scholarly journals Stem-cell niche self-restricts the signaling range via receptor-ligand degradation

2018 ◽  
Author(s):  
Sophia Ladyzhets ◽  
Matthew Antel ◽  
Taylor Simao ◽  
Nathan Gasek ◽  
Mayu Inaba
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Germ Cells ◽  
Stem Cell Niche ◽  
Short Range ◽  
Receptor Interaction ◽  
Germline Stem Cells ◽  
Dual Roles ◽  
Ectopic Activation ◽  
Cell Niche

AbstractStem-cell niche signaling is short-range in nature, such that only stem cells but not their differentiating progeny experience self-renewing signals. At the apical tip of the Drosophila testes, 8 to 10 germline stem cells (GSCs) surround the hub, a cluster of somatic cells that function as the major component of the stem cell niche. We have shown that GSCs form microtubule-based nanotubes (MT-nanotubes), which project into the hub cells, serving as the platform for niche signal reception: the receptor Tkv expressed by GSCs localizes to the surface of MT-nanotubes, where it receives the hub-derived ligand Decapentaplegic (Dpp), ensuring the reception of the ligand specifically by stem cells but not by differentiating cells.Here we show that receptor (Tkv)-ligand (Dpp) interaction at the surface of MT-nanotubes serves a second purpose of dampening the niche signaling: we found that the receptor Tkv and the ligand Dpp are internalized into hub cells and are degraded in the hub cell lysosomes. Perturbation of hub lysosomal function or MT-nanotube formation leads to excess receptor retention within germ cells as well as excess Dpp that diffuses out of the hub, leading to ectopic activation of niche signal in differentiating germ cells. Our results demonstrate that MT-nanotubes plays dual roles in ensuring the short-range nature of the niche signaling by 1) providing exclusive interphase of the niche ligand-receptor interaction and 2) limiting the amount of available ligand-receptor via their degradation.

scholarly journals Self-limiting stem-cell niche signaling through degradation of a stem-cell receptor

PLoS Biology ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. e3001003
Author(s):  
Sophia Ladyzhets ◽  
Matthew Antel ◽  
Taylor Simao ◽  
Nathan Gasek ◽  
Ann E. Cowan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Short Range ◽  
Spatial Arrangement ◽  
Cell Receptor ◽  
Receptor Interaction ◽  
Germline Stem Cells ◽  
Dual Roles ◽  
Cell Niche

Stem-cell niche signaling is short-range in nature, such that only stem cells but not their differentiating progeny receive self-renewing signals. At the apical tip of the Drosophila testis, 8 to 10 germline stem cells (GSCs) surround the hub, a cluster of somatic cells that organize the stem-cell niche. We have previously shown that GSCs form microtubule-based nanotubes (MT-nanotubes) that project into the hub cells, serving as the platform for niche signal reception; this spatial arrangement ensures the reception of the niche signal specifically by stem cells but not by differentiating cells. The receptor Thickveins (Tkv) is expressed by GSCs and localizes to the surface of MT-nanotubes, where it receives the hub-derived ligand Decapentaplegic (Dpp). The fate of Tkv receptor after engaging in signaling on the MT-nanotubes has been unclear. Here we demonstrate that the Tkv receptor is internalized into hub cells from the MT-nanotube surface and subsequently degraded in the hub cell lysosomes. Perturbation of MT-nanotube formation and Tkv internalization from MT-nanotubes into hub cells both resulted in an overabundance of Tkv protein in GSCs and hyperactivation of a downstream signal, suggesting that the MT-nanotubes also serve a second purpose to dampen the niche signaling. Together, our results demonstrate that MT-nanotubes play dual roles to ensure the short-range nature of niche signaling by (1) providing an exclusive interface for the niche ligand-receptor interaction; and (2) limiting the amount of stem cell receptors available for niche signal reception.

scholarly journals Mad dephosphorylation at the nuclear envelope is essential for asymmetric stem cell division

2019 ◽  
Author(s):  
Justin Sardi ◽  
Muhammed Burak Bener ◽  
Taylor Simao ◽  
Abigail E. Descoteaux ◽  
Boris M. Slepchenko ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Short Range ◽  
Bmp Signaling ◽  
Nuclear Pore ◽  
Germline Stem Cells ◽  
Daughter Cells ◽  
Stem Cell Division ◽  
Cell Niche

SummaryStem cell niche signals act over a short range so that only stem cells but not the differentiating daughter cells receive the self-renewal signals. Drosophila female germline stem cells (GSCs) are maintained by short range BMP signaling; BMP ligands Dpp/Gbb activate receptor Tkv to phosphorylate Mad (phosphor-Mad or pMad) which accumulates in the GSC nucleus and activates the stem cell transcription program. pMad is highly concentrated in the nucleus of the GSC, but is immediately downregulated in the nucleus of the pre-cystoblast (preCB), a differentiating daughter cell, that is displaced away from the niche. Here we show that this asymmetry in the intensity of pMad is formed even before the completion of cytokinesis. A delay in establishing the pMad asymmetry leads to germline tumors through conversion of differentiating cells into a stem cell-like state. We show that a Mad phosphatase Dullard (Dd) interacts with Mad at the nuclear pore, where it may dephosphorylate Mad. A mathematical model explains how an asymmetry can be established in a common cytoplasm. It also demonstrates that the ratio of pMad concentrations in GSC/preCB is highly sensitive to Mad dephosphorylation rate. Our study reveals a previously unappreciated mechanism for breaking symmetry between daughter cells during asymmetric stem cell division.

scholarly journals Somatic CG6015 mediates cyst stem cell maintenance and germline stem cell differentiation via EGFR signaling in Drosophila testes

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qianwen Zheng ◽  
Xia Chen ◽  
Chen Qiao ◽  
Min Wang ◽  
Wanyin Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Stem Cell Differentiation ◽  
Germline Stem Cell ◽  
Germline Stem Cells ◽  
Egfr Signaling ◽  
Extrinsic Factors ◽  
Cell Niche ◽  
Underlying Mechanisms

AbstractStem cell niche is regulated by intrinsic and extrinsic factors. In the Drosophila testis, cyst stem cells (CySCs) support the differentiation of germline stem cells (GSCs). However, the underlying mechanisms remain unclear. In this study, we found that somatic CG6015 is required for CySC maintenance and GSC differentiation in a Drosophila model. Knockdown of CG6015 in CySCs caused aberrant activation of dpERK in undifferentiated germ cells in the Drosophila testis, and disruption of key downstream targets of EGFR signaling (Dsor1 and rl) in CySCs results in a phenotype resembling that of CG6015 knockdown. CG6015, Dsor1, and rl are essential for the survival of Drosophila cell line Schneider 2 (S2) cells. Our data showed that somatic CG6015 regulates CySC maintenance and GSC differentiation via EGFR signaling, and inhibits aberrant activation of germline dpERK signals. These findings indicate regulatory mechanisms of stem cell niche homeostasis in the Drosophila testis.

Tissue Stem Cells and Stem Cell Niche of the Human Vocal Fold

2020 ◽  
Vol 71 (2) ◽  
pp. 211-213
Author(s):  
K. Sato ◽  
S. Chitose ◽  
K. Sato ◽  
F. Sato ◽  
T. Kurita ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Vocal Fold ◽  
Cell Niche

scholarly journals Immunostaining of Lgr5, an Intestinal Stem Cell Marker, in Normal and Premalignant Human Gastrointestinal Tissue

2008 ◽  
Vol 8 ◽  
pp. 1168-1176 ◽  
Author(s):  
Laren Becker ◽  
Qin Huang ◽  
Hiroshi Mashimo
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Intestinal Stem Cells ◽  
Stem Cell Marker ◽  
Tumor Initiating Cells ◽  
Colonic Adenomas ◽  
Potential Marker ◽  
Cell Niche ◽  
Crypt Base

Lgr5 has recently been identified as a murine marker of intestinal stem cells. Its expression has not been well characterized in human gastrointestinal tissues, but has been reported in certain cancers. With the increasing appreciation for the role of cancer stem cells or tumor-initiating cells in certain tumors, we sought to explore the expression of Lgr5 in normal and premalignant human gastrointestinal tissues. Using standard immunostaining, we compared expression of Lgr5 in normal colon and small intestine vs. small intestinal and colonic adenomas and Barrett's esophagus. In the normal tissue, Lgr5 was expressed in the expected stem cell niche, at the base of crypts, as seen in mice. However, in premalignant lesions, Lgr5+cells were not restricted to the crypt base. Additionally, their overall numbers were increased. In colonic adenomas, Lgr5+cells were commonly found clustered at the luminal surface and rarely at the crypt base. Finally, we compared immunostaining of Lgr5 with that of CD133, a previously characterized marker for tumor-initiating cells in colon cancer, and found that they identified distinct subpopulations of cells that were in close proximity, but did not costain. Our findings suggest that (1) Lgr5 is a potential marker of intestinal stem cells in humans and (2) loss of restriction to the stem cell niche is an early event in the premalignant transformation of stem cells and may play a role in carcinogenesis.

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