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bioRxiv · 10.1101/2023.04.04.535583

Impaired centrosome biogenesis in kidney stromal progenitors reduces abundance of interstitial lineages and accelerates injury-induced fibrosis

Langner, E.·Cheng, T.·Kefaloyianni, E.·Gluck, C.·Wang, B.·Mahjoub, M. R.
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Abstract

Defective centrosome function can disrupt embryonic kidney development, by causing changes to the renal interstitium that leads to fibrocystic disease pathologies. Yet, it remains unknown how mutations in centrosome genes impact kidney interstitial cells. Here, we examined the consequences of defective centrosome biogenesis on stromal progenitor cell growth, differentiation and fate. Conditional deletion of Cep120, a ciliopathy gene essential for centrosome duplication, in the stromal mesenchyme resulted in reduced abundance of pericytes, interstitial fibroblasts and mesangial cells. This was due to delayed mitosis, increased apoptosis, and changes in Wnt and Hedgehog signaling essential for differentiation of stromal lineages. Cep120 ablation resulted in hypoplastic kidneys with medullary atrophy and delayed nephron maturation. Finally, centrosome loss in the interstitium sensitized kidneys of adult mice, causing rapid fibrosis via enhanced TGF-{beta}/Smad3-Gli2 signaling after renal injury. Our study defines the cellular and developmental defects caused by centrosome dysfunction in embryonic kidney stroma. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/535583v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@a3b059org.highwire.dtl.DTLVardef@8ed18corg.highwire.dtl.DTLVardef@5f573borg.highwire.dtl.DTLVardef@1581c20_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDefective centrosome biogenesis in kidney stroma causes: C_LIO_LIReduced abundance of stromal progenitors, interstitial and mesangial cell populations C_LIO_LIDefects in cell-autonomous and paracrine signaling C_LIO_LIAbnormal/delayed nephrogenesis and tubular dilations C_LIO_LIAccelerates injury-induced fibrosis via defective TGF-{beta}/Smad3-Gli2 signaling axis C_LI

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Langner, E., Cheng, T., Kefaloyianni, E., Gluck, C., Wang, B., Mahjoub, M. R.. 2023-04-06. Impaired centrosome biogenesis in kidney stromal progenitors reduces abundance of interstitial lineages and accelerates injury-induced fibrosis. https://doi.org/10.1101/2023.04.04.535583

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