Concise review: Kidney stem/progenitor cells: differentiate, sort out, or reprogram?

Abstract

End-stage renal disease (ESRD) is defined as the inability of the kidneys to remove waste products and excess fluid from the blood. ESRD progresses from earlier stages of chronic kidney disease (CKD) and occurs when the glomerular filtration rate (GFR) is below 15 ml/minute/1.73 m(2). CKD and ESRD are dramatically rising due to increasing aging population, population demographics, and the growing rate of diabetes and hypertension. Identification of multipotential stem/progenitor populations in mammalian tissues is important for therapeutic applications and for understanding developmental processes and tissue homeostasis. Progenitor populations are ideal targets for gene therapy, cell transplantation, and tissue engineering. The demand for kidney progenitors is increasing due to severe shortage of donor organs. Because dialysis and transplantation are currently the only successful therapies for ESRD, cell therapy offers an alternative approach for kidney diseases. However, this approach may be relevant only in earlier stages of CKD, when kidney function and histology are still preserved, allowing for the integration of cells and/or for their paracrine effects, but not when small and fibrotic end-stage kidneys develop. Although blood- and bone marrow-derived stem cells hold a therapeutic promise, they are devoid of nephrogenic potential, emphasizing the need to seek kidney stem cells beyond known extrarenal sources. Moreover, controversies regarding the existence of a true adult kidney stem cell highlight the importance of studying cell-based therapies using pluripotent cells, progenitor cells from fetal kidney, or dedifferentiated/reprogrammed adult kidney cells.

Figure 1

Kidney development. (A): The kidney is formed via reciprocal interactions between two precursor tissues derived form the intermediate mesoderm: the Wolffian duct and the MM. (B): MM-derived signals, mainly the glial-derived neurotrphic factor, induce an outgrowth from the Wolffian duct, termed the UB. The UB then invades the MM and secretes WNT9b, thereby attracting MM cells. (C): MM cells condense around the tips of the branching UB, forming the condensed or CM. The CM expresses a unique combination of genes (red) and the mesenchymal marker, vimentin. The CM contains the kidney stem cells and is capable of self-renewal. In response to UB signals, CM cells start to produce WNT4, which acts in an autocrine fashion, leading to epithelialization of the cells. (D–F): The induced cells acquire an epithelial phenotype. This change is accompanied by the shutting down of the major transcription factors described before (B) and by the acquisition of the epithelial marker E-cadherin. The cells sequentially form the pretubular aggregate, renal vesicle, C-, and S-shaped bodies, and finally the mature nephron. The cells derived from the CM form most of the nephron body (from glomerulus to distal tubule), whereas the UB-derived cells form the collecting duct. Abbreviations: CD, collecting duct; CM, cap mesenchyme; DT, distal tubule; PECs, parietal epithelial cells; PT, proximal tubule; UB, ureteric bud.

Figure 2

SIX2 immunostaining in human fetal kidney: SIX2, playing a major role in the self-renewal of the nephron's stem/progenitor cells, is seen here localizing to the MM, predominantly to the cap mesenchyme (arrows), and also to some tubular derivatives (arrowheads). This corresponds to the findings in mice [15], where it was shown that by 15.5 days postcoitum, SIX2 expression is restricted to the cap mesenchyme and early pretubular aggregates. SIX2 expression ceases 34 weeks postgestation in humans and in the immediate postnatal period in mice, leading to exhaustion of the stem cell pool and lack of true regenerative capacity (The figure obtained from [17]).

Figure 3

Regenerating nephrons: The cap mesenchyme cells (red) are the main players toward the ultimate goal of renal regenerative medicine and therefore different strategies are envisioned to obtain these cells or create an equivalent population of cells with nephrogenic potential: differentiation from pluripotent cells (ESCs or iPS cells), sorting of these cells from human fetal kidneys and de-differentiation via genetic reprogramming of adult kidney cells. Abbreviations: CM, cap mesenchyme; ESCs, embryonic stem cells; iPS, induced pluripotent stem cell; UB, ureteric bud.

Figure 4

Two strategies for kidney repair after injury: (A): Truly committed renal stem cells (blue) harbor nephrogenic potential and contribute to kidney regeneration via engraftment into damaged tubuli and differentiation into tubular cells (left: blue-green tubular cells that originated from stem cells) and also by the creation of new nephrons (neo-nephrogenesis; right: cells in the new tubule originate from the stem cells and are therefore all blue-green). (B): Various extrarenal stem cells (HSCs, MSCs, EPCs) can assist kidney repair through different paracrine effects, possibly leading to the restoration of the damaged microvasculature, thereby allowing the surviving tubular cells to proliferate and reconstitute a functioning tubule (all cells in the repaired tubule are green, originating from the surviving cells). Abbreviations: EPC, endothelial progenitor cell; HSC, hematopoietic stem cell; MSC, mesenchymal stromal cell.

Figure 5

Strategy for the identification of human renal stem/progenitor markers. (A): Histological appearance of normal fetal kidney. (B): Histological appearance of primary WT. WT arises from multipotent renal embryonic precursors that undergo partial differentiation arrest, leading to a tri-phasic appearance of undifferentiated blastema (b) that resembles the MM, as well as differentiated tubular epithelial (e), and stromal (st) elements. (C): Establishment of WT-xenografts (Xn). Primary WT were implanted into SCID mice and then serially propagated, eventually leading to enrichment of stem/progenitor cells (blastema) at the expense of differentiated elements (seen in [D]). (E): Renal “stemness” markers are those elevated in microarrays of both stem-like WT-xenografts and human fetal kidneys, but not renal cell carcinoma or adult kidneys. Abbreviations: AK, adult kidney; C, C-shaped body; FK, fetal kidney; G, glomerulus; MM, metanephric mesenchyme; RCC, renal cell carcinoma; S, S-shaped body; WT, Wilms' tumor.

Figure 6

Possible explanations for the isolation of progenitor cells from developed kidneys. (1) and (2): Isolation of resident progenitors, for example, kidney MSCs (1, blue) or hemato-vascular progenitors (2, pink). (3): Isolation of a stromal progenitor cell (brown). (4): Isolation of a fully differentiated cell type (green) that acquires some progenitor properties on in vitro culturing (demonstrated by the transition in the culture dish into an orange cell type). (5): Isolation of tubular progenitors with a more restricted potential (orange).