A Functional Screen to Identify Novel Effectors of Hematopoietic Stem Cell Activity

Deneault, Éric; Cellot, Sonia; Faubert, Amélie; Laverdure, Jean‐Philippe; Fréchette, Mélanie; Chagraoui, Jalila; Mayotte, Nadine; Sauvageau, Martin; Ting, Stephen B.; Sauvageau, Guy

doi:10.1016/j.cell.2009.03.026

Cited by 114 publications

(132 citation statements)

References 22 publications

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“…This involves a delicate balance between HSC self-renewal and differentiation into progenitor populations. The molecular networks that control these processes have begun to be elucidated in recent years, and several regulatory proteins have been shown to manage stem-cell physiology (2)(3)(4)(5)(6). Additionally, there is a substantial overlap between the proteins that regulate HSC biology and those that are dysregulated in cancers of immunological origin or other hematopoietic diseases, underlying the importance of these factors in maintaining homeostasis.…”

mentioning

confidence: 99%

MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output

O’Connell

Chaudhuri

Rao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

256

278

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The production of blood cells depends on a rare hematopoietic stem-cell (HSC) population, but the molecular mechanisms underlying HSC biology remain incompletely understood. Here, we identify a subset of microRNAs (miRNAs) that is enriched in HSCs compared with other bone-marrow cells. An in vivo gain-of-function screen found that three of these miRNAs conferred a competitive advantage to engrafting hematopoietic cells, whereas other HSC miRNAs attenuated production of blood cells. Overexpression of the most advantageous miRNA, miR-125b, caused a dose-dependent myeloproliferative disorder that progressed to a lethal myeloid leukemia in mice and also enhanced hematopoietic engraftment in human immune system mice. Our study identifies an evolutionarily conserved subset of miRNAs that is expressed in HSCs and functions to modulate hematopoietic output.

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mentioning

confidence: 99%

MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output

O’Connell

Chaudhuri

Rao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

256

278

View full text Add to dashboard Cite

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“…S4B). This finding is intriguing, because Prdm16 was originally isolated as a leukemia-associated gene (42) and is known to enhance HSC activity (41). The mechanism underlying the enhanced expression of Prdm16 remains unclear, but one possibility is that Prdm16 is up-regulated to compensate for the impaired proliferative ability of FL HSCs induced by Hemp deficiency.…”

Section: Discussionmentioning

confidence: 88%

“…Recently, a functional screen for gene products supporting HSC activity identified 18 molecules, and the overexpression of 10 of these was shown to increase HSC repopulating activity (41). Interestingly, 3 of the 10 genes overlapped with the 39 genes identified in this study (Table 1 and Fig.…”

Section: Discussionmentioning

confidence: 91%

Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation

Honda

Takubo

Oda

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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To clarify the molecular pathways governing hematopoietic stem cell (HSC) development, we screened a fetal liver (FL) HSC cDNA library and identified a unique gene, hematopoietic expressed mammalian polycomb ( hemp ), encoding a protein with a zinc-finger domain and four malignant brain tumor (mbt) repeats. To investigate its biological role, we generated mice lacking Hemp ( hemp −/− ). Hemp −/− mice exhibited a variety of skeletal malformations and died soon after birth. In the FL, hemp was preferentially expressed in the HSC and early progenitor cell fractions, and analyses of fetal hematopoiesis revealed that the number of FL mononuclear cells, including HSCs, was reduced markedly in hemp −/− embryos, especially during early development. In addition, colony-forming and competitive repopulation assays demonstrated that the proliferative and reconstitution abilities of hemp −/− FL HSCs were significantly impaired. Microarray analysis revealed alterations in the expression levels of several genes implicated in hematopoietic development and differentiation in hemp −/− FL HSCs. These results demonstrate that Hemp, an mbt-containing protein, plays essential roles in HSC function and skeletal formation. It is also hypothesized that Hemp might be involved in certain congenital diseases, such as Klippel-Feil anomaly.

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“…The transcription factor Tcfec, for example, is important for IL-4-inducible gene expression in macrophages [27] and has been associated with important differentiation processes [28]. The adaptor protein Sla has been reported to suppress T-cell responses by downregulating TCR signaling.…”

Section: Discussionmentioning

confidence: 99%

The CD20 homolog Ms4a8a integrates pro‐ and anti‐inflammatory signals in novel M2‐like macrophages and is expressed in parasite infection

et al. 2012

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Recently, we identified the CD20 homolog Ms4a8a as a novel molecule expressed by tumor-associated macrophages that directly enhances tumor growth. Here, we analyzed Ms4a8a + macrophages in M2-associated infectious pathologies. In late-stage Trypanosoma congolense and Taenia crassiceps infections, Ms4a8a expression was detected in hepatic and peritoneal macrophages respectively. Innate immunity in these infections is modulated by Toll-like receptor (TLR) signaling and TLR2/4/7 agonists strongly induced Ms4a8a expression in bone marrow derived macrophages (BMDMs) treated with M2 mediators (glucocorticoids/IL-4). LPS/dexamethasone/IL-4-induced Ms4a8a + BMDMs were characterized by strong expression of mRNA of mannose receptor (Mmr), arginase 1, and CD163, and by decreased iNOS expression. Coinduction of Ms4a8a by M2 mediators and TLR agonists involved the classical TLR signaling cascade via activation of MyD88/TRIF and NF-κB. Forced overexpression of Ms4a8a modulated the TLR4 response of RAW264.7 cells as shown by gene expression profiling. Upregulation of Hdc, Tcfec, and Sla was confirmed both in primary LPS/dexamethasone/IL-4-stimulated Ms4a8a + BMDMs and in peritoneal macrophages from late-stage Taenia crassiceps infection. In conclusion, we show that TLR signaling skews the typical alternative macrophage activation program to induce a special M2-like macrophage subset in vitro that also occurs in immunomodulatory immune reactions in vivo, a process directly involving the CD20 homolog Ms4a8a. Eur. J. Immunol. 2012Immunol. . 42: 2971Immunol. -2982 IntroductionMacrophages have an extraordinary ability to rapidly adapt to new environmental stimuli by altering their gene expression profile and functions [1]. These enormous variations enable macrophages to participate in different biological and pathological processes such as the maintenance of tissue homeostasis, orchestration of defense responses, and healing processes in tissues. The phenotypic plasticity and functional heterogeneity of macrophages renders their classification difficult. Thus, a simplified approach was put forward in analogy to the Th1/Th2 dichotomy [2,3]. Accordingly, M1 or classically activated macrophages differentiate from monocytes under the predominant influence of pro-inflammatory cytokines such as IFN-γ, IL-12, or TNF-α, while M2, or alternative, macrophage activation was primarily described as a response to Th2 cytokines such as IL-4, IL-13, and IL-10, as well as to anti-inflammatory mediators such as glucocorticoids (GCs) [4][5][6][7]. As these macrophage phenotypes influence the tissue environment, for example, via secretion of active mediators, a solid characterization of macrophages, especially in pathological processes such as cancer or chronic inflammation, is needed to uncover unique key cellular regulators [8].In a previous study, the CD20 homolog Ms4a8a was found to be expressed by M2-like tumor-associated macrophages (TAMs) in murine mammary carcinoma and malignant melanoma [9]. For the induction of Ms4a8a expression in these ...

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A Functional Screen to Identify Novel Effectors of Hematopoietic Stem Cell Activity

Cited by 114 publications

References 22 publications

MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output

MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output

Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation

The CD20 homolog Ms4a8a integrates pro‐ and anti‐inflammatory signals in novel M2‐like macrophages and is expressed in parasite infection

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