Proliferative stem cells maintain quiescence of their niche by secreting the Activin inhibitor Follistatin

Herrera, Salvador C.; Maza, Diego Sainz de la; Grmai, Lydia; Margolis, Shally R.; Plessel, Rebecca; Burel, Michael; O’Connor, Michael B.; Amoyel, Marc; Bach, Erika A.

doi:10.1016/j.devcel.2021.07.010

Cited by 30 publications

(27 citation statements)

References 53 publications

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“…The zonal relationship of these cells, schematized in Fig. 4D, suggests a stem cell niche, where external and internal cells serve different roles (Herrera et al, 2021; Knight et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

“…Traditionally, stem cell pools or hub cells are not highly mitotic, but slowly cycling or dormant (Lilly et al , 2011). In certain niches, however, particularly cancer stem cell niches, hub cells may transdifferentiate to stem cells as needed (Herrera et al , 2021; Raz and Yamashita, 2021). We hypothesized that in ES cells, zone-2 stem cells may be in exchange with zone-1 perimeter high Nanog 3UTR cells, with proliferation more likely to occur in zone-2 than zone-1.…”

Section: Resultsmentioning

confidence: 99%

“…This aligns with previous findings that extrinsic signals act on undifferentiated embryonic stem cells (Davey and Zandstra, 2006), and that in particular activin/nodal signaling modulates Nanog levels (Peerani et al , 2007; Vallier et al, 2009). Activin signaling is asymmetrically higher in the epiblast than the trophectoderm (Herrera et al , 2021), suggesting that a check on activin activity may prolong pluripotency. Activin also plays a critical role in hub cell interchange with stem cells in other systems, as secretion of Follistatin (an activin inhibitor) from the internal cells is necessary for hub cell survival (Raz and Yamashita, 2021).…”

Section: Discussionmentioning

confidence: 99%

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Differential expression of Nanog 3UTR and coding region mRNA components defines an embryonic stem cell niche

Yang

Gozali

et al. 2022

Preprint

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The known molecular heterogeneity among pluripotent embryonic stem cells (ESCs) in culture may be maladaptive or a beneficial determinant of normal biology. In other systems such as hair and intestine, normal and dynamic heterogeneity among stem cells is necessary for balancing stem cell division and quiescence in order to maintain the stem cell pool. In ESCs, Sox2, Oct4 and Nanog (the SON genes) critically regulate pluripotency but their role in stem cell heterogeneity or pool maintenance is not clear. We previously reported an additional level of gene expression, the unexpected differential expression of mRNA coding region (CDS) and cognate 3′untranslated region (3UTR) components, often revealing novel developmental patterns. Here we show dramatic, patterned, concentric, differential expression of pluripotent gene 3UTR and CDS mRNA components in both undifferentiated ESCs in culture and in developing human and mouse embryos. This differential expression reveals robust pluripotent ESC heterogeneity that provides the underpinnings of a previously unrecognized ESC cell niche structure. A hallmark of the niche is the presence of cells expressing high levels of Nanog 3UTR but only low or no Nanog CDS at structure perimeters, We used a novel bioinformatic approach combining the 3UTR to CDS ratio and gene expression, and identified unique ESC clusters. High Nanog 3UTR cells have lower cell cycle activity and higher quiescence than other ESCs and express a distinct complement of cellular histone marks. These quiescent perimeter cells exchange with interior domains, opening the possibility that they act as cell replenishment reservoirs in the niche or the embryo. Functionally, the Nanog 3UTR, independent of its CDS, is critical, as its selective deletion decreases ESC cell division while increasing trophectoderm markers. Lastly, self-organization of ESCs according to pluripotent gene differential 3UTR and CDS expression is modified by activin signaling, indicating extrinsic modulation of the niche structure. Pluripotent embryonic stem cells, actively display regulated, dynamic differential expression of SON gene mRNA components, allowing the formation of a heterogenous, ordered, stem cell niche bordered by quiescent hub stem cells, thus illuminating the role of SON genes in pluripotent embryonic stem cell pool maintenance. More generally this suggests that differential mRNA component expression may widely define cell types that exist in non-permanent, different states in either development or disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Differential expression of Nanog 3UTR and coding region mRNA components defines an embryonic stem cell niche

Yang

Gozali

et al. 2022

Preprint

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“…We reveal an association between initial niche assembly and quiescence. It is clear that quiescence is important to the biology of the testis, as aberrantly dividing niche cells can generate extraneous niches located away from the testis tip and even lead to niche decay (Greenspan and Matunis, 2018; Herrera et al, 2021). There is evidence for feedback from other adult somatic cells in maintaining niche quiescence, but how niche cells first enter quiescence is unknown.…”

Section: Discussionmentioning

confidence: 99%

Visceral mesoderm signaling regulates assembly position and function of the Drosophila testis niche

Anllo

DiNardo

2021

Preprint

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Tissue homeostasis often requires a properly placed niche to support stem cells. The morphogenetic processes that position a niche are just being described. We recently showed that Drosophila testis pro niche cells, specified at disparate positions during early gonadogenesis, must assemble in one collective at the gonad anterior. Here, we identify Slit and FGF signals emanating from adjacent visceral mesoderm (Vm) that regulate assembly. In response to signaling, niche cells express islet, which we find is also required for positioning the niche. Without signaling, niche cells specified furthest from the anterior are unable to migrate, remaining dispersed. Function of the dispersed niche is severely disrupted, with pro-niche cells evading cell cycle quiescence, compromised in their ability to signal the incipient stem cell pool, and failing to orient stem cell divisions properly. Our work identifies both extrinsic signaling and intrinsic responses required for proper assembly and placement of the testis niche.

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“…In the adult stage, hub cells become quiescent, but CySCs maintain mitotic activity; however, hub-specific overexpression of Cyclin D together with Cdk4 induces the hub-to-CySC conversion, indicating that re-entry into cell cycle is sufficient for the cell fate conversion [ 117 ]. Intriguingly, while hub cells maintain the stemness of CySCs, CySCs in turn maintain quiescence of hub cells by secreting Follistatin, which suppresses Activin signalling in hub cells [ 116 , 122 , 123 ]. These findings together suggest that the male testis is equipped with sophisticated mechanisms that precisely control the timing of cell fate conversion.…”

Section: Cell Fate Plasticitymentioning

confidence: 99%

Cellular mechanisms underlying adult tissue plasticity in Drosophila

Nagai

Miura

Nakajima

2022

Fly

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Adult tissues in Metazoa dynamically remodel their structures in response to environmental challenges including sudden injury, pathogen infection, and nutritional fluctuation, while maintaining quiescence under homoeostatic conditions. This characteristic, hereafter referred to as adult tissue plasticity, can prevent tissue dysfunction and improve the fitness of organisms in continuous and/or severe change of environments. With its relatively simple tissue structures and genetic tools, studies using the fruit fly Drosophila melanogaster have provided insights into molecular mechanisms that control cellular responses, particularly during regeneration and nutrient adaptation. In this review, we present the current understanding of cellular mechanisms, stem cell proliferation, polyploidization, and cell fate plasticity, all of which enable adult tissue plasticity in various Drosophila adult organs including the midgut, the brain, and the gonad, and discuss the organismal strategy in response to environmental changes and future directions of the research.

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Proliferative stem cells maintain quiescence of their niche by secreting the Activin inhibitor Follistatin

Cited by 30 publications

References 53 publications

Differential expression of Nanog 3UTR and coding region mRNA components defines an embryonic stem cell niche

Differential expression of Nanog 3UTR and coding region mRNA components defines an embryonic stem cell niche

Visceral mesoderm signaling regulates assembly position and function of the Drosophila testis niche

Cellular mechanisms underlying adult tissue plasticity in Drosophila

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