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Cell Biology |
* Department of Medicine and Stem Cell Institute, University of Minnesota, and Veterans Affairs Medical Center, Minneapolis, Minnesota
Address correspondence to: Dr. Sandeep Gupta, Division of Renal Diseases and Hypertension, Department of Medicine, University of Minnesota, 516 Delaware Street SE, Box 736, Minneapolis, MN 55455. Phone: 612-624-9444; Fax: 612-626-3840; E-mail: gupta024{at}umn.edu
Received for publication March 24, 2006. Accepted for publication August 7, 2006.
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionReferences |
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There is evidence to support a role for less injured tubular cells. Recapitulating developmental paradigms, these cells dedifferentiate, proliferate, and eventually reline denuded tubules, restoring the structural and functional integrity of the kidney (1–5). Molecular events that define this renal regeneration have been characterized, and strategies to accelerate the repair process have been tested in both experimental models and in humans. Recent studies have demonstrated that the contribution of extrarenal cells to the regenerative renal response is minimal to none (6–11).
Tissue-specific stem cells have been found in many organs, including bone marrow, gastrointestinal mucosa, liver, brain, prostate, and skin (12–16). These cells participate in the normal cell turnover of these organs and are a potential source of cells after organ injury. In regard to the kidney, stem cells exist in the metanephric mesenchyme and can give rise to all of the cell types of the adult kidney, except those that are derived from ureteric bud (17,18). Renal stem cells persist in the adult kidneys of other organisms, such as the skate and the fresh water teleost. These cells can participate in new nephron formation after partial nephrectomy (19–21). Potential candidate stem cells have been detected in the adult mammalian kidney using different identification methods (22–26).
The purpose of this study was to test the hypothesis that renal stem cells exist in the adult kidney. We used an approach and culture conditions similar to those used to isolate multipotent adult progenitor cells from bone marrow, muscle, and brain (27). We refer to progenitor cells that were isolated from the kidney as multipotent renal progenitor cells (MRPC).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionReferences |
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-Geo transgenic rats that contain a transgene that combines a neomycin-resistance gene with a lacZ reporter under the control of 3.6 kb of the mouse Oct4 upstream sequence, including both proximal and distal enhancers (gift from Dr. Austin Smith, University of Edinburgh, Edinburgh, Scotland) (28). Oct4 is a POU family transcription factor that is expressed in embryonic and adult stem cells and immortalized nontumorigenic cell lines and tumor cells but not in differentiated cells (27,29–31). Kidneys were perfused in vivo with saline to flush the blood from the kidney, harvested, minced, and partially digested using collagenase in the presence of soybean trypsin inhibitor. The cell suspension was washed and plated in a medium that consisted of 60% DMEM-LG (Life Technologies-BRL, Grand Island, NY), 40% MCDB-201 (Sigma Chemical Co., St. Louis, MO), 1x insulin-transferrin-selenium, LA-BSA 1 mg/ml (Sigma), 0.05 µM dexamethasone (Sigma) and 0.1 mM ascorbic acid 2-phosphate (Sigma), 100 U penicillin and 1000 U streptomycin (Life Technologies) with 2% FCS (Hyclone Laboratories, Logan, UT), 10 ng/ml EGF, 10 ng/ml PDGF-BB, and 10 ng/ml leukemia inhibitory factor (all from R&D Systems, Minneapolis, MN). The cells were plated on fibronectin coated culture flasks at low density (300 cells/cm2), to avoid cell–cell contact, and cultured at 37°C in the presence of 5% CO2. After 4 to 6 wk, most of the cell types died out and the cultures became monomorphic with spindle-shaped cells (Figure 1a). Single clones of cells were obtained by plating the cells at nontouching density and then using cloning rings to pick individual colonies of cells at the five- to 10-cell stage.
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Telomere Length and Telomerase Enzyme Assay.
For measurement of telomere length, DNA was prepared from cells by standard methods of proteinase K digestion followed by salt precipitation and digested overnight with Hinf III and RsaI. Fragments were run on a 0.6% agarose gel and vacuum blotted to positively charged nylon. The blot was probed overnight with a digoxigenin-labeled hexamer (TTAGGG) and then incubated with anti–digoxigenin-alkaline phosphatase-labeled antibody for 30 min. Telomere fragments were detected by chemiluminescence. The TRAP protocol adapted by Roche Applied Science (Indianapolis, IN) was used to assay for telomerase activity.
DNA Analysis by FACS.
MRPC were fixed in ice-cold 70% ethanol for 10 min and treated with 1 mg/ml ribonuclease for 5 min at room temperature. Propidium iodide (50 µg/ml) was added to the cell suspension and analyzed using 488 nm excitation, gating out doublets and clumps, using pulse processing and collecting fluorescence above 620 nm on a FACS Calibur (BD Bioscience, San Jose, CA). Data were analyzed using Modfit LT software (Verity Software House, Topsham, ME).
In Vitro Differentiation
For differentiation of MRPC toward a renal cell lineage, cells were grown to confluence on fibronectin-coated four-well chamber slides and incubated with a "nephrogenic cocktail" that contained fibroblast growth factor 2 (FGF2; 50 ng/ml), TGF- (4 ng/ml), and leukemia inhibitory factor (20 ng/ml) (32,33). All differentiation cultures were maintained for 2 wk except where stated, and medium was renewed every 48 h. For determination of whether MRPC could differentiate into cells of other germ cell layers, cells were incubated under conditions that promoted differentiation into endothelium (mesoderm), neurons (ectoderm), and hepatocytes (endoderm). Endothelial differentiation was induced by growing MRPC on fibronectin-coated wells (15,000 cells/cm2) in the presence of 10 ng/ml vascular endothelial growth factor. Neuronal differentiation was induced by growing MRPC on fibronectin-coated wells (5000 cells/cm2) in the presence of 100 ng/ml basic FGF. Hepatocyte differentiation was induced by growing MRPC on Matrigel (20,000 cells/cm2) in the presence of 10 ng/ml FGF-4 and 20 ng/ml hepatocyte growth factor. Cells were characterized by reverse transcriptase–PCR (RT-PCR) and immunofluorescence as described in the RT-PCR section. For the MRPC that were differentiated into endothelial cells, we examined LDL uptake by incubating the cells with Dil-Ac-LDL (10 µg/ml) at 37°C for 60 min. Undifferentiated MRPC were used as a control.
In Vivo Differentiation
Ischemia Reperfusion Experiment.
For these experiments, MRPC were transduced using a murine stem cell virus–enhanced green fluorescence protein (eGFP) retrovirus. These cells expressed eGFP and are referred to as eMRPC. Rats were anesthetized with pentobarbital (35 to 60 mg/kg intraperitoneally) and prepared, and using a midline incision, nontraumatic vascular clamps were applied across both renal pedicles for 35 min. Immediately after ischemia, 100 µl (106 cells) of an eMRPC cell suspension in PBS was injected directly into the abdominal aorta, above the renal arteries, after application of a vascular clamp to the abdominal aorta below the renal arteries to direct the flow of the injected cells. The kidneys were harvested 10 d later to examine in vivo differentiation of the injected cells.
Subcapsular Injection Experiment.
Rats were anesthetized, the kidneys exposed, and eMRPC (106 cells) were injected under the renal capsule. Rats were killed 3 wk later, and kidneys were harvested for tissue analysis.
Effect of MRPC on Renal Function after Ischemia-Reperfusion
For determination of whether MRPC injection facilitated renal functional recovery, Fisher rats underwent 30 min of ischemia induced by bilateral renal artery clamps followed immediately by injection of MRPC as described above. As controls, rats were treated identically except that they received either the saline vehicle or an MRPC cell suspension (106 cells) that had been preincubated for 12 h with actinomycin D (1 µg/ml) to block transcription in the injected cells. For determination of whether injected MRPC had a deleterious effect on renal function, experiments were performed injecting saline vehicle (n = 2) or an MRPC cell suspension (106 cells; n = 2) after sham operation. Renal function was assessed by serial measurement of serum creatinine and 24-h creatinine clearance.
RT-PCR
Total RNA was isolated using the RNeasy Mini Kit (Qiagen, Valencia, CA). The RNA was DNAse 1 treated, and cDNA was synthesized using the Taqman Reverse Transcription Kit (Applied Biosystems, Foster City, CA). The forward and reverse primers used are listed in Table 1. For Pax2, we used the RT2 PCR primer set for rat (LOC293992; Superarray Bioscience Corp., Frederick, MD). The BD rat universal reference total RNA was used as a positive control for this reaction (BD Biosciences).
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Immunohistochemistry
Kidney tissue sections were fixed in 4% paraformaldehyde and permeabilized with Triton X-100. After blocking with 1% BSA/PBS for 1 h, sections were incubated with primary antibodies diluted in 0.3% BSA/PBS overnight at 4°C. Slides subsequently were washed in PBS and incubated with secondary fluorochrome-conjugated antibodies for 45 min. The following antibodies were used in 1:100 dilution: Anti–von Willebrand factor (anft-vWF; F-3220; Sigma), anti-albumin (55442; ICN/Cappel, Costa Mesa, CA), FITC-conjugated anti-pan cytokeratin (F0397; Sigma), anti-neurofilament 200 (N0142; Sigma), Texas red–conjugated anti-GFP (600-109-215; Rockland, Gilbertsville, PA), anti–zona occludens-1 (anti–ZO-1; 61-7300; Zymed, San Francisco, CA), anti–MHC I (12-5321-81; eBioscience, San Diego, CA), anti–MHC II (12-5999-81; eBioscience), TRITC-conjugated anti-PCNA (SC-7907; Santa Cruz Biotechnology, Santa Cruz, CA), anti-THP (CL-1032-A; Cedarlane, Burlington, NC), and anti-vimentin (V4630; Sigma). The following lectins were used in 1:500 dilutions for 45 min at room temperature: Rhodamine Peanut Agglutinin (RL-1072; Vector Laboratories, Burlingame, CA) and Rhodamine Phaseolus Vulgaris Erythroagglutinin (RL-1122; Vector Laboratories).
For detection of Oct4, 8-µm-thick formalin-fixed, paraffin-embedded sections of rat kidney were deparaffinized in xylene for 10 min, followed by hydration through graded ethanol. Endogenous peroxidase activity was blocked in 0.3% hydrogen peroxide solution in methanol at room temperature for 30 min. Antigens were retrieved by Antigen Unmasking Solution (Vector Laboratory, H-3300) as per the manufacturer’s protocol. Sections were incubated overnight with anti-Oct4 antibody (Santa Cruz Biotechnology sc-8629). Primary antibody was detected, and signal amplified using Vectastain Elite ABC kit (PK-6105; Vector Laboratories). Diaminobenzidine was used as peroxidase substrate (SK-4100; Vector Laboratories).
X-Gal Staining.
Staining was done using Invitrogen Kit per manufacturer’s protocol at pH 7.4 using 5- to 10-µm cryosections that were fixed for 10 min in 20% formaldehyde and 2% glutaraldehyde. Kidneys from ROSA26 mice or Fisher rats were used as positive and negative controls, respectively.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionReferences |
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-Geo transgenic rats or nontransgenic Fisher rats and with or without G418 selection. G418 selection shortened the duration of isolation but did not improve the success of the isolation procedure. We were unable to isolate MRPC from the blood of these rats despite multiple attempts.
Characterization of MRPC
By FACS analysis, 89% of cultured MRPC were positive for CD90 (thy1.1) and 86% were positive for CD44. MRPC were negative for SSEA-1, CD-11b, CD45, CD133, CD106, MHC class I (RT1A) and class II (RT1B), CD31, and CD56 (NCAM). By immunohistochemistry, MRPC expressed vimentin but not cytokeratin (Figure 1, b and c). Incubation of undifferentiated MRPC with the -galactosidase fluorescence substrate fluorescein di--d-galactopyranoside resulted in cell fluorescence consistent with Oct4 expression (Figure 1, d and f). This fluorescence and hence -galactosidase activity disappeared when the cells were allowed to differentiate by growing them to confluence (Figure 1, e and g). Oct4 expression was confirmed by immunostaining (Figure 1j). Average telomere length of MRPC that were cultured for 30 population doublings was 23 kb; when retested at 120 population doublings, average telomere length remained unchanged (Figure 1h). Similarly, no change in telomerase enzyme activity was observed at the two population doublings. Rat MRPC that were examined at 200 population doublings had a normal karyotype by cytogenetic analysis and normal DNA content by FACS analysis (data not shown).
In vitro Differentiation
MRPC were incubated with a nephrogenic cocktail (see Materials and Methods) that has been shown to induce rat metanephric mesenchymes to differentiate into nephron epithelia (32,33). After 14 d, the phenotype of the cells changed from a monolayer of spindle-shaped cells to cell aggregates as shown in Figure 2, a and b. In the absence of the nephrogenic cocktail, cells grew to confluence and no cell aggregation was seen. In addition to changing morphology, 54% of the cells expressed the epithelial cell marker cytokeratin and 48% of the cells expressed zona occludens-1 (ZO-1; Figure 2, c and d).
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In Vivo Localization
Oct4 was expressed by RT-PCR in both normal Fisher rat kidneys and kidneys that were harvested 5 d after 45 min of ischemia (Figure 6). Rex-1, a transcription factor downstream of Oct4, also was expressed in these kidneys (Figure 6). Kidneys from Oct4 -Geo transgenic rats also were positive by RT-PCR for Oct4. Taking advantage of the fact that the promoter and enhancer elements of the Oct4 gene drive the expression of -galactosidase in these rats, we stained for -galactosidase protein and activity as a marker of Oct4 expression. Control kidneys from nontransgenic rats were negative for X-gal staining (Figure 7a). Positive blue staining cells were seen primarily at the cortical medullary junction, with X-gal–positive cells being associated with the proximal tubule as demonstrated by periodic acid-Schiff staining of the brush border (Figure 7b). Very occasional cells were seen in the other parts of the cortex, and none was detected in the medulla. Positive cells co-stained with the proximal tubule marker Phaseolus Vulgaris Erythroagglutinin (Figure 7c). No positive cells were seen in the distal tubule as evidenced by the lack of co-localization with the distal tubule marker Peanut Agglutinin (Figure 7d). Oct4 immunostaining was seen in isolated tubular cells, consistent with the pattern of X-gal staining (Figure 8). Only rare tubules expressed Oct4, and when present, Oct4 immunostaining was seen only in a single tubular cell in a given tubule profile (Figure 8).
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Effect of MRPC on Renal Injury
For determination of whether injected MRPC altered the course of kidney injury after ischemia-reperfusion, renal function was assessed by serial measurement of serum creatinine and 24-h creatinine clearance. Rats received either untreated MRPC or MRPC that had been preincubated for 12 h with actinomycin D to block transcription (Figure 11). As can be seen in Figure 9a, the time course and the severity of renal injury were similar between the two groups. A separate group of rats were studied to compare stem cell injection (106 cells; n = 6) with a different control, that of the saline vehicle. No differences in serum creatinine were observed between these two groups. We also studied the effects of stem cell injection in sham-operated rats. After sham operation, serum creatinine and creatinine clearance remained normal with no difference being seen between saline-treated and MRPC-injected rats (Table 2).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionReferences |
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Our in vitro findings suggest that MRPC can be induced to a renal phenotype, although definitive tubule formation has not been demonstrated. Incubation of MRPC in a nephrogenic media that is known to induce tubulogenesis in isolated metanephric mesenchyme resulted in aggregation of cells and transition from mesenchymal-like cells that expressed vimentin and CD90 (thy1.1) to epithelial cells that expressed cytokeratin and ZO-1. Undifferentiated MRPC expressed Pax-2, a transcription factor that is expressed by stem cells that are present in the metanephric mesenchyme and by other stem cells that were isolated from adult kidneys (18,22).
MRPC can be transduced easily with murine stem cell virus–eGFP, allowing the cells to be tracked in vivo. This enabled us to inject the cells either under the renal capsule or into the aorta after ischemia-reperfusion injury and to track their differentiation. After subcapsular injection, the cells not only formed tubules at the site of injection but also migrated and became incorporated into renal tubules that were more distant from the injection site. This finding in a noninjury model suggest that the MRPC can be induced to undergo tubulogenesis and can participate in the normal cell turnover of the kidney. We cannot exclude release of GFP by dead cells and uptake by proximal tubular cells. However, we believe that this is less likely given the pattern of GFP fluorescence that was seen in tubular cells with intense staining in groups of adjacent cells and no staining in other neighboring cells.
MRPC also participated in the regenerative response after renal injury. The injected cells became incorporated into renal tubules and showed evidence of proliferation and differentiation. Intra-arterial injection of the cells also resulted in some cells being lodged in the glomerulus and others forming tubular casts. Finding cells in these locations is a potential adverse consequence of the exogenous cell administration, although no adverse effects were seen after cell injection in sham-operated rats. In addition, we preincubated MRPC with the transcription inhibitor actinomycin D as a cellular control. We reasoned that these cells, although viable, would not be able to participate in the regenerative response but would be of similar size and morphology as the untreated cells. The lack of a difference in injury between the untreated and the actinomycin D–treated MRPC suggests that no therapeutic benefit at the dosage and timing selected. However, we cannot exclude the possibility that the actinomycin D–treated cells had beneficial paracrine effects, even though they could not proliferate or synthesize new RNA (35,36). No incorporation of the actinomycin D–treated MRPC was seen in the injured kidney (data not shown).
The mechanism of how some of the injected cells become incorporated into tubules is intriguing with a number of potential possibilities. The cells could have passed through the glomerulus into the tubule lumen and attached to sites of denuded tubular basement membrane. The finding of tubular casts that were made up of injected MRPC support the feasibility of such a mechanism. Alternatively, the cells may migrate out from peritubular capillaries and cross the tubular basement membrane in a process that is the reverse of epithelial-mesenchymal transformation. Whatever the mechanism, strategies to enhance delivery of cells to the injured kidney that maximize incorporation into tubules and minimize ischemic or obstructive injury is an important area of investigation.
We propose that the kidney contains stem cells that are localized to the renal tubule. We base this proposal on the expression of the POU family transcription factor Oct4 in a rare population of tubular cells. Oct4 controls the differentiation potential of cells and has a limited range of expression being confined to embryonic and adult stem cells, immortalized nontumorigenic cell lines and tumor cells, but not differentiated cells (27,29–31). Expression of Oct4 was demonstrated by RT-PCR and immunostaining and was confirmed by X-gal staining in the Oct4 -Geo transgenic rats. The identification of stem cells that were associated with the tubule is consistent with the localization of label-retaining cells by Maeshima et al. (23) and the tubular expression of Oct4 and Rex-1 in human kidneys demonstrated by Raman et al. (37). MRPC can be cultured from adult rat kidneys and are likely the in vitro correlate of the Oct4-expressing cells that were seen in vivo. These cells express Oct4, can undergo trilineage differentiation, and can be induced in vitro to develop a renal phenotype. Most important, MRPC can form tubules when injected under the renal capsule.
The existence of a renal stem cell in the adult kidney that is capable of self-renewal and differentiation into various cell types of the kidney is consistent with the finding of tissue-specific stem cells in other locations, such as the skin, brain, and gastrointestinal tract (12–16). Other studies have attempted to isolate renal stem cells. For example, Oliver et al. (24) isolated from the renal papilla of young mice and rats slow-cycling cells that have characteristics of renal stem cells. When grown in culture, these papillary cells express epithelial and mesenchymal markers, form cellular spheres, and display some evidence of plasticity with differentiation into neurons under appropriate culture conditions. Bussolati et al. (22) isolated and cultured a population of cells from adult human kidney using CD133 as a selection marker. These cells could be differentiated in vitro and in vivo into epithelial and endothelial cells, could form tubules and vessels, and expressed early and late nephron markers. These cells differed from MRPC in that they had limited self-renewal and differentiation potential and expressed different markers. Taking advantage of the slow cycling of stem cells, Maeshima et al. (23) identified a population of cells scattered among renal tubular cells in the adult rat kidney. These cells were identified as label-retaining cells and were found predominantly in proximal tubules. The cells, which subsequently were isolated, demonstrate plasticity and can be integrated into the developing kidney (25). Kitamura et al. (26) isolated a population of rapidly proliferating cells from microdissected proximal tubules that expressed the stem cell markers Sca-1 and Musahi-1 as well as early nephron markers. The cells could be differentiated into mature tubular cells in culture. These cells had a triploid karyotype but did not undergo tumor formation in nude mice. Differences in the cells that were isolated in these studies may be due to different selection markers, species, age of the kidneys, and culture conditions.
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Conclusion |
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Acknowledgments |
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We are thankful to Dr. Austin G. Smith (University of Edinburgh) for generously sharing with us Oct--Geo rats. We thank Dr. Julie Ingelfinger for the IRPTC cells and Uma Lakshmipati for technical assistance with the transfection studies.
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Footnotes |
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References |
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