Identification of immune-activated hematopoietic stem cells

Bujanover, Nir; Goldstein, Oron; Greenshpan, Yariv; Turgeman, Hodaya; Klainberger, Amit; Scharff, Ye’ela; Gazit, Roi

doi:10.1038/s41375-018-0220-z

Cited by 31 publications

(42 citation statements)

References 15 publications

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“…Together, these data indicate that the Fgd5-ZSGreen reporter faithfully marks phenotypic and functional HSCs after chronic IL-1 exposure. These findings are consistent with a report that Fgd5 reporter expression enriches for functional HSCs after acute poly I:C stimulation [48]. These data also suggest that the EPCR + /CD34 − surface marker combination may have predictive value in assessing the degree to which HSCspecific reporter strains faithfully mark functional HSCs in inflammatory conditions.…”

Section: Fgd5 Enriches For Functional Hscs In Homeostatic and Inflammsupporting

confidence: 92%

“…We found that more stringent approaches to enrich for functional HSCs, including the EPCR + /CD34 − SLAM and Fgd5-ZsGreen + SLAM definitions, provided superior enrichment for HSC activity and molecular phenotype relative to unfractionated SLAM cells following chronic IL-1 exposure. Similarly, a recent study reported long-term myeloid/lymphoid reconstitution activity in Fgd5-mCherry + SLAM cells from poly I:Ctreated mice was essentially identical to that of control mice [48], whereas prior work had shown that unfractionated IFN-exposed SLAM cells exhibited impaired long-term reconstitution activity [19,23]. As our current study and previous work both found that Fgd5 + SLAM cells are highly enriched for EPCR + /CD34 − cells [30], we anticipate the EPCR + /CD34 − definition may be useful for enriching HSCs under multiple inflammatory contexts.…”

Section: Discussionmentioning

confidence: 61%

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

Rabe

Hernández

Mills

et al. 2020

Experimental Hematology

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Section: Fgd5 Enriches For Functional Hscs In Homeostatic and Inflammsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 61%

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

Rabe

Hernández

Mills

et al. 2020

Experimental Hematology

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“…CD69 and HLA-DRB1 are genes that play a central role in the immune system and are constitutively expressed in T cells. This result is important since CD69 has been described as heterogeneous in HSCs, and our observation marks this gene as important for the mobilization and activation of stem cells in hematopoietic differentiation [29,30].…”

Section: Differential Gene Expression Profiling Of Mscs Versus Relatesupporting

confidence: 52%

Deciphering Master Gene Regulators and Associated Networks of Human Mesenchymal Stromal Cells

et al. 2020

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Mesenchymal Stromal Cells (MSC) are multipotent cells characterized by self-renewal, multilineage differentiation, and immunomodulatory properties. To obtain a gene regulatory profile of human MSCs, we generated a compendium of more than two hundred cell samples with genome-wide expression data, including a homogeneous set of 93 samples of five related primary cell types: bone marrow mesenchymal stem cells (BM-MSC), hematopoietic stem cells (HSC), lymphocytes (LYM), fibroblasts (FIB), and osteoblasts (OSTB). All these samples were integrated to generate a regulatory gene network using the algorithm ARACNe (Algorithm for the Reconstruction of Accurate Cellular Networks; based on mutual information), that finds regulons (groups of target genes regulated by transcription factors) and regulators (i.e., transcription factors, TFs). Furtherly, the algorithm VIPER (Algorithm for Virtual Inference of Protein-activity by Enriched Regulon analysis) was used to inference protein activity and to identify the most significant TF regulators, which control the expression profile of the studied cells. Applying these algorithms, a footprint of candidate master regulators of BM-MSCs was defined, including the genes EPAS1, NFE2L1, SNAI2, STAB2, TEAD1, and TULP3, that presented consistent upregulation and hypomethylation in BM-MSCs. These TFs regulate the activation of the genes in the bone marrow MSC lineage and are involved in development, morphogenesis, cell differentiation, regulation of cell adhesion, and cell structure.

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“…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%

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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Identification of immune-activated hematopoietic stem cells

Cited by 31 publications

References 15 publications

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

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

Deciphering Master Gene Regulators and Associated Networks of Human Mesenchymal Stromal Cells

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

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