Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency

Liang, Raymond; Arif, Tasleem; Kalmykova, Svetlana; Kasianov, Artem S.; Miao, Lin; Menon, Vijay; Qiu, Jiajing; Bernitz, Jeffrey; Moore, Kateri; Lin, Fangming; Benson, Deanna L.; Tzavaras, Nikolaos; Mahajan, Milind; Papatsenko, Dmitri; Ghaffari, Saghi

doi:10.1016/j.stem.2020.01.013

Cited by 177 publications

(243 citation statements)

References 88 publications

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“…We found the Glut1 low JAM3 high cells to be the only cell type giving rise to the most primitive GEMM colonies ( Figure 3C). These findings are in line with previous studies, showing high JAM3 and low Glut1 expression in functional HSCs [27,34,[38][39][40].…”

Section: Characterization Of Glut1 and Jam3 As Asymmetric Cell Divisisupporting

confidence: 93%

“…These data suggested a different signature in asymmetry expression in control and IFNα cells. Previous studies have shown higher JAM3 [34,38,39] and lower Glut1 expression [27,40] on functional HSCs. Therefore, we assumed that PDCs with a Glut1 low JAM3 high phenotype could represent a more primitive cell type as compared with other combinations.…”

Section: Analysis Of the Protein Expression Of Glut1 Jam3 And Hk2mentioning

confidence: 85%

“…Interestingly, the cellular metabolic machinery has also been implicated in ACD of HSCs. Long-term continuous imaging revealed asymmetric partitioning of lysosomes and autophagosomes upon HSC division, predicting an asymmetric fate of the two daughters [26], with low lysosomal activity corresponding to an improved reconstitution capability [27]. Additionally, asymmetric segregation of mitochondria was also believed to influence the fate of HSC daughters [28,29].…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Pre-Instructed HSCs Robustly Execute Asymmetric Cell Divisions In Vitro

Girotra

Trachsel

Roch

2020

IJMS

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Hematopoietic stem cells (HSCs) are responsible for life-long production of all mature blood cells. Under homeostasis, HSCs in their native bone marrow niches are believed to undergo asymmetric cell divisions (ACDs), with one daughter cell maintaining HSC identity and the other committing to differentiate into various mature blood cell types. Due to the lack of key niche signals, in vitro HSCs differentiate rapidly, making it challenging to capture and study ACD. To overcome this bottleneck, in this study, we used interferon alpha (IFNα) treatment to ”pre-instruct” HSC fate directly in their native niche, and then systematically studied the fate of dividing HSCs in vitro at the single cell level via time-lapse analysis, as well as multigene and protein expression analysis. Triggering HSCs’ exit from dormancy via IFNα was found to significantly increase the frequency of asynchronous divisions in paired daughter cells (PDCs). Using single-cell gene expression analyses, we identified 12 asymmetrically expressed genes in PDCs. Subsequent immunocytochemistry analysis showed that at least three of the candidates, i.e., Glut1, JAM3 and HK2, were asymmetrically distributed in PDCs. Functional validation of these observations by colony formation assays highlighted the implication of asymmetric distribution of these markers as hallmarks of HSCs, for example, to reliably discriminate committed and self-renewing daughter cells in dividing HSCs. Our data provided evidence for the importance of in vivo instructions in guiding HSC fate, especially ACD, and shed light on putative molecular players involved in this process. Understanding the mechanisms of cell fate decision making should enable the development of improved HSC expansion protocols for therapeutic applications.

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Section: Characterization Of Glut1 and Jam3 As Asymmetric Cell Divisisupporting

confidence: 93%

Section: Analysis Of the Protein Expression Of Glut1 Jam3 And Hk2mentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In Vivo Pre-Instructed HSCs Robustly Execute Asymmetric Cell Divisions In Vitro

Girotra

Trachsel

Roch

2020

IJMS

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“…[79]). Interestingly, deeply quiescent HSCs, which contain small punctate mitochondria with low mitochondrial activity, express elevated levels of lysosomal genes; however, this causes not the degradation of mitochondria, but rather their transient sequestration into enlarged lysosomes [80]. Autophagy, including mitophagy, involves many regulatory steps prior to fusion with lysosomes, but the mechanisms by which HSCs regulate lysosomal activity in the enlarged lysosomes remain unknown.…”

Section: Lysosomes In Other Quiescent Cellsmentioning

confidence: 99%

Lysosomes and signaling pathways for maintenance of quiescence in adult neural stem cells

Kobayashi

Kageyama

2020

The FEBS Journal

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Quiescence is a cellular strategy for maintaining somatic stem cells in a specific niche in a low metabolic state without senescence for a long period of time. During development, neural stem cells (NSCs) actively proliferate and self-renew, and their progeny differentiate into both neurons and glial cells to form mature brain tissues. On the other hand, most NSCs in the adult brain are quiescent and arrested in G0/G1 phase of the cell cycle. Quiescence is essential in order to avoid the precocious exhaustion of NSCs, ensuring a sustainable source of available stem cells in the brain throughout the lifespan. After receiving activation signals, quiescent NSCs reenter the cell cycle and generate new neurons. This switching between quiescence and proliferation is tightly regulated by diverse signaling pathways. Recent studies suggest significant involvement of cellular proteostasis (homeostasis of the proteome) in the quiescent state of NSCs. Proteostasis is the result of integrated regulation of protein synthesis, folding, and degradation. In this review, we discuss regulation of quiescence by multiple signaling pathways, especially bone morphogenetic protein and Notch signaling, and focus on the functional involvement of the lysosome, an organelle governing cellular degradation, in quiescence of adult NSCs.

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“…Hematopoietic stem cell (HSC) quiescence promotes lifelong blood regeneration and is controlled by a complex regulatory network including cell-intrinsic transcription factors and epigenetic modifiers (Pietras et al, 2011), organelle homeostasis mechanisms (Hinge et al, 2020;Liang et al, 2020), and signals generated from the bone marrow (BM) niche (Morrison and Scadden, 2014). HSC can be briefly forced out of quiescence to facilitate blood system regeneration by numerous stressors such as, infection (Prendergast and Essers, 2014), chronic stress (Heidt et al, 2014) and myeloablative injury (Harrison and Lerner, 1991) demonstrating that HSC are responsive to disruptions in BM homeostasis (King and Goodell, 2011).…”

Section: Introductionmentioning

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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Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency

Cited by 177 publications

References 88 publications

In Vivo Pre-Instructed HSCs Robustly Execute Asymmetric Cell Divisions In Vitro

In Vivo Pre-Instructed HSCs Robustly Execute Asymmetric Cell Divisions In Vitro

Lysosomes and signaling pathways for maintenance of quiescence in adult neural stem cells

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

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