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Lithium induces mesenchymal-epithelial differentiation during human kidney development by activation of the Wnt signalling system

Price, KL; Kolatsi-Joannou, M; Mari, C; Long, DA; Winyard, PJ; (2018) Lithium induces mesenchymal-epithelial differentiation during human kidney development by activation of the Wnt signalling system. Cell Death and Discovery , 4 , Article 13. 10.1038/s41420-017-0021-6. Green open access

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Abstract

Kidney function is directly linked to the number of nephrons which are generated until 32–36 weeks gestation in humans. Failure to make nephrons during development leads to congenital renal malformations, whilst nephron loss in adulthood occurs in progressive renal disease. Therefore, an understanding of the molecular processes which underlie human nephron development may help design new treatments for renal disease. Mesenchyme to epithelial transition (MET) is critical for forming nephrons, and molecular pathways which control rodent MET have been identified. However, we do not know whether they are relevant in human kidney development. In this study, we isolated mesenchymal cell lines derived from human first trimester kidneys in monolayer culture and investigated their differentiation potential. We found that the mesenchymal cells could convert into osteogenic, but not adipogenic or endothelial lineages. Furthermore, addition of lithium chloride led to MET which was accompanied by increases in epithelial (CDH1) and tubular (ENPEP) markers and downregulation of renal progenitor (SIX2, EYA1, CD133) and mesenchymal markers (HGF, CD24). Prior to phenotypic changes, lithium chloride altered Wnt signalling with elevations in AXIN2, GSK3β phosphorylation and β-catenin. Collectively, these studies provide the first evidence that lithium-induced Wnt activation causes MET in human kidneys. Therapies targeting Wnts may be critical in the quest to regenerate nephrons for human renal diseases.

Type: Article
Title: Lithium induces mesenchymal-epithelial differentiation during human kidney development by activation of the Wnt signalling system
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41420-017-0021-6
Publisher version: http://doi.org/10.1038/s41420-017-0021-6
Language: English
Additional information: Copyright © The Author(s). 2018 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/.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10042960
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