Preferential Propagation of Competent SIX2+ Nephronic Progenitors by LIF/ROCKi Treatment of the Metanephric Mesenchyme

Stem Cell Reports
Shunsuke TanigawaAlan O Perantoni

Abstract

Understanding the mechanisms responsible for nephrogenic stem cell preservation and commitment is fundamental to harnessing the potential of the metanephric mesenchyme (MM) for nephron regeneration. Accordingly, we established a culture model that preferentially expands the MM SIX2+ progenitor pool using leukemia inhibitory factor (LIF), a Rho kinase inhibitor (ROCKi), and extracellular matrix. Passaged MM cells express the key stem cell regulators Six2 and Pax2 and remain competent to respond to WNT4 induction and form mature tubular epithelia and glomeruli. Mechanistically, LIF activates STAT, which binds to a Stat consensus sequence in the Six2 proximal promoter and sustains SIX2 levels. ROCKi, on the other hand, attenuates the LIF-induced differentiation activity of JNK. Concomitantly, the combination of LIF/ROCKi upregulates Slug expression and activates YAP, which maintains SIX2, PAX2, and SALL1. Using this novel model, our study underscores the pivotal roles of SIX2 and YAP in MM stem cell stability.

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Citations

Feb 10, 2016·Differentiation; Research in Biological Diversity·Shunsuke Tanigawa, Alan O Perantoni
Aug 30, 2016·Cell Stem Cell·Zhongwei LiJuan Carlos Izpisua Belmonte
Oct 16, 2016·Kidney International·Shunsuke Tanigawa, Ryuichi Nishinakamura
Jan 17, 2017·Stem Cell Reports·Shunsuke YuriNorimoto Yanagawa
Sep 5, 2017·Stem Cells·Ryuji MorizaneJoseph V Bonventre
Feb 7, 2019·The New England Journal of Medicine·Mo Li, Juan C Izpisua Belmonte
Mar 7, 2019·American Journal of Physiology. Renal Physiology·Yu Leng PhuaJacqueline Ho
Mar 13, 2020·Stem Cells Translational Medicine·Biao HuangZhongwei Li
Dec 30, 2016·American Journal of Physiology. Renal Physiology·Renfang SongIhor V Yosypiv
Aug 28, 2020·Frontiers in Cell and Developmental Biology·Boon C HengXuliang Deng
Aug 6, 2019·Stem Cell Reports·Shunsuke TanigawaRyuichi Nishinakamura
Mar 3, 2020·Biochemical and Biophysical Research Communications·Hiraku TsujimotoKenji Osafune
Oct 2, 2021·Nature Reviews. Nephrology·Melissa H LittleJessica M Vanslambrouck

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Methods Mentioned

BETA
genetic modifications
immunoprecipitation
ChIP
protein assay
PCR

Software Mentioned

ZEN
TFSearch

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