Understanding repair options via an understanding of renal development
The prevalence and incidence of chronic kidney disease (CKD) is increasing at 6–8% per annum in the USA alone, largely as a result of increased prevalence of diabetes and obesity 1. To understand what might be possible with respect to cellular therapies or regenerative medicine for the kidney, one first needs to consider what is understood about normal renal development and response to injury. The kidney has been classically regarded as an organ with minimal cellular turnover and no capacity for regeneration. The subsequent identification of stem cells in a number of such organs, including the brain, has challenged this view. However, the dogma remains that the kidney reaches a maximal complement of nephrons and then loses these over time 2. This dogma is drawn from our understanding of the development of this organ.
The progenitor population during development
The kidney is mesodermal in origin and develops from two populations derived from intermediate mesoderm, the ureteric bud (UB) and the metanephric mesenchyme (MM). While an even broader potential had been proposed 3, genetic and lineage analyses have confirmed that the MM gives rise to all portions of the nephron other than the collecting ducts and also gives rise to elements of the renal interstitium 4–6. The UB gives rise to the ureter and collecting ducts only. The MM is apparently not homogeneous but forms condensed mesenchyme around the tips of the branching UB. This cap mesenchyme (CM) contains self-renewing progenitors capable of generating all cells of the nephron other than the collecting ducts via an initial mesenchyme–epithelial transition (MET) event throughout the prenatal developmental period 6. The continued expression of the transcription factor Six2 in CM is required for maintenance of this stem cell population during kidney development 5. As the UB branches and extends through the MM, individual MET events occur at the underside of each tip to form a new nephron 2. This nephron endowment therefore proceeds from the centre of the kidney out to the periphery, with the CM stem cell field remaining on the outer edge of the expanding organ. Endowment of new nephrons is restricted to prenatal development in humans, while in rodents it persists only until the immediate postnatal period. Cessation of nephrogenesis, as assessed as the last MET event, occurs within the first 2–3 days of birth in the mouse, after which time there is no remaining CM. Hartman et al7 investigated whether this involved the active death of the remaining CM and concluded that this was not the case. In contrast, all remaining CM exhibited spontaneous commitment to MET, presumably by ceasing asymmetric division and self-renewal, resulting in exhaustion of this cell population. This would suggest that complete epimorphic regeneration of nephrons (regeneration involving a complete replacement of the tissue lost in its original form) does not occur in the mammalian kidney.
In organisms other than mammals, regeneration via the continued endowment of nephrons in response to damage is observed. This has been well documented in the elasmobranchs. In these animals, the excretory organ is the mesonephros rather than the metanephros, and the latter continues to maintain a progenitor mesenchyme in the periphery of the organ. In response to resection or damage, this mesenchyme once again generates nephrons by undergoing MET and these new nephrons are connected to the existing collecting duct network 8.
Renal repair recapitulating development: yes or no?
Although true regeneration is not thought to occur, the kidney does maintain a significant capacity to undergo repair after acute damage. For example, even after prolonged unilateral ureteric obstruction (UUO), involving considerable inflammation, tubular necrosis and apoptosis, the renal cortex can substantially remodel 9 (see Figure 1). Such postnatal repair has been proposed to involve the re-expression of genes previously critical to the development of the normal kidney. Indeed, the re-expression of developmental genes in response to renal damage has been reported in a number of human diseases and animal models, including ischaemia–reperfusion injury and diabetes 10, 11. However, the re-expression of Six2 in response to tubular injury, which might signal the reactivation of the embryonic nephron induction pathway, is not observed 12. This raises the question of whether renal repair does involve recapitulation of development at all. Indeed, the inappropriate activity of developmental pathways can be causative of renal disease. Niranjan et al13 report that over-activity of the Notch pathway in podocytes can lead to apoptosis and resultant proteinuria, while genetic or biochemical suppression of this pathway, which is known to be critical for normal proximal tubular development 14, 15, prevents glomerulosclerosis and proteinuria.
If the CM population does become exhausted when nephrogenesis ceases in the mammalian kidney, then do endogenous renal stem cells generate new renal cells using a different mechanism of differentiation? As will be discussed, Vogetesder et al16 argue that repair involves the recruitment of fully differentiated cells into the cell cycle and does not involve a source of stem cells. Alternatively, postnatal renal progenitors may not be the same as embryonic renal progenitors, and may or may not re-use similar gene expression pathways to reach the same endpoint. If no such stem cell population exists in the kidney itself, repair may require stem cells from some other location (embryonic stem cells, mesenchymal stem cells, bone marrow-derived stem cells, reprogrammed cells). In the following sections, we discuss these possibilities further.