor cell candidates. This has created confusion, as there are profound differences between these cell definitions based on isolation methodology, characterization, and reparative biology. Here, a stricter definition based on stem cell biology principles is proposed. Although preclinical studies have often been promising, results from clinical trials have been highly contradictory and served to highlight multiple challenges associated with disappointing therapeutic benefit. This article reviews recent accomplishments in the field and discusses current difficulties when developing endothelial stem cell therapies. Emerging evidence that disputes the classic view of the bone marrow as the source for these cells and supports the vascular wall as the niche for these tissue-resident endothelial stem cells is considered. In addition, novel markers to identify endothelial stem cells, including CD157, EPCR, and CD31low VEGFR2low IL33+ Sox9+, are described.

show abstract

APEX1 Nuclease and Redox Functions are Both Essential for Adult Mouse Hematopoietic Stem and Progenitor Cells

Zaunz

Smedt

Lauwereins

et al. 2023

Stem Cell Rev and Rep

View full text Add to dashboard Cite

Self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) are carefully controlled by extrinsic and intrinsic factors, to ensure the lifelong process of hematopoiesis. Apurinic/apyrimidinic endonuclease 1 (APEX1) is a multifunctional protein implicated in DNA repair and transcriptional regulation. Although previous studies have emphasized the necessity of studying APEX1 in a lineage-specific context and its role in progenitor differentiation, no studies have assessed the role of APEX1, nor its two enzymatic domains, in supporting adult HSPC function. In this study, we demonstrated that complete loss of APEX1 from murine bone marrow HSPCs (induced by CRISPR/Cas9) caused severe hematopoietic failure following transplantation, as well as a HSPC expansion defect in culture conditions maintaining in vivo HSC functionality. Using specific inhibitors against either the nuclease or redox domains of APEX1 in combination with single cell transcriptomics (CITE-seq), we found that both APEX1 nuclease and redox domains are regulating mouse HSPCs, but through distinct underlying transcriptional changes. Inhibition of the APEX1 nuclease function resulted in loss of HSPCs accompanied by early activation of differentiation programs and enhanced lineage commitment. By contrast, inhibition of the APEX1 redox function significantly downregulated interferon-stimulated genes and regulons in expanding HSPCs and their progeny, resulting in dysfunctional megakaryocyte-biased HSPCs, as well as loss of monocytes and lymphoid progenitor cells. In conclusion, we demonstrate that APEX1 is a key regulator for adult regenerative hematopoiesis, and that the APEX1 nuclease and redox domains differently impact proliferating HSPCs. Graphical Abstract

show abstract

CD34 and EPCR coordinately enrich functional murine hematopoietic stem cells under normal and inflammatory conditions

Cited by 39 publications

References 63 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

Current Concepts on Endothelial Stem Cells Definition, Location, and Markers

APEX1 Nuclease and Redox Functions are Both Essential for Adult Mouse Hematopoietic Stem and Progenitor Cells

Contact Info

Product

Resources

About