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Klotho inhibits neuronal senescence in human brain organoids

Aging is a major risk factor for many neurodegenerative diseases. Klotho (KL) is a glycosylated transmembrane protein that is expressed in the choroid plexus and neurons of the brain. KL exerts potent anti-aging effects on multiple cell types in the body but its role in human brain cells remains lar...

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Autores principales: Shaker, Mohammed R., Aguado, Julio, Chaggar, Harman Kaur, Wolvetang, Ernst J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329278/
https://www.ncbi.nlm.nih.gov/pubmed/34341344
http://dx.doi.org/10.1038/s41514-021-00070-x
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author Shaker, Mohammed R.
Aguado, Julio
Chaggar, Harman Kaur
Wolvetang, Ernst J.
author_facet Shaker, Mohammed R.
Aguado, Julio
Chaggar, Harman Kaur
Wolvetang, Ernst J.
author_sort Shaker, Mohammed R.
collection PubMed
description Aging is a major risk factor for many neurodegenerative diseases. Klotho (KL) is a glycosylated transmembrane protein that is expressed in the choroid plexus and neurons of the brain. KL exerts potent anti-aging effects on multiple cell types in the body but its role in human brain cells remains largely unclear. Here we show that human cortical neurons, derived from human pluripotent stem cells in 2D cultures or in cortical organoids, develop the typical hallmarks of senescent cells when maintained in vitro for prolonged periods of time, and that moderate upregulation or repression of endogenous KL expression in cortical organoids inhibits and accelerates senescence, respectively. We further demonstrate that KL expression alters the expression of senescence-associated genes including, extracellular matrix genes, and proteoglycans, and can act in a paracrine fashion to inhibit neuronal senescence. In summary, our results establish an important role for KL in the regulation of human neuronal senescence and offer new mechanistic insight into its role in human brain aging.
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spelling pubmed-83292782021-08-03 Klotho inhibits neuronal senescence in human brain organoids Shaker, Mohammed R. Aguado, Julio Chaggar, Harman Kaur Wolvetang, Ernst J. NPJ Aging Mech Dis Article Aging is a major risk factor for many neurodegenerative diseases. Klotho (KL) is a glycosylated transmembrane protein that is expressed in the choroid plexus and neurons of the brain. KL exerts potent anti-aging effects on multiple cell types in the body but its role in human brain cells remains largely unclear. Here we show that human cortical neurons, derived from human pluripotent stem cells in 2D cultures or in cortical organoids, develop the typical hallmarks of senescent cells when maintained in vitro for prolonged periods of time, and that moderate upregulation or repression of endogenous KL expression in cortical organoids inhibits and accelerates senescence, respectively. We further demonstrate that KL expression alters the expression of senescence-associated genes including, extracellular matrix genes, and proteoglycans, and can act in a paracrine fashion to inhibit neuronal senescence. In summary, our results establish an important role for KL in the regulation of human neuronal senescence and offer new mechanistic insight into its role in human brain aging. Nature Publishing Group UK 2021-08-02 /pmc/articles/PMC8329278/ /pubmed/34341344 http://dx.doi.org/10.1038/s41514-021-00070-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Shaker, Mohammed R.
Aguado, Julio
Chaggar, Harman Kaur
Wolvetang, Ernst J.
Klotho inhibits neuronal senescence in human brain organoids
title Klotho inhibits neuronal senescence in human brain organoids
title_full Klotho inhibits neuronal senescence in human brain organoids
title_fullStr Klotho inhibits neuronal senescence in human brain organoids
title_full_unstemmed Klotho inhibits neuronal senescence in human brain organoids
title_short Klotho inhibits neuronal senescence in human brain organoids
title_sort klotho inhibits neuronal senescence in human brain organoids
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329278/
https://www.ncbi.nlm.nih.gov/pubmed/34341344
http://dx.doi.org/10.1038/s41514-021-00070-x
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