Renal interstitial cells promote nephron regeneration by secreting prostaglandin E2
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Curated by eLife
eLife assessment
This fundamental work substantially advances our understanding of the kidney interstitium and how it influences kidney development focusing on zebrafish as a model organism. The evidence supporting the conclusions is compelling, using single-cell analysis combined with in vivo zebrafish studies to mechanistically explore the functional importance of the discovery. The work will be of broad interest to cell and developmental biologists as well as the kidney community.
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Abstract
In organ regeneration, progenitor and stem cells reside in their native microenvironment, which provides dynamic physical and chemical cues essential to their survival, proliferation, and differentiation. However, the types of cells that form the native microenvironment for renal progenitor cells (RPCs) have not been clarified. Here, single-cell sequencing of zebrafish kidney reveals fabp10a as a principal marker of renal interstitial cells (RICs), which can be specifically labeled by GFP under the control of fabp10a promoter in the fabp10a:GFP transgenic zebrafish. During nephron regeneration, the formation of nephrons is supported by RICs that form a network to wrap the RPC aggregates. RICs that are in close contact with RPC aggregates express cyclooxygenase 2 (Cox2) and secrete prostaglandin E2 (PGE2). Inhibiting PGE2 production prevents nephrogenesis by reducing the proliferation of RPCs. PGE2 cooperates with Wnt4a to promote nephron maturation by regulating β-catenin stability of RPC aggregates. Overall, these findings indicate that RICs provide a necessary microenvironment for rapid nephrogenesis during nephron regeneration.
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eLife assessment
This fundamental work substantially advances our understanding of the kidney interstitium and how it influences kidney development focusing on zebrafish as a model organism. The evidence supporting the conclusions is compelling, using single-cell analysis combined with in vivo zebrafish studies to mechanistically explore the functional importance of the discovery. The work will be of broad interest to cell and developmental biologists as well as the kidney community.
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Reviewer #1 (Public Review):
Liu, et al. describe an essential role for prostaglandin signaling during neonephrogenesis in the zebrafish kidney following acute kidney injury. They identified that renal interstitial cells are the source of prostaglandin, and demonstrated which components of the prostaglandin biosynthesis pathway as well as which receptor is involved in the signaling. Further, they determined the mechanism by which PGE2 stimulates the proliferation of renal progenitor cells which make the new nephrons, namely to regulate B-catenin levels. This work is systematic, thorough, and well-controlled. The applications of these findings may have a profound impact on the formulation of regenerative medicine treatments for kidney disease.
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Reviewer #2 (Public Review):
Previous studies have shown that lhx1 progenitors proliferate upon AKI in adult zebrafish mesonephros. However, these studies have focused primarily on renal progenitor cells (RPCs). This study uses single-cell mRNA sequencing to identify a novel cell type (RICs) in the zebrafish mesonephros that is marked by fabp10a expression within a previously generated GFP transgenic zebrafish line. The authors show that RICs express cox2 to synthesize PGE2 upon gentamicin-mediated AKI, which correlates with PRC proliferation. They demonstrate that PGE2 stimulates RPC proliferation through EP4b receptor activation of PKA, which in turn stabilizes beta-catenin through phosphorylation of both beta-catenin and GSK3beta. They also indicate that beta-catenin stabilization and RPC proliferation is dependent upon wnt4 …
Reviewer #2 (Public Review):
Previous studies have shown that lhx1 progenitors proliferate upon AKI in adult zebrafish mesonephros. However, these studies have focused primarily on renal progenitor cells (RPCs). This study uses single-cell mRNA sequencing to identify a novel cell type (RICs) in the zebrafish mesonephros that is marked by fabp10a expression within a previously generated GFP transgenic zebrafish line. The authors show that RICs express cox2 to synthesize PGE2 upon gentamicin-mediated AKI, which correlates with PRC proliferation. They demonstrate that PGE2 stimulates RPC proliferation through EP4b receptor activation of PKA, which in turn stabilizes beta-catenin through phosphorylation of both beta-catenin and GSK3beta. They also indicate that beta-catenin stabilization and RPC proliferation is dependent upon wnt4 expression by the RPC itself. The topic of the paper is significant in that it identifies an interstitial in the zebrafish kidney and suggests several mechanisms by which it supports nephron regeneration.
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