IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33848-y.html
   My bibliography  Save this article

HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids

Author

Listed:
  • Manuela Völkner

    (Technische Universität Dresden
    German Center for Neurodegenerative Diseases (DZNE) Dresden)

  • Felix Wagner

    (Technische Universität Dresden
    German Center for Neurodegenerative Diseases (DZNE) Dresden)

  • Lisa Maria Steinheuer

    (Helmholtz Centre for Environmental Research—UFZ)

  • Madalena Carido

    (Technische Universität Dresden)

  • Thomas Kurth

    (Technology Platform Core Facility Electron Microscopy and Histology)

  • Ali Yazbeck

    (Helmholtz Centre for Environmental Research—UFZ)

  • Jana Schor

    (Helmholtz Centre for Environmental Research—UFZ)

  • Stephanie Wieneke

    (German Center for Neurodegenerative Diseases (DZNE) Dresden)

  • Lynn J. A. Ebner

    (German Center for Neurodegenerative Diseases (DZNE) Dresden)

  • Claudia Toro Runzer

    (German Center for Neurodegenerative Diseases (DZNE) Dresden)

  • David Taborsky

    (German Center for Neurodegenerative Diseases (DZNE) Dresden)

  • Katja Zoschke

    (German Center for Neurodegenerative Diseases (DZNE) Dresden)

  • Marlen Vogt

    (Technische Universität Dresden)

  • Sebastian Canzler

    (Helmholtz Centre for Environmental Research—UFZ)

  • Andreas Hermann

    (Technische Universität Dresden
    German Center for Neurodegenerative Diseases (DZNE) Dresden
    Technische Universität Dresden)

  • Shahryar Khattak

    (Technische Universität Dresden
    Technology Platform Core Facility Electron Microscopy and Histology)

  • Jörg Hackermüller

    (Helmholtz Centre for Environmental Research—UFZ
    Leipzig University)

  • Mike O. Karl

    (Technische Universität Dresden
    German Center for Neurodegenerative Diseases (DZNE) Dresden)

Abstract

Human organoids could facilitate research of complex and currently incurable neuropathologies, such as age-related macular degeneration (AMD) which causes blindness. Here, we establish a human retinal organoid system reproducing several parameters of the human retina, including some within the macula, to model a complex combination of photoreceptor and glial pathologies. We show that combined application of TNF and HBEGF, factors associated with neuropathologies, is sufficient to induce photoreceptor degeneration, glial pathologies, dyslamination, and scar formation: These develop simultaneously and progressively as one complex phenotype. Histologic, transcriptome, live-imaging, and mechanistic studies reveal a previously unknown pathomechanism: Photoreceptor neurodegeneration via cell extrusion. This could be relevant for aging, AMD, and some inherited diseases. Pharmacological inhibitors of the mechanosensor PIEZO1, MAPK, and actomyosin each avert pathogenesis; a PIEZO1 activator induces photoreceptor extrusion. Our model offers mechanistic insights, hypotheses for neuropathologies, and it could be used to develop therapies to prevent vision loss or to regenerate the retina in patients suffering from AMD and other diseases.

Suggested Citation

  • Manuela Völkner & Felix Wagner & Lisa Maria Steinheuer & Madalena Carido & Thomas Kurth & Ali Yazbeck & Jana Schor & Stephanie Wieneke & Lynn J. A. Ebner & Claudia Toro Runzer & David Taborsky & Katja, 2022. "HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33848-y
    DOI: 10.1038/s41467-022-33848-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33848-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-33848-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Madhvi Menon & Shahin Mohammadi & Jose Davila-Velderrain & Brittany A. Goods & Tanina D. Cadwell & Yu Xing & Anat Stemmer-Rachamimov & Alex K. Shalek & John Christopher Love & Manolis Kellis & Brian P, 2019. "Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    2. S. A. Gudipaty & J. Lindblom & P. D. Loftus & M. J. Redd & K. Edes & C. F. Davey & V. Krishnegowda & J. Rosenblatt, 2017. "Mechanical stretch triggers rapid epithelial cell division through Piezo1," Nature, Nature, vol. 543(7643), pages 118-121, March.
    3. Christine Wolf & Alexander Rapp & Nicole Berndt & Wolfgang Staroske & Max Schuster & Manuela Dobrick-Mattheuer & Stefanie Kretschmer & Nadja König & Thomas Kurth & Dagmar Wieczorek & Karin Kast & M. C, 2016. "RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Haoqing Jerry Wang & Yao Wang & Seyed Sajad Mirjavadi & Tomas Andersen & Laura Moldovan & Parham Vatankhah & Blake Russell & Jasmine Jin & Zijing Zhou & Qing Li & Charles D. Cox & Qian Peter Su & Lini, 2024. "Microscale geometrical modulation of PIEZO1 mediated mechanosensing through cytoskeletal redistribution," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Samuel D. Chauvin & Shoichiro Ando & Joe A. Holley & Atsushi Sugie & Fang R. Zhao & Subhajit Poddar & Rei Kato & Cathrine A. Miner & Yohei Nitta & Siddharth R. Krishnamurthy & Rie Saito & Yue Ning & Y, 2024. "Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    3. K. Sri-Ranjan & J. L. Sanchez-Alonso & P. Swiatlowska & S. Rothery & P. Novak & S. Gerlach & D. Koeninger & B. Hoffmann & R. Merkel & M. M. Stevens & S. X. Sun & J. Gorelik & Vania M. M. Braga, 2022. "Intrinsic cell rheology drives junction maturation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Sine Yaganoglu & Konstantinos Kalyviotis & Christina Vagena-Pantoula & Dörthe Jülich & Benjamin M. Gaub & Maaike Welling & Tatiana Lopes & Dariusz Lachowski & See Swee Tang & Armando Del Rio Hernandez, 2023. "Highly specific and non-invasive imaging of Piezo1-dependent activity across scales using GenEPi," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Nathalia G. Amado & Elena D. Nosyreva & David Thompson & Thomas J. Egeland & Osita W. Ogujiofor & Michelle Yang & Alexandria N. Fusco & Niccolo Passoni & Jeremy Mathews & Brandi Cantarel & Linda A. Ba, 2024. "PIEZO1 loss-of-function compound heterozygous mutations in the rare congenital human disorder Prune Belly Syndrome," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    6. Manik Kuchroo & Marcello DiStasio & Eric Song & Eda Calapkulu & Le Zhang & Maryam Ige & Amar H. Sheth & Abdelilah Majdoubi & Madhvi Menon & Alexander Tong & Abhinav Godavarthi & Yu Xing & Scott Gigant, 2023. "Single-cell analysis reveals inflammatory interactions driving macular degeneration," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    7. Timo N. Kohler & Joachim Jonghe & Anna L. Ellermann & Ayaka Yanagida & Michael Herger & Erin M. Slatery & Antonia Weberling & Clara Munger & Katrin Fischer & Carla Mulas & Alex Winkel & Connor Ross & , 2023. "Plakoglobin is a mechanoresponsive regulator of naive pluripotency," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    8. Mohammad Ikbal Choudhury & Yizeng Li & Panagiotis Mistriotis & Ana Carina N. Vasconcelos & Eryn E. Dixon & Jing Yang & Morgan Benson & Debonil Maity & Rebecca Walker & Leigha Martin & Fatima Koroma & , 2022. "Kidney epithelial cells are active mechano-biological fluid pumps," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    9. Yingying Ye & Mohammad Barghouth & Haiqiang Dou & Cheng Luan & Yongzhi Wang & Alexandros Karagiannopoulos & Xiaoping Jiang & Ulrika Krus & Malin Fex & Quan Zhang & Lena Eliasson & Patrik Rorsman & Enm, 2022. "A critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic β-cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Ariadna Marín-Llauradó & Sohan Kale & Adam Ouzeri & Tom Golde & Raimon Sunyer & Alejandro Torres-Sánchez & Ernest Latorre & Manuel Gómez-González & Pere Roca-Cusachs & Marino Arroyo & Xavier Trepat, 2023. "Mapping mechanical stress in curved epithelia of designed size and shape," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33848-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.