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Departments of *Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; Stowers Institute for Medical Research, Kansas City, Missouri; Institute for Systems Biology, Seattle, Washington; and ¶Department of Medicine, University of Washington, Seattle, Washington.
Correspondence to Dr. Fangming Lin, Division of Pediatric Nephrology, Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Mail Code 9063, Dallas, TX 75390-9063. Phone: 214-648-3438; Fax: 214-648-2034;
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Abstract |
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-galactosidase constitutively were transplanted into female nontransgenic mice after unilateral renal I/R injury. Four weeks after HSC transplantation, -galactosidase-positive cells were detected in renal tubules of the recipients by X-Gal staining. PCR analysis of the male-specific Sry gene and Y chromosome fluorescence in situ hybridization confirmed the presence of male-derived cells in the kidneys of female recipients. Antibody co-staining showed that -galactosidase was primarily expressed in renal proximal tubules. This is the first report to show that HSC can differentiate into renal tubular cells after I/R injury. Because of their availability, HSC may be useful for cell replacement therapy of acute renal failure. E-mail: fangming.lin@UTSouthwestern.edu |
Introduction |
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The pluripotency of HSC is evidenced by their capacity to differentiate into multiple lineages within the blood and immune system, as well as cells of non-hematopoietic tissues, such as hepatocytes, cardiac myocytes, gastrointestinal epithelial cells, and vascular endothelial cells (7–11). The discovery that adult HSC can cross lineage boundaries to become cells of other tissues has challenged the traditional view that somatic stem cells are lineage-restricted and organ-specific (12). One possibility is that HSC retain developmental plasticity and can be reprogrammed to express genes that are required to differentiate into the cells of the organs into which they are introduced. Another distinguishing feature of HSC is their ready availability from bone marrow, cord blood, and mobilized peripheral blood. This property makes HSC potentially useful for cell replacement therapy in regenerative medicine.
Acute renal failure (ARF) is a common disease with high morbidity and mortality. Current treatment options for acute renal failure are limited, and mortality remains 30 to 50% (13). Renal ischemia-reperfusion injury (I/R injury) is one of the most common causes of ARF. I/R injury is characterized by alterations in cell metabolism, inflammation, free radical generation, and apoptosis that result in the detachment of renal tubular cells from the basement membrane and shedding into the urine (14–16). The S3 segments of the proximal tubules located in the outer stripe of the outer medulla are particularly susceptible to ischemic injury and are primarily responsible for the pathophysiological and clinical presentations of ARF (17–19). Recovery from ARF requires the replacement or regeneration of lost tubular epithelial cells. This process is accompanied by complex changes in gene expression of growth modulatory molecules, such as EGF, IGF-1, and HGF (20,21). It has been generally believed that some of the surviving renal tubular cells dedifferentiate and reenter the cell cycle to produce epithelial cells that rebuild the structure and function of the renal tubules. However, the origin of the regenerating cells has not been clearly established. The ability of HSC to adopt the cell fate of the organs in which they reside suggests that HSC could potentially differentiate into kidney cells during kidney regeneration. In this report we provide evidence showing that adult murine bone marrow-derived HSC integrate into injured kidneys and differentiate into tubular epithelial cells in mice.
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Materials and Methods |
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antibodies (PharMingen, San Diego, CA) and goat anti-rabbit IgG coupled to magnetic beads (M-450; Dynal, Lake Success, NY). Unbound Lin- cells were incubated with antibodies to Sca-1-cychrome and c-Kit-PE as well as rhodamine before isolation by FACS (FACSVantage; Becton Dickinson, San Jose, CA). Sca-1– and c-kit–positive cells exhibiting less than 15% rhodamine staining intensity (Rhlo) were sorted out and designated RhloLin-Sca-1+ckit+ cells. The purity of the sorted cells was confirmed by staining with an antibody to common leukocyte antigen, CD45.2 (PharMingen, San Diego, CA).
Fluorescein D-Galactopyranoside (FDG) Staining of White Blood Cells
Peripheral blood was obtained from B6-Ly5.2/Cr–recipient mice 4 to 12 wk after kidney I/R injury and transplantation with RhloLin-Sca-1+ckit+ cells from Rosa26 mice. Blood was also collected from Rosa26 donor mice and untransplanted B6-Ly5.2/Cr mice as positive and negative controls, respectively. Using a published method (22), nucleated blood cells were loaded with FDG (Molecular Probes, Eugene, OR) and analyzed for fluorescence intensity by flow cytometry. The viability of the cells was confirmed by low staining with propidium iodide.
Kidney I/R Injury and HSC Transplantation
Six-week-old female B6-Ly5.2/Cr mice (National Cancer Institute, Frederick, MD) were given 11 Gy 
-irradiation 2 h before surgery. The left renal artery was separated from the vein and clamped for 15 min followed by clamp release to allow reperfusion. A group of mice also underwent right nephrectomy for evaluation of blood urea nitrogen (BUN) after left renal I/R injury. Two to four hours after surgery, RhloLin-Sca-1+ckit+ cells (2 x103 cells/mouse) isolated from male Rosa26 mice were injected via tail vein together with syngeneic Lin- bone marrow cells (2 x105 cells/mouse). Control mice that had irradiation and renal I/R injury received syngeneic Lin- bone marrow cells only. Sham-operated mice underwent irradiation and syngeneic Lin- bone marrow cell injection but did not receive kidney I/R injury. Mice were kept in a specific pathogen-free facility and were given drinking water containing baytril (0.15 mg/ml) and amoxicillin (1 mg/ml) for 2 wk. Four to twelve weeks after transplantation, peripheral blood was obtained via retro-orbital venous puncture to evaluate the engraftment. Animals were euthanized and perfused with saline to remove blood cells. Kidneys were fixed with 4% paraformaldehyde, embedded in OCT medium, frozen in isopentane, and sectioned at 5- or 10-µm-thick before mounting on Vectabond-treated slides (Vector Laboratories, Burlingame, CA). The animal protocols were approved by The Institutional Animal Care and Resource Advisory Committee.
TUNEL Staining and Anti-BrdU Staining
Paraffin sections of the kidney were stained with In Situ Cell Death Detection Kit (Roche, Germany) according to the manufacturer’s instruction. For BrdU incorporation, mice were injected with 50 µg/kg bromodeoxyuridine intraperitoneally 2 h before harvesting. Paraffin sections of the kidney were stained with FITC-labeled anti-BrdU antibody (BD Biosciences, San Jose, CA). Nuclei were counterstained with propidium iodide.
X-Gal Staining
Tissue sections (10-µm-thick) were fixed with 1% paraformaldehyde in PBS (150 mM NaCl, 15 mM sodium phosphate, pH 7.3) for 30 min on ice and then washed three times with PBS. The sections were incubated with staining solution (PBS containing 20 mM Tris-Cl, pH 7.3, 1.8 mM spermidine, 2 mM MgCl2, 0.02% Nonidet P-40, 0.01% sodium deoxycholate, 5 mM potassium ferrocyanide, 5 mM potassium ferricyanide, and 1 mg/ml X-gal) at 32°C for 16 h followed by 37°C for 4 h in dark. Stained sections were washed with PBS, and some samples were counterstained with hematoxylin and eosin (H&E) before visualization by light microscope (TE200; Nikon, Tokyo, Japan). Photographs were taken with a CCD camera coupled to a computer with analytic software.
PCR of Sry Gene
The primers used to amplify the mouse Sry gene were 5'-CAGCTAACACTGATCTTTTC-3' and 5'-TTACTGAGCCAGAATCATAG-3'. Genomic DNA isolated from kidney was used for amplification. The PCR conditions were incubation at 94°C for 3 min; 35 cycles of incubation at 94°C for 30 s, 50°C for 30 s, and 72°C for 2.5 min; followed by a final incubation at 72°C for 5 min. The PCR products were resolved by 1.2% agarose gel electrophoresis.
Y Chromosome Fluorescence In Situ Hybridization (FISH)
Kidney sections (5-µm-thick) were fixed with 3:1 methanol:acetic acid for 30 min at room temperature then baked at 70°C for 1.5 h. A biotin-labeled mouse Y chromosome painting probe (Applied Genetics Laboratory, Melbourne, FL) was denatured at 75°C for 10 min then immediately transferred to 37°C to allow pre-annealing for 1 h. The tissue sections were pretreated at 70°C for 2 min in 2 x SSC containing 70% formamide and immediately dehydrated through a graded ethanol series (70%, 90%, and 100%; 2 min each). Samples were air dried at room temperature and then overlaid with denatured probe (10 µl). The sections were covered with a cover slip, sealed with rubber cement, and incubated at 37°C overnight. Sections were washed twice in 2 x SSC for 10 min at 70°C and then twice in 0.1 x SSC for 10 min at 70°C. Slides were incubated in 4 x SSC containing 0.1% Tween-20 for 3 min at room temperature, then 30 µl of a 1:400 dilution of avidin-fluorescein (Vector Laboratories, Burlingame, CA) in 4 x SSC containing 1% BSA, and 0.1% Tween-20 was added. Slides were incubated at 37°C for 15 min in a humidified chamber before washing with three changes of 4 x SSC containing 0.1% Tween-20 for 3 min at room temperature. Sections were counterstained with propidium iodide before visualization by fluorescence microscopy (TE200; Nikon, Tokyo, Japan).
Immunostaining
Kidney sections were serially stained with an antibody to -galactosidase followed by antibodies or lectins to various renal cell markers (23–27). Kidney frozen sections (10-µm-thick) were fixed with ice-cold 1:1 methanol:acetone for 10 min. After washing with PBS, the sections were blocked with both avidin/biotin Blocking Kit (Vector Laboratories) and PBS containing 1% BSA before incubation with a rabbit antibody against Escherichia coli -galactosidase (Molecular Probes). The antibody was used at a dilution of 1:5000 in PBS containing 0.1% BSA, and sections were incubated at 4°C overnight. The sections were then washed and incubated with a 1:1000 dilution of biotinylated anti-rabbit IgG (Vector Laboratories) at room temperature for 1.5 h before further incubation with a 1:400 dilution of avidin-FITC (Vector Laboratories) at room temperature for 40 min. Next, the sections were stained with antibodies or lectins that recognize specific nephron segments. Proximal tubules were stained with an antibody to Fx1A at 1:100 dilution (23) or an antibody to sodium/phosphate cotransporter type 2 (NaPi-2; Dr. Heini Murer, University of Zurich-Irchel, Zurich, Switzerland) at 1:2000 dilution (24). Thick ascending limbs of loops of Henle (TALH) and distal tubules were stained with an antibody to Tamm-Horsfall Protein (THP: Dr. John Hoyer, Children’s Hospital of Philadelphia, Philadelphia, PA) at 1:100 dilution (26). TALH were also stained with an antibody to the sodium/potassium/chloride co-transporter (NKCC2; Dr. Mark Knepper, NIH, Bethesda, MD) at 1:100 dilution (27). Collecting ducts were stained with TRITC-coupled Dolichos biflorus agglutinin (DBA; Vector Laboratories) at 1:40 dilution and an antibody to the aquaporin-2 water channel (AQP2; Dr. Mark Knepper, NIH, Bethesda, MD) at 1:2000 dilution (25). All primary antibodies were rabbit anti-mouse or rabbit anti-rat IgG except anti-Fx1A, which was biotinylated sheep anti-rat IgG. Incubation with primary antibodies was performed at room temperature for 2 h, and incubation with Alexa Fluor 594 anti-rabbit IgG (Vector Laboratories) secondary antibody at 1:400 dilution was performed at room temperature for 40 min. For anti-Fx1A staining, incubation with avidin-peroxidase at a 1:1000 dilution was performed at room temperature for 40 min followed by color development with Noval-red (Vector Laboratories).
Some kidney sections were incubated with biotinylated anti-CD45.2 (PharMingen, San Diego, CA) at 1:100 dilution at room temperature for 2 h or with rat anti-mouse macrophage, F4/80 (Caltag, Burlingame, CA) at 1:100 dilution at 4°C overnight. Avidin-FITC was used to visualize CD45.2-positive cells, and biotin anti-rat IgG (Vector Laboratories) followed by avidin-FITC was used to visualize macrophages. Sections were postfixed with 2% paraformaldehyde, rinsed with PBS, and then mounted with Vectashield (Vector Laboratories). Stained sections were photographed under epifluorescence illumination using a Zeiss Axioplan microscope, and the images were analyzed using OpenLab software.
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Results |
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-galactosidase produces fluorescein that can be detected by flow cytometry analysis. The results showed that 35% and 39% of the nucleated blood cells were able to hydrolyze FDG to fluorescein at 4 wk and 12 wk after HSC transplantation, respectively (Figure 2). The generation of fluorescein in the recipient nucleated blood cells indicated repopulation of peripheral blood cells by HSC of Rosa26 mice.
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-galactosidase) in all tissues (29). Therefore, donor-derived cells can be identified by their blue color after staining with X-Gal. Figure 4 shows representative X-Gal staining of regenerating kidneys harvested from mice that were injected with RhloLin-Sca-1+ckit+ cells from male Rosa26 mice. An intense distribution of LacZ-positive cells was seen in the outer stripe of the outer medulla where the S3 segments of the proximal tubules are located (Figure 4A). Under higher magnification, the LacZ-positive cells were identified within the renal tubules (Figure 4, B and E). The X-Gal staining was specific because no staining was seen in normal age-matched kidneys (data not shown) or in the kidneys from mice that had renal I/R injury but without HSC transplantation (Figure 4C). Similarly, no positive staining was observed in the kidneys harvested from sham-operated mice that received Rosa26 mice-derived HSC transplants but did not undergo renal I/R injury (Figure 4, D and F). No -galactosidase activity was detected in the renal vessels and glomeruli.
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Co-Staining of Antibodies to -Galactosidase and Markers of Renal Tubular Cells
To test if HSC-derived cells in the kidney expressed renal cell markers, the kidney sections were serially stained with antibodies to -galactosidase and markers of specific nephron segments. In regenerating kidneys from mice that did not receive HSC transplants, no specific signals were detected with anti--galactosidase staining, indicating that the immunostaining was specific (Figure 6A, panel a). In contrast, kidneys from Rosa26 control mice showed generalized cortical staining (Figure 6A, panel b). The kidneys of nontransgenic mice that were injected with Rosa26-derived HSC showed areas containing -galactosidase-positive cells, mostly in the outer stripe of outer medulla and the cortex (Figure 6A, panel c). Compared with the staining in the Rosa26 mouse kidney, a heterogeneous pattern of -galactosidase staining was seen even within the same tubule, suggesting some of the tubular cells were derived from HSC of Rosa26 mice during regeneration. Panels d through f of Figure 6A show immunostaining of sodium/phosphate cotransporter type 2 (Na/Pi-2), which is located in the brush border of the renal proximal tubule. The merged image shows that most of the -galactosidase–expressing cells also expressed Na/Pi-2 (Figure 6A, panels g through i). Similarly, co-staining with an antibody to Fx1A, a proximal tubule-specific brush border glycoprotein, showed -galactosidase expression in Fx1A-positive proximal tubule cells (Figure 6B, panels a through c). About 80% of the proximal tubules contained some cells that were co-stained with antibodies to -galactosidase and antibodies to Na/Pi-2 or Fx1A. These results suggest that during kidney regeneration, some of the cells in the kidney that are derived from -galactosidase–expressing HSC have adopted a renal proximal tubular cell phenotype.
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-galactosidase. Figure 7a shows that there was no co-localization of -galactosidase and Tamm-Horsfall protein, which is expressed in the thick ascending limb of loop of Henle (TALH) and distal tubules. Likewise, there was no co-localization of -galactosidase and NKCC2, a sodium/potassium/chloride co-transporter expressed in the TALH (Figure 7b). Figures 7c and 7d show that -galactosidase was not expressed in collecting ducts that stained positive with DBA and AQP2.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-galactosidase antibody. In addition, -galactosidase–positive cells did not stain positive for endothelial cell marker, vWF, suggesting no formation of endothelial cells from HSC in our mouse model.
Using whole bone marrow cell transplantation, Poulsom et al. (34) reported that bone marrow derived cells expressing epithelial cell markers were detected in histologically normal mouse kidneys. In male patients who received kidney transplant from female donors, 7.9% of the cortical epithelial cells in the injured kidneys are positive for Y chromosome and renal tubular cell markers. These results suggest that bone marrow cells contribute to renal parenchymal turnover and regeneration in mice and humans. Similarly, when kidneys from female donors were transplanted into male recipients, 1% of the kidney tubules contained Y chromosome–positive cells (35). In both studies, the exact source(s) of these male extrarenal-derived cells were not clear. Although bone marrow–derived cells have previously been identified in the kidney, the current study is the first report to show that a purified population of HSC can differentiate into renal tubular cells after I/R injury in the murine model. In our study, the percentage of Y chromosome–positive cells in the regenerating kidney was 8.3 ± 3.2%. Furthermore co-staining with antibodies to -galactosidase and Na/Pi-2 or Fx1A showed that approximately 80% of the proximal tubules contained some cells that express both -galactosidase and Na/Pi-2 or Fx1A. No -galactosidase–positive cells were observed in the kidneys of mice that were transplanted from Rosa26 donors but that did not receive renal I/R injury. These results indicate that the integration of HSC-derived cells in the kidney is enhanced after I/R injury. Interestingly, we found that a small number of cells (3 to 5 cells per section) in the contralateral kidney were stained positive with X-Gal staining, suggesting that systemic factors may facilitate recruitment and differentiation of HSC in the kidney.
Differentiation of HSC to nonhematopoietic cells does not occur in every animal model. A recent report by Weissman and colleagues (36) showed very limited developmental plasticity of HSC in previously healthy mice. After irradiation, the mice were given primitive HSC isolated from GFP mice. Few GFP+ non-hematopoietic cells were detected in the brain and liver and no HSC-derived cells were observed in the kidney, gut, skeletal muscle, heart, and lung. Except irradiation, no specific organ injury was induced in this study, which might explain why few HSC-derived cells were observed in the recipient organs.
The term "transdifferentiation" has been suggested to describe the phenotypic conversion of pluripotent somatic stem cells of one tissue type to another tissue type (12). One explanation for this phenomenon is genetic reprogramming of the stem cells once they are introduced into a new environment (12). Upon instruction by environmental signals, pluripotent stem cells exhibit developmental plasticity and transdifferentiate into alternative cell types. Two recent studies challenging this view have suggested that under selection pressure bone marrow cells or neural stem cells can fuse with embryonic stem cells (ES cells) in cultures. Terada et al. (37) showed that bone marrow cells could fuse with ES cells, adopt an ES cell phenotype. In this in vitro study mixed bone marrow cells were used, and the frequency of fusion was 2 to 11 per 106 bone marrow cells. The Sca+Lin- fraction of bone marrow cells did not increase the frequency of fusion, suggesting that HSC were unlikely to be involved in the fusion event. Similarly, neural stem cells fused with ES cells and subsequently differentiated to many cell types. The frequency of fusion was in the range of 10-4 to 10-5 per brain cell (38). Fusion is unlikely to explain our results because the number of HSC-derived cells greatly exceeds the reported frequency of spontaneous cell fusion. In addition, fusion of HSC with adult somatic cells has not been shown in vivo during normal development or recovery from injury. Although the concept of transdifferentiation has been challenged, transplantation of highly purified HSC into tyrosinemic mice resulted in the cure of the metabolic liver disease, demonstrating the therapeutic potential of HSC (7).
After renal I/R injury and transplantation of exogenous HSC, most of the HSC-derived cells were observed in renal proximal tubules. By X-Gal staining and immunohistochemistry study, the outer stripe of outer medulla was the most extensive site of HSC-derived cells. This result is consistent with the sensitivity of S3 segments of the proximal tubules to I/R injury. In the cortex, a few -galactosidase–positive cells were negative for the proximal tubular marker, Na/Pi-2. This absence of Na/Pi-2 staining likely reflects the weak expression of Na/Pi-2 in the proximal convoluted tubules of superficial nephrons (39). No -galactosidase–positive, HSC-derived cells were observed in the distal nephron or collecting ducts, which are less susceptible to ischemic injury. The expression of a proximal tubular transporter in the newly formed tubules suggests that HSC-derived tubular cells may mediate ion transport. Further studies will be required to determine whether transplanted HSC can accelerate functional recovery after bilateral ischemic renal injury. Because HSC are more readily available compared with other somatic stem cells they can potentially be utilized as a source for cell replacement therapy.
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