Stem cell options for kidney disease

Abstract

Chronic kidney disease (CKD) is increasing at the rate of 6-8% per annum in the US alone. At present, dialysis and transplantation remain the only treatment options. However, there is hope that stem cells and regenerative medicine may provide additional regenerative options for kidney disease. Such new treatments might involve induction of repair using endogenous or exogenous stem cells or the reprogramming of the organ to reinitiate development. This review addresses the current state of understanding with respect to the ability of non-renal stem cell sources to influence renal repair, the existence of endogenous renal stem cells and the biology of normal renal repair in response to damage. Understanding repair options via an understanding of renal developmentThe 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 developmentThe 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][5][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 imm...

The Interface Between Generating Renal Tubules and a Polyester Fleece in Comparison to the Interstitium of the Developing Kidney

“…An increasing number of papers is therefore dealing with strategies for repair of parenchyma by the help of stem/progenitor cells. 5,12 However, recent data show that an effective therapy is still far away from a widespread clinic application. Unsolved issues in renal tissue engineering are the concentration of stem/progenitor cells at the site of damage, their integration in a diseased environment, the process of differentiation into nephron-specific cells, and the spatial development of tubules within the kidney.…”

Renal organogenesis

“…29,30 Far from providing evidence for a stem cell role in renal repair, this body of literature more accurately suggests that the endogenous response of the renal epithelium itself can be modulated via favorable humoral conditions. 3,29,30 What had been lacking from the field was the prospective isolation of any cell population based upon evidence of stem cell activity. By definition, a stem cell must be capable of long-term self renewal, clonogenicity and a capacity to differentiate into one or more distinct differentiated end states.…”

“…We have previously proposed that renal therapeutic options that could be considered would encompass the spectrum of therapeutic options being investigated for other organs. 3 These would include either improvements in organ repair or de novo organ regeneration. Within organ repair, one might envisage a spectrum of options, including in situ repair, either via the delivery of reparative growth factors, the recruitment of stem cells from distant sites, such as the bone marrow, or the stimulation of endogenous stem cell populations.…”

“…Identification of genes specifically expressed in a single spatial cellular include either the bioengineering of a device to replace or substitute for nephron activity or the bioengineering of an entire replacement organ. 3 Any of these approaches will rely upon the level to which we understand how the organ forms in the first place, from where the component cell types arise and how these cells are able to respond to different challenges. In other organs, notably the hematopoietic system, a substantial body of understanding exists with respect to component cell types, specific markers for the identification and isolation of these populations, their lineage relationships, repopulating capacities and response to injury.…”

Stem cells in pathobiology and regenerative medicine

“…As in many organs, cell replacement from ES-derived cells is a likely therapy for the future [20]. In the kidney, Hopkins et al critically examine the credentials of putative endogenous kidney stem cells, and provide an exhaustive review of the numerous studies examining the therapeutic potential of extrarenal stem cells from the bone marrow, particularly mesenchymal stem cells (MSCs), in ameliorating renal disease [21]. Prostate gland stem cells and prostate cancer stem cells are discussed by Lang et al, who note that, like many other neoplastic stem cells, they are resistant to conventional therapies, in this case due to an enhanced DNA damage response [22].…”