Discrimination of Dormant and Active Hematopoietic Stem Cells by G0 Marker Reveals Dormancy Regulation by Cytoplasmic Calcium

Tanaka, Yosuke; Hamey, Fiona; Chang, Chih‐Hsiang; Oki, Toshihiko; Asada, Shuhei; Hayashi, Yasutaka; Fujino, Takeshi; Yonezawa, Taishi; Takeda, Reina; Kawabata, Kimihito C.; Umemoto, Terumasa; Takubo, Keiyo; Takizawa, Hajime; Goyama, Susumu; Ishihama, Yasushi; Honda, Hiroaki; Göttgens, Berthold; Kitamura, Toshio

doi:10.1016/j.celrep.2019.11.061

Cited by 35 publications

(54 citation statements)

References 72 publications

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“…The study also highlighted how intracellular calcium levels regulate calpain and subsequently the activity of TET (Ten-eleven Review translocation) enzymes for HSC maintenance. However, high concentration of cytoplasmic calcium has also been associated with dormant HSCs (Fukushima et al, 2019).…”

Section: Regulation Of Ros In Adult Hscsmentioning

confidence: 99%

Hematopoietic Stem Cell Metabolism during Development and Aging

2020

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Cellular metabolism in hematopoietic stem cells (HSCs) is an area of intense research interest, but the metabolic requirements of HSCs and their adaptations to their niches during development have remained largely unaddressed. Distinctive from other tissue stem cells, HSCs transition through multiple hematopoietic sites during development. This transition requires drastic metabolic shifts, insinuating the capacity of HSCs to meet the physiological demand of hematopoiesis. In this review, we highlight how mitochondrial metabolism determines HSC fate, and especially focus on the links between mitochondria, endoplasmic reticulum (ER), and lysosomes in HSC metabolism.

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Section: Regulation Of Ros In Adult Hscsmentioning

confidence: 99%

Hematopoietic Stem Cell Metabolism during Development and Aging

2020

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“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted September 27, 2021. ; https://doi.org/10.1101/2021.09.27.461900 doi: bioRxiv preprint 0.01), whereas CPA3, ABCA1, CDK6 and IRF8 were highly DEGs in PLXDC2 -HSCs (FDR < 0.01) (Figures 5A and 5B). Interestingly, CDK6 expression has been shown to mark active HSCs in mouse and human studies (Laurenti et al, 2015;Cabezas-Wallscheid et al, 2017;Fukushima et al, 2019) and IRF8 is a differential marker for myeloid cells (Kurotaki et al, 2013;Kurotaki et al, 2018). The gene expression data therefore suggest that PLXDC2 -HSCs express a more differentiated gene signature than PLXDC2 + HSCs.…”

Section: Plxdc2 + Hscs Express More Hsc Signature Genes Than Plxdc2 -Hscsmentioning

confidence: 99%

Prospective isolation of mouse and human hematopoietic stem cells using Plexin domain containing 2

Tanaka

Kubota

Lieberam

et al. 2021

Preprint

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Numerous strategies exist to isolate hematopoietic stem cells (HSCs) using complex combinations of markers and flow cytometry. However, robust identification of HSCs using imaging techniques is substantially more challenging which has prompted the recent development of HSC reporter mice. To date, none of the molecules used in these reporters have been useful for human HSC identification. Here we report that PLXDC2 is a useful marker for both mouse and human HSCs. Using a green fluorescent protein (GFP) knock-in at the Plxdc2 locus in mice (hereafter denoted as Plxdc2-GFP), we showed that Plxdc2-GFP is highly expressed in HSCs with 1 in 2.8 Plxdc2-GFP+CD150+ cells giving long-term multi-lineage reconstitution in transplantation. Moreover, we developed a novel human PLXDC2 antibody and showed that human PLXDC2+ HSCs have stronger long-term multilineage reconstitution ability compared with PLXDC2- HSCs in a xenograft model. Thus, our study identifies PLXDC2 as a highly relevant molecule in HSC identification, potentially allowing greater purity and live in vivo tracking of these cells.

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“…We introduced G0 marker (G0M) to a mouse CML-like model to visualize quiescent CML LSCs. We retrovirally overexpressed BCR-ABL1 fusion gene in BM cells from 5FUtreated G0M mice, in which Cre-inducible G0M in a Rosa26 allele is regulated by Vav1-Cre 44 , and then injected the cells into lethally irradiated wild-type recipient mice to develop mouse CML-like disease (Figure 1A). CML derived from BM cells carrying G0M was developed in about 3 weeks, and imatinib treatment prolonged the survival of leukemic mice (Figure 1B), ensuring that G0M did not affect CML development or imatinib treatment.…”

Section: Identification Of CML Lscs By G0 Marker and Cd27mentioning

confidence: 99%

“…Previously we reported that G0 marker (G0M), a fusion protein between the fluorescent protein mVenus and p27K-, which is a p27 mutant lacking cyclin dependent kinase (Cdk) inhibitory activity, is a useful tool for visualizing the quiescent states of conventional long-term HSCs, and the stemness of the cells was correlated with the intensity of G0M 43,44 . In the present study, we applied G0M to identify and visualize quiescent CML LSCs.…”

Section: Introductionmentioning

confidence: 99%

Eradicating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors

Tanaka¹,

Mikami²,

Tsuchiya³

et al. 2021

Preprint

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Leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) are quiescent, insensitive to BCR-ABL1 tyrosine kinase inhibitors (TKIs) and responsible for CML relapse. Therefore, eradicating quiescent CML LSCs is a major goal in CML therapy. Here, using a novel G0 marker (G0M), we narrowed down CML LSCs as G0M- and CD27- double positive cells among the conventional CML LSCs. Whole transcriptome analysis revealed NF-κB activation via inflammatory signals in imatinib-insensitive quiescent CML LSCs. Blocking NF-κB signals by IRAK1/4 inhibitors together with imatinib eradicated mouse and human CML LSCs. Intriguingly, IRAK1/4 inhibitors attenuated PD-L1 expression on CML LSCs, and blocking PD-L1 together with imatinib also effectively eradicated CML LSCs in the presence of T cell immunity. Thus, IRAK1/4 inhibitors could eradicate CML LSCs through inhibiting NF-ΚB activity and reducing PD-L1 expression. Collectively, the combination of TKIs and IRAK1/4 inhibitors is an attractive strategy to achieve a radical cure of CML.

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Discrimination of Dormant and Active Hematopoietic Stem Cells by G0 Marker Reveals Dormancy Regulation by Cytoplasmic Calcium

Cited by 35 publications

References 72 publications

Hematopoietic Stem Cell Metabolism during Development and Aging

Hematopoietic Stem Cell Metabolism during Development and Aging

Prospective isolation of mouse and human hematopoietic stem cells using Plexin domain containing 2

Eradicating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors

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