Renal stem cells: fact or science fiction?

Abstract

The kidney is widely regarded as an organ without regenerative abilities. However, in recent years this dogma has been challenged on the basis of observations of kidney recovery following acute injury, and the identification of renal populations that demonstrate stem cell characteristics in various species. It is currently speculated that the human kidney can regenerate in some contexts, but the mechanisms of renal regeneration remain poorly understood. Numerous controversies surround the potency, behaviour and origins of the cell types that are proposed to perform kidney regeneration. The present review explores the current understanding of renal stem cells and kidney regeneration events, and examines the future challenges in using these insights to create new clinical treatments for kidney disease.

Figure 1. Composition of the adult mammalian kidney

(A) The mammalian kidney is comprised of an outer cortex and inner medulla, and urinary waste from the collecting ducts is drained into the respective calyxes and then funneled through the renal pelvis to the ureter. (B) The functional units of the kidney are situated throughout various strata in the cortex, and many tubules elongate throughout the medulla region. Each nephron consist of three main components: a renal corpuscle (1), a tubule with many discrete functional segments in respective proximal, intermediate and distal regions (2), and lastly a collecting duct (3). Sites that have been proposed to house adult renal stem cells are indicated with an asterisk (*).

Figure 2. Kidney dysfunction: disruptions to the embryonic and adult kidney

Kidney disorders that interfere with healthy kidney functions can be generally characterized into CAKUT conditions with affect renal development (left) and conditions that injure the normally developed organ (right). Left: kidney development defects can lead to the absence of one or both kidneys, termed agenesis (top), a significantly smaller kidney termed hypoplastic (middle), or a kidney with malformed or cystic (fluid-filled and enlarged) kidneys (bottom). Right: post-natal to adult disruptions in kidney function arise from acute injuries (top), from which complete or partial function can be restored through to regeneration and chronic injuries (bottom) which progressively scar the organ and are thought to be irreparable.

Figure 3. Definition and identification of the stem cells

Middle and right: stem cells are operationally defined by having the ability to self-renew upon division and produce more differentiated offspring. Often, the immediate offspring are transit-amplifying cells that have great proliferative capacity and exhibit the ability to make multiple differentiated cell types. Left: stem cells can be assessed by multiple criteria that gauge stemness, or stem cell-like qualities of a cell. Stemness attributes fall into two broad categories: (1) their phenotype on the basis of gene expression, epigenetic signature and a label-retaining ability indicating rare division events, and (2) their functionality on the basis of analysis of their ability to give rise to cells in culture and in vivo, such as measured by lineage tracing.

Figure 4. The mammalian kidney develops from distinct pools of renal progenitors

(A) Top left: the mammalian embryo will form a series of three kidney structures from the intermediate mesoderm (indicated in grey and purple) in a caudal region of the trunk. Enlargement: the three kidneys from along the rostral–caudal axis in an archetypal order, with the pronephros first, followed by the mesonephros and finally the metanephros. The pronephros and mesonephros consist of simple tiered arrays of nephrons. The pronephros is vestigial, whereas the mesonephros functions for a short time and then degenerates upon metanephros formation. (B) The metanephros develops when the nephric duct (grey) is induced to form the UB outgrowth by the MM (purple). Branching morphogenesis of the UB generates a highly branched collecting duct system. (C) The MM gives rise to two mesenchymal compartments, the CM which caps the UB branch points, and the SM, which is loosely distributed in the vicinity. The CM is a Six2⁺ self-renewing stem cell compartment, and adjacent to each UB branch points forms a PA, which initially maintains Six2⁺ and will become a nephron. The PA progresses to form an epithelial RV that is Six2⁻Wnt4⁺, and grows to make various shapes, including an S-shaped body that will eventually proliferate and elongate to make nascent nephrons that connect to the UB ductal network.

Figure 5. Glomerular injury and source(s) of replacement cells

The renal corpuscle is composed of (1) a glomerulus, which is a ball of capillaries made of fenestrated epithelial cells that are surrounded by a GBM and podocytes, and (2) the Bowman's capsule, which is an epithelium that encapsulates the glomerulus and serves as a collecting space for fluid filtered through the glomerulus. Current evidence is consistent with the epithelium at the urinary pole, the so-called PECs, containing a podocyte stem cell that is CD24⁺CD133⁺PDX⁻. The PEC stem cell gives rise to transitional offspring that are podocyte progenitor cells; these transitional cells express CD24⁺CD133⁺PDX⁺ and are speculated to migrate around the capsule and later enter the glomerulus (pathway indicated by green arrows), where they differentiate into CD24⁻CD133⁻PDX⁺ podocytes.

Figure 6. Tubular injury and source(s) of replacement cells

(A) Injury models that damage the proximal tubule by ischaemia/reperfusion or nephrotoxins have been most extensively used to study tubular regeneration. These analyses have led to a current debate between several cellular sources of regeneration that have converged to focus on (1) differentiated tubule epithelial cells (labelled with Six2-reporter expression) and (2) intratubular stem cells (labeled by BrdU and CD24⁺CD133⁺Aldh^high in various studies). A third cell source, the extratubular compartment, which over the years has been speculated to include kidney-resident interstitial fibroblasts, BMSCs and MSCs, has been negated by evidence of intratubular sources of regeneration. (B) The scenarios of tubular regeneration are proposed to involve either a dedifferentiation (1, top panel) or a stem cell mechanism (2, bottom panel). Dedifferentiation includes events through which the tubular epithelium oscillates between a mesenchymal phenotype (EMT and then MET), with the mesenchyme purported to show migration and division to replace lost tubular cells. A tubular stem cell has been proposed to share hallmarks with its differentiated neighbours, and replace lost cells through division that may or may not involve transit-amplifying progenitors.

Figure 7. The renal papilla and its proliferative compartments

The renal papilla is a zone of the kidney that contains collecting ducts, nephron tubule portions that include the intermediate and distal segments, and interstitial fibroblast cells. BrdU-labelled LRCs have been found in all three cellular compartments, although whether these represent self-renewing stem or progenitor cells is not known. In addition, interstitial cells that are Nestin⁺CD133⁺ have been detected and are speculated to represent a potential stem cell compartment.