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Article ; Online: Apoptotic regulation of epithelial cellular extrusion.

Andrade, Daniel / Rosenblatt, Jody

Apoptosis : an international journal on programmed cell death

2011 Volume 16, Issue 5, Page(s) 491–501

Abstract: ... that both intrinsic and extrinsic apoptotic pathways activate cellular extrusion. The contraction force that drives ... Cellular extrusion is a mechanism that removes dying cells from epithelial tissues to prevent ... a ring that contracts in the surrounding cells that drives cellular extrusion. It is not clear ...

Abstract	Cellular extrusion is a mechanism that removes dying cells from epithelial tissues to prevent compromising their barrier function. Extrusion occurs in all observed epithelia in vivo and can be modeled in vitro by inducing apoptosis in cultured epithelial monolayers. We established that actin and myosin form a ring that contracts in the surrounding cells that drives cellular extrusion. It is not clear, however, if all apoptotic pathways lead to extrusion and how apoptosis and extrusion are molecularly linked. Here, we find that both intrinsic and extrinsic apoptotic pathways activate cellular extrusion. The contraction force that drives cellular extrusion requires caspase activity. Further, necrosis does not trigger the cellular extrusion response, but instead necrotic cells are removed from epithelia by a passive, stochastic movement of epithelial cells.
MeSH term(s)	Actins/metabolism ; Animals ; Apoptosis/genetics ; Apoptosis/physiology ; Apoptosis Regulatory Proteins/metabolism ; Caspases/metabolism ; Cell Line ; Dogs ; Epithelial Cells/cytology ; Epithelial Cells/physiology ; Humans ; Myosins/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; bcl-2-Associated X Protein/genetics ; bcl-2-Associated X Protein/metabolism
Chemical Substances	Actins ; Apoptosis Regulatory Proteins ; Proto-Oncogene Proteins c-bcl-2 ; bcl-2-Associated X Protein ; Caspases (EC 3.4.22.-) ; Myosins (EC 3.6.4.1)
Language	English
Publishing date	2011-03-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1452360-7
ISSN	1573-675X ; 1360-8185
ISSN (online)	1573-675X
ISSN	1360-8185
DOI	10.1007/s10495-011-0587-z
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Article ; Online: Epithelial apoptotic pattern emerges from global and local regulation by cell apical area.

Cachoux, Victoire M L / Balakireva, Maria / Gracia, Mélanie / Bosveld, Floris / López-Gay, Jesús M / Maugarny, Aude / Gaugué, Isabelle / di Pietro, Florencia / Rigaud, Stéphane U / Noiret, Lorette / Guirao, Boris / Bellaïche, Yohanns

Current biology : CB

2023 Volume 33, Issue 22, Page(s) 4807–4826.e6

Abstract: ... lives and well before extrusion, apoptosis commitment is linked to two distinct geometric features ... to determine how apoptosis is controlled during epithelial tissue development. We found that early in cell ... that the coupling between these two geometric features and apoptotic cells is dependent on the Hippo/YAP and Notch ...

Abstract	Geometry is a fundamental attribute of biological systems, and it underlies cell and tissue dynamics. Cell geometry controls cell-cycle progression and mitosis and thus modulates tissue development and homeostasis. In sharp contrast and despite the extensive characterization of the genetic mechanisms of caspase activation, we know little about whether and how cell geometry controls apoptosis commitment in developing tissues. Here, we combined multiscale time-lapse microscopy of developing Drosophila epithelium, quantitative characterization of cell behaviors, and genetic and mechanical perturbations to determine how apoptosis is controlled during epithelial tissue development. We found that early in cell lives and well before extrusion, apoptosis commitment is linked to two distinct geometric features: a small apical area compared with other cells within the tissue and a small relative apical area with respect to the immediate neighboring cells. We showed that these global and local geometric characteristics are sufficient to recapitulate the tissue-scale apoptotic pattern. Furthermore, we established that the coupling between these two geometric features and apoptotic cells is dependent on the Hippo/YAP and Notch pathways. Overall, by exploring the links between cell geometry and apoptosis commitment, our work provides important insights into the spatial regulation of cell death in tissues and improves our understanding of the mechanisms that control cell number and tissue size.
MeSH term(s)	Animals ; Epithelium/physiology ; Drosophila/genetics ; Apoptosis/physiology ; Cell Death ; Mitosis ; Epithelial Cells
Language	English
Publishing date	2023-10-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2023.09.049
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Article ; Online: ECM-transmitted shear stress induces apoptotic cell extrusion in early breast gland development

F. Friedland / S. Babu / R. Springer / J. Konrad / Y. Herfs / S. Gerlach / J. Gehlen / H.-J. Krause / L. De Laporte / R. Merkel / E. Noetzel

Frontiers in Cell and Developmental Biology, Vol

2022 Volume 10

Abstract: ... into dynamic shear strain-induced mechanobiological regulation circuits between cells and their ECM. ... polarization. Most intriguingly, poorly developed spheroids were prone to cyclic strain-induced extrusion ... of apoptotic cells from the spheroid body. In contrast, matured spheroids were insensitive ...

Abstract	Epithelial cells of human breast glands are exposed to various mechanical ECM stresses that regulate tissue development and homeostasis. Mechanoadaptation of breast gland tissue to ECM-transmitted shear stress remained poorly investigated due to the lack of valid experimental approaches. Therefore, we created a magnetic shear strain device that enabled, for the first time, to analyze the instant shear strain response of human breast gland cells. MCF10A-derived breast acini with basement membranes (BM) of defined maturation state and basoapical polarization were used to resemble breast gland morphogenesis in vitro. The novel biophysical tool was used to apply cyclic shear strain with defined amplitudes (≤15%, 0.2 Hz) over 22 h on living spheroids embedded in an ultrasoft matrix (<60 Pa). We demonstrated that breast spheroids gain resistance to shear strain, which increased with BM maturation and basoapical polarization. Most intriguingly, poorly developed spheroids were prone to cyclic strain-induced extrusion of apoptotic cells from the spheroid body. In contrast, matured spheroids were insensitive to this mechanoresponse—indicating changing mechanosensing or mechanotransduction mechanisms during breast tissue morphogenesis. Together, we introduced a versatile tool to study cyclic shear stress responses of 3D cell culture models. It can be used to strain, in principle, all kinds of cell clusters, even those that grow only in ultrasoft hydrogels. We believe that this approach opens new doors to gain new insights into dynamic shear strain-induced mechanobiological regulation circuits between cells and their ECM.
Keywords	epithelial mechanobiology ; shear strain ; cellular mechanotransduction ; multicellular spheroids ; apoptosis ; cell extrusion ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: Desmosomal Junctions Govern Tissue Integrity and Actomyosin Contractility in Apoptotic Cell Extrusion.

Thomas, Minnah / Ladoux, Benoit / Toyama, Yusuke

Current biology : CB

2020 Volume 30, Issue 4, Page(s) 682–690.e5

Abstract: ... in maintaining epithelial sheet integrity during apoptotic cell extrusion. ... by coordinated processes between the dying cell and its neighbors. Apoptotic cell extrusion is driven ... homeostasis [1]. Although much is known about the regulation of adherens junctions (AJs) in apoptotic cell ...

Abstract	During apoptosis, or programmed cell death, a dead cell could be expelled from the tissue by coordinated processes between the dying cell and its neighbors. Apoptotic cell extrusion is driven by actomyosin cable formation and its contraction and lamellipodial crawling of the neighboring cells [1-4]. Throughout cell extrusion, the mechanical coupling of epithelia needs to be maintained in order to preserve tissue homeostasis [1]. Although much is known about the regulation of adherens junctions (AJs) in apoptotic cell extrusion [4-7], the role and dynamics of desmosomal junctions (DJs) during this process remain poorly understood. Here, we show that DJs stay intact throughout and are crucial for cell extrusion. Pre-existing DJs between the apoptotic cell and neighboring cells remain intact, even during the formation of de novo DJs between non-dying cells, suggesting the neighboring cells possess two DJs in the middle of apoptotic cell extrusion. We further found that an actomyosin cable formed in the vicinity of DJs upon apoptosis and subsequently deviated from DJs during its constriction. Interestingly, the departure of the actomyosin cable from DJs coincided with the timing when DJs lost their straightness, suggesting a release of junctional tension at DJs and a mechanical coupling between DJs and actomyosin contractility. The depletion of desmoplakin resulted in defective contractility and an inability to form de novo DJs, leading to a failure of apoptotic cell extrusion. Our study provides a framework to explain how desmosomes play pivotal roles in maintaining epithelial sheet integrity during apoptotic cell extrusion.
MeSH term(s)	Actomyosin/metabolism ; Animals ; Apoptosis/physiology ; Cell Transformation, Neoplastic/metabolism ; Desmosomes/metabolism ; Dogs ; Madin Darby Canine Kidney Cells
Chemical Substances	Actomyosin (9013-26-7)
Language	English
Publishing date	2020-01-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2020.01.002
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Article ; Online: Bifidobacterium breve reduces apoptotic epithelial cell shedding in an exopolysaccharide and MyD88-dependent manner.

Hughes, K R / Harnisch, L C / Alcon-Giner, C / Mitra, S / Wright, C J / Ketskemety, J / van Sinderen, D / Watson, A J M / Hall, L J

Open biology

2017 Volume 7, Issue 1

Abstract: ... patients, who also have impaired epithelial barrier function, including elevated rates of apoptotic ... extrusion of small intestinal epithelial cells (IECs) from villi-a process termed 'cell shedding'. Using ... resulting in downregulation of intrinsic and extrinsic apoptotic responses to protect epithelial cells under ...

Abstract	Certain members of the microbiota genus Bifidobacterium are known to positively influence host well-being. Importantly, reduced bifidobacterial levels are associated with inflammatory bowel disease (IBD) patients, who also have impaired epithelial barrier function, including elevated rates of apoptotic extrusion of small intestinal epithelial cells (IECs) from villi-a process termed 'cell shedding'. Using a mouse model of pathological cell shedding, we show that mice receiving Bifidobacterium breve UCC2003 exhibit significantly reduced rates of small IEC shedding. Bifidobacterial-induced protection appears to be mediated by a specific bifidobacterial surface exopolysaccharide and interactions with host MyD88 resulting in downregulation of intrinsic and extrinsic apoptotic responses to protect epithelial cells under highly inflammatory conditions. Our results reveal an important and previously undescribed role for B. breve, in positively modulating epithelial cell shedding outcomes via bacterial- and host-dependent factors, supporting the notion that manipulation of the microbiota affects intestinal disease outcomes.
MeSH term(s)	Animals ; Apoptosis ; Bifidobacterium breve/physiology ; Disease Models, Animal ; Epithelial Cells/cytology ; Epithelial Cells/drug effects ; Epithelial Cells/microbiology ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; Humans ; Intestine, Small/cytology ; Intestine, Small/drug effects ; Intestine, Small/microbiology ; Lipopolysaccharides/toxicity ; Mice ; Myeloid Differentiation Factor 88/metabolism ; Polysaccharides, Bacterial/metabolism
Chemical Substances	Lipopolysaccharides ; Myd88 protein, mouse ; Myeloid Differentiation Factor 88 ; Polysaccharides, Bacterial
Language	English
Publishing date	2017-01-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2630944-0
ISSN	2046-2441 ; 2046-2441
ISSN (online)	2046-2441
ISSN	2046-2441
DOI	10.1098/rsob.160155
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Article ; Online: Bifidobacterium breve reduces apoptotic epithelial cell shedding in an exopolysaccharide and MyD88-dependent manner

K. R. Hughes / L. C. Harnisch / C. Alcon-Giner / S. Mitra / C. J. Wright / J. Ketskemety / D. van Sinderen / A. J. M. Watson / L. J. Hall

Open Biology, Vol 7, Iss

2017 Volume 1

Abstract: ... patients, who also have impaired epithelial barrier function, including elevated rates of apoptotic ... extrusion of small intestinal epithelial cells (IECs) from villi—a process termed ‘cell shedding’. Using ... resulting in downregulation of intrinsic and extrinsic apoptotic responses to protect epithelial cells under ...

Abstract	Certain members of the microbiota genus Bifidobacterium are known to positively influence host well-being. Importantly, reduced bifidobacterial levels are associated with inflammatory bowel disease (IBD) patients, who also have impaired epithelial barrier function, including elevated rates of apoptotic extrusion of small intestinal epithelial cells (IECs) from villi—a process termed ‘cell shedding’. Using a mouse model of pathological cell shedding, we show that mice receiving Bifidobacterium breve UCC2003 exhibit significantly reduced rates of small IEC shedding. Bifidobacterial-induced protection appears to be mediated by a specific bifidobacterial surface exopolysaccharide and interactions with host MyD88 resulting in downregulation of intrinsic and extrinsic apoptotic responses to protect epithelial cells under highly inflammatory conditions. Our results reveal an important and previously undescribed role for B. breve, in positively modulating epithelial cell shedding outcomes via bacterial- and host-dependent factors, supporting the notion that manipulation of the microbiota affects intestinal disease outcomes.
Keywords	bifidobacterium ; epithelial cell shedding ; inflammatory bowel disease ; exopolysaccharide ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	The Royal Society
Document type	Article ; Online
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Article ; Online: Extracellular ATP facilitates cell extrusion from epithelial layers mediated by cell competition or apoptosis.

Mori, Yusuke / Shiratsuchi, Naoka / Sato, Nanami / Chaya, Azusa / Tanimura, Nobuyuki / Ishikawa, Susumu / Kato, Mugihiko / Kameda, Ikumi / Kon, Shunsuke / Haraoka, Yukinari / Ishitani, Tohru / Fujita, Yasuyuki

Current biology : CB

2022 Volume 32, Issue 10, Page(s) 2144–2159.e5

Abstract: ... apoptotic cells. The downregulation of ROS suppresses the extrusion process. Furthermore, ATP is ... toward extruding cells in both cell-competition-mediated and apoptotic extrusion. Hence, extracellular ATP acts ... eliminated from epithelial layers. This cell extrusion process mainly falls into two modes: cell-competition ...

Abstract	For the maintenance of epithelial homeostasis, various aberrant or dysfunctional cells are actively eliminated from epithelial layers. This cell extrusion process mainly falls into two modes: cell-competition-mediated extrusion and apoptotic extrusion. However, it is not clearly understood whether and how these processes are governed by common molecular mechanisms. In this study, we demonstrate that the reactive oxygen species (ROS) levels are elevated within a wide range of epithelial layers around extruding transformed or apoptotic cells. The downregulation of ROS suppresses the extrusion process. Furthermore, ATP is extracellularly secreted from extruding cells, which promotes the ROS level and cell extrusion. Moreover, the extracellular ATP and ROS pathways positively regulate the polarized movements of surrounding cells toward extruding cells in both cell-competition-mediated and apoptotic extrusion. Hence, extracellular ATP acts as an "extrude me" signal and plays a prevalent role in cell extrusion, thereby sustaining epithelial homeostasis and preventing pathological conditions or disorders.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Apoptosis ; Cell Competition ; Epithelial Cells/metabolism ; Reactive Oxygen Species/metabolism
Chemical Substances	Reactive Oxygen Species ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2022-04-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2022.03.057
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Article ; Online: The role of apoptosis in shaping the tracheal system in the Drosophila embryo.

Baer, Magdalena M / Bilstein, Andreas / Caussinus, Emmanuel / Csiszar, Agnes / Affolter, Markus / Leptin, Maria

Mechanisms of development

2010 Volume 127, Issue 1-2, Page(s) 28–35

Abstract: ... of epithelial placodes by cell migration, rearrangements, fusions and shape changes. A designated ... by macrophages. Our results suggest that the pattern of cell extrusion and death is not hard-wired, but is ... but also by elimination of cells from the developing branch. Extruded cells die and are engulfed ...

Abstract	The tubular network of the tracheal system in the Drosophila embryo is created from a set of epithelial placodes by cell migration, rearrangements, fusions and shape changes. A designated number of cells is initially allocated to each branch of the system. We show here that the final cell number in the dorsal branches is not only determined by early patterning events and subsequent cell rearrangements but also by elimination of cells from the developing branch. Extruded cells die and are engulfed by macrophages. Our results suggest that the pattern of cell extrusion and death is not hard-wired, but is determined by environmental cues.
MeSH term(s)	Animals ; Anoikis ; Apoptosis ; Body Patterning/genetics ; Cell Differentiation ; Cell Movement ; Developmental Biology ; Drosophila/embryology ; Epithelium/embryology ; Gene Expression Regulation, Developmental ; Genes, Insect ; Green Fluorescent Proteins/metabolism ; Macrophages/metabolism ; Models, Biological ; Trachea/embryology
Chemical Substances	Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2010-01
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1055986-3
ISSN	1872-6356 ; 0925-4773
ISSN (online)	1872-6356
ISSN	0925-4773
DOI	10.1016/j.mod.2009.11.003
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Zs.A 1152: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Parvin overexpression uncovers tissue-specific genetic pathways and disrupts F-actin to induce apoptosis in the developing epithelia in Drosophila.

Chountala, Maria / Vakaloglou, Katerina M / Zervas, Christos G

PloS one

2012 Volume 7, Issue 10, Page(s) e47355

Abstract: ... apoptosis, alterations in cell shape, basal extrusion and invasion. These defects were closely correlated ... blocked Parvin-induced lethality and apoptosis and partially ameliorated cell delamination in epithelia ... with abnormalities in the organization of F-actin at the basal epithelial surface and of integrin-matrix adhesion ...

Abstract	Parvin is a putative F-actin binding protein important for integrin-mediated cell adhesion. Here we used overexpression of Drosophila Parvin to uncover its functions in different tissues in vivo. Parvin overexpression caused major defects reminiscent of metastatic cancer cells in developing epithelia, including apoptosis, alterations in cell shape, basal extrusion and invasion. These defects were closely correlated with abnormalities in the organization of F-actin at the basal epithelial surface and of integrin-matrix adhesion sites. In wing epithelium, overexpressed Parvin triggered increased Rho1 protein levels, predominantly at the basal side, whereas in the developing eye it caused a rough eye phenotype and severely disrupted F-actin filaments at the retina floor of pigment cells. We identified genes that suppressed these Parvin-induced dominant effects, depending on the cell type. Co-expression of both ILK and the apoptosis inhibitor DIAP1 blocked Parvin-induced lethality and apoptosis and partially ameliorated cell delamination in epithelia, but did not rescue the elevated Rho1 levels, the abnormal organization of F-actin in the wing and the assembly of integrin-matrix adhesion sites. The rough eye phenotype was suppressed by coexpression of either PTEN or Wech, or by knock-down of Xrp1. Two main conclusions can be drawn from our studies: (1), high levels of cytoplasmic Parvin are toxic in epithelial cells; (2) Parvin in a dose dependent manner affects the organization of actin cytoskeleton in both wing and eye epithelia, independently of its role as a structural component of the ILK-PINCH-Parvin complex that mediates the integrin-actin link. Thus, distinct genetic interactions of Parvin occur in different cell types and second site modifier screens are required to uncover such genetic circuits.
MeSH term(s)	Actins/metabolism ; Animals ; Apoptosis/genetics ; Cell Adhesion ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/growth & development ; Drosophila melanogaster/metabolism ; Epithelium/growth & development ; Epithelium/metabolism ; Gene Expression Regulation, Developmental ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Organ Specificity/genetics ; Signal Transduction/genetics
Chemical Substances	Actins ; Drosophila Proteins ; Microfilament Proteins ; PARVA protein, human ; parvin protein, Drosophila
Language	English
Publishing date	2012-10-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0047355
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Article: RNA interference-mediated silencing of the fatty acid synthase gene attenuates growth and induces morphological changes and apoptosis of LNCaP prostate cancer cells.

De Schrijver, Ellen / Brusselmans, Koen / Heyns, Walter / Verhoeven, Guido / Swinnen, Johannes V

Cancer research

2003 Volume 63, Issue 13, Page(s) 3799–3804

Abstract: ... overexpressed in many human epithelial cancers, rendering it an interesting target for antineoplastic therapy ... down-regulation of FASE expression resulted in a major decrease in the synthesis of triglycerides and ... cell contacts, and the formation of spider-like extrusions. Furthermore, silencing of the FASE gene ...

Abstract	Fatty acid synthase (FASE), a key enzyme in the biosynthesis of fatty acids, is markedly overexpressed in many human epithelial cancers, rendering it an interesting target for antineoplastic therapy. Here, using the potent and highly sequence-specific mechanism of RNA interference (RNAi), we have silenced the expression of FASE in lymph node carcinoma of the prostate (LNCaP) cells. RNAi-mediated down-regulation of FASE expression resulted in a major decrease in the synthesis of triglycerides and phospholipids and induced marked morphological changes, including a reduction in cell volume, a loss of cell-cell contacts, and the formation of spider-like extrusions. Furthermore, silencing of the FASE gene by RNAi significantly inhibited LNCaP cell growth and ultimately resulted in induction of apoptosis. Importantly and in striking contrast with LNCaP cells, RNAi-mediated inhibition of FASE did not influence growth rate or viability of nonmalignant cultured skin fibroblasts. These data indicate that RNAi opens new avenues toward the study of the role of FASE overexpression in tumor cells and provides an interesting and selective alternative to chemical FASE inhibitors in the development of antineoplastic therapy.
MeSH term(s)	Apoptosis/genetics ; Cell Division/genetics ; Fatty Acid Synthases/genetics ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Genetic Markers ; Humans ; Luciferases/genetics ; Lymph Nodes/enzymology ; Lymph Nodes/pathology ; Male ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; RNA, Small Interfering/genetics ; Transfection
Chemical Substances	Genetic Markers ; RNA, Small Interfering ; Luciferases (EC 1.13.12.-) ; Fatty Acid Synthases (EC 2.3.1.85)
Language	English
Publishing date	2003-07-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
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