Renal interstitial cells promote nephron regeneration by secreting prostaglandin E2

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.

Esrrγa regulates nephron and ciliary development by controlling prostaglandin synthesis

“…Prostaglandins are formed by the metabolism of arachidonic acid by cyclooxygenase enzymes to form PGH 2 , which can then be further metabolized by prostaglandin synthase enzymes to form prostanoids ( Funk, 2001 ). Early zebrafish embryos contain four prostaglandin signaling molecules (PGE 2 , PGF2α, PGI 2 and TXA2) ( Cha et al, 2005 ), and essential roles for PGE 2 have been elucidated in the development and regeneration of kidney, blood and endoderm progenitors ( Goessling et al, 2009 ; Liu et al, 2023 ; Nissim et al, 2014 ; North et al, 2007 ; Poureetezadi et al, 2016 ). Further, prostaglandin signaling via PGE 2 is required broadly for vertebrate ciliogenesis, and specifically for renal MCC cell fate choice during zebrafish embryo pronephros development while simultaneously not being sufficient to increase MCC number nor alter cilia formation in WT animals ( Chambers et al, 2020b ; Jin et al, 2014 ; Marra et al, 2019a ).…”

Principles of Zebrafish Nephron Segment Development

“…Compared to mammalian kidneys, which cannot regenerate nephrons, in the zebrafish kidney, zebrafish keep adding nephrons to their kidney throughout their lifetime. In addition to nephron addition throughout development, the mesonephros can also regenerate damage to existing nephrons after injury [ 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ].…”

Modeling Podocyte Ontogeny and Podocytopathies with the Zebrafish

“…These clusters then expand into S-shaped bodies that mature into nephrons that fuse with preexisting nephrons [ 119 , 157 , 238 ]. Understanding the molecular attributes of these cells is an attractive option to identify cell features that could allow for similar events to be induced in humans, and there has been ongoing progress in identifying signaling pathways and cell interactions that mediate nephron regeneration in zebrafish [ 239 , 240 , 241 , 242 ].…”