ABSTRACT
Acute kidney injury (AKI) is the rapid onset of decreased kidney function that ultimately increases mortality and morbidity. Stem cell research is a promising avenue for curative and preventative therapies of kidney injury, however, there are many types of stem cells under investigation. Currently there is no research to compare the value of one stem cell method over another. Induced pluripotent stem cells (iPSCs) and spermatogonial stem cells (SSCs) have been shown to differentiate into renal cells, though further clinical research is needed to fully explore potential therapeutic strategies. Mesenchymal stem cells (MSCs) have long been investigated in the preclinical setting and have recently been successful in Phase I clinical trials. MSCs may represent a promising new therapeutic approach to treat AKI as they demonstrate renoprotective effects post-injury via the secretion of promitotic, anti-apoptotic, anti-inflammatory, and immunomodulatory factors. Given the most current research, MSCs appear to offer a promising course of treatment for AKI.
ABSTRACT
The kidney is comprised of working units known as nephrons, which are epithelial tubules that contain a series of specialized cell types organized into a precise pattern of functionally distinct segment domains. There is a limited understanding of the genetic mechanisms that establish these discrete nephron cell types during renal development. The zebrafish embryonic kidney serves as a simplified yet conserved vertebrate model to delineate how nephron segments are patterned from renal progenitors. Here, we provide a concise review of recent advances in this emerging field, and discuss how continued research using zebrafish genetics can be applied to gain insights about nephrogenesis.
ABSTRACT
The zebrafish pronephros provides a conserved model to study kidney development, in particular to delineate the poorly understood processes of how nephron segment pattern and cell type choice are established. Zebrafish nephrons are divided into distinct epithelial regions that include a series of proximal and distal tubule segments, which are comprised of intercalated transporting epithelial cells and multiciliated cells (MCC). Previous studies have shown that retinoic acid (RA) regionalizes the renal progenitor field into proximal and distal domains and that Notch signaling later represses MCC differentiation, but further understanding of these pathways has remained unknown. The transcription factor mecom (mds1/evi1 complex) is broadly expressed in renal progenitors, and then subsequently marks the distal tubule. Here, we show that mecom is necessary to form the distal tubule and to restrict both proximal tubule formation and MCC fate choice. We found that mecom and RA have opposing roles in patterning discrete proximal and distal segments. Further, we discovered that RA is required for MCC formation, and that one mechanism by which RA promotes MCC fate choice is to inhibit mecom. Next, we determined the epistatic relationship between mecom and Notch signaling, which limits MCC fate choice by lateral inhibition. Abrogation of Notch signaling with the γ-secretase inhibitor DAPT revealed that Notch and mecom did not have additive effects in blocking MCC formation, suggesting that they function in the same pathway. Ectopic expression of the Notch signaling effector, Notch intracellular domain (NICD), rescued the expansion of MCCs in mecom morphants, indicating that mecom acts upstream to induce Notch signaling. These findings suggest a model in which mecom and RA arbitrate proximodistal segment domains, while MCC fate is modulated by a complex interplay in which RA inhibition of mecom, and mecom promotion of Notch, titrates MCC number. Taken together, our studies have revealed several essential and novel mechanisms that control pronephros development in the zebrafish.
