Concise Review: Understanding the Renal Progenitor Cell Niche In Vivo to Recapitulate Nephrogenesis In Vitro

Abstract

Chronic kidney disease (CKD), defined as progressive kidney damage and a reduction of the glomerular filtration rate, can progress to end-stage renal failure (CKD5), in which kidney function is completely lost. CKD5 requires dialysis or kidney transplantation, which is limited by the shortage of donor organs. The incidence of CKD5 is increasing annually in the Western world, stimulating an urgent need for new therapies to repair injured kidneys. Many efforts are directed toward regenerative medicine, in particular using stem cells to replace nephrons lost during progression to CKD5. In the present review, we provide an overview of the native nephrogenic niche, describing the complex signals that allow survival and maintenance of undifferentiated renal stem/progenitor cells and the stimuli that promote differentiation. Recapitulating in vitro what normally happens in vivo will be beneficial to guide amplification and direct differentiation of stem cells toward functional renal cells for nephron regeneration.

Significance: Kidneys perform a plethora of functions essential for life. When their main effector, the nephron, is irreversibly compromised, the only therapeutic choices available are artificial replacement (dialysis) or renal transplantation. Research focusing on alternative treatments includes the use of stem cells. These are immature cells with the potential to mature into renal cells, which could be used to regenerate the kidney. To achieve this aim, many problems must be overcome, such as where to take these cells from, how to obtain enough cells to deliver to patients, and, finally, how to mature stem cells into the cell types normally present in the kidney. In the present report, these questions are discussed. By knowing the factors directing the proliferation and differentiation of renal stem cells normally present in developing kidney, this knowledge can applied to other types of stem cells in the laboratory and use them in the clinic as therapy for the kidney.

Keywords: Differentiation; Embryonic stem cells; Induced pluripotent stem cells; Kidney; Progenitor cells; Self-renewal; Stem cell culture; Stem/progenitor cell.

Figure 1.

Schematic illustration of stages of nephron development. The ureteric bud grows out from the nephric duct and invades the surrounding metanephric mesenchyme, initiating nephron development. Subsets of mesenchymal cells in the metanephric blastema are induced to condense around the ureteric bud tips. This population is the potential source of renal stem/progenitor cells termed “cap mesenchyme.” Cap mesenchyme forms pretubular aggregates, then epithelializes to renal vesicles, which elongate to comma- and S-shaped bodies. These connect to the ureteric bud stalk, which gives rise to the collecting duct. The S-shaped bodies differentiate into distal tubules, proximal tubule, loop of Henle, glomerular Bowman’s capsule (derived from parietal epithelium), and podocytes (derived from visceral epithelium).

Figure 2.

Renal stem/progenitor cell (RSPC) compartments in the nephrogenic niche and the signals promoting survival, proliferation, and differentiation. (A): The outer cortex of the developing kidney is the site of nephrogenesis. Here, the ureteric bud branches many times, inducing new nephrons with each tip. RSPCs, in the induced cap mesenchyme, progress through different stages, each with a distinct molecular signature. Early undifferentiated RSPCs express the transcription factors Cited1 and sine oculis-related h omeobox 2 (Six2); further differentiation is characterized by the downregulation of first Cited1 and then Six2, with concomitant upregulation of Lef1. LEF1 cells form pretubular aggregates, which then undergo mesenchymal to epithelial transition to form renal vesicles. (B): The nephrogenic niche provides signals promoting survival and differentiation. FGF2, FGF9, FGF20, and BMP7 act synergistically via MAPK and WNT9b/β-catenin to promote the survival and proliferation of the mesenchyme. The ureteric bud, expressing BMP7 via SMAD, LIF, WNT9b/β-catenin, and stromal cells (FOXD1+), releases factors such as FAT4, which induce epithelial differentiation of cap mesenchymal cells. FAT4 acts with WNT9b to enhance the inactivation of YAP/TAZ and further transcription of WNT9b/β-catenin differentiation target genes. Abbreviations: BMP, bone morphogenetic protein; CITED1, Cpb/300-interacting transactivator 1; FAT4, FAT atypical cadherin 4; FGF, fibroblast growth factor; FOXD1, winged-fork head transcription factor 1; HOXB7, homeobox B7; LEF1, lymphoid enhancer factor 1; MAPK, mitogen-activated protein kinase; PA, pretubular aggregates; RV, renal vesicle; SIX2, sine oculis-related homeobox 2; S-W-H, Salvador-Warts-Hippo; TAZ/YAP, transcriptional coactivator with PDZ binding motif/Yes associated protein; UB, ureteric bud; WNT, wingless-type MMTV integration site family.