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BASIC SCIENCE |
*Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Department of Histopathology, Imperial College London, Hammersmith Hospital, London, United Kingdom; and Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy
Correspondence to Dr. Marina Morigi, "Mario Negri" Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. Phone: +39-035-319-888; Fax: +39-035-319-331; E-mail: morigi{at}marionegri.it
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Abstract |
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Introduction |
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Dysfunction and loss of tubular epithelial cells play central roles in the process underlying the failure of the kidney after ischemic or toxic challenge (2,7,8). After detachment from the tubular basement membrane, both sublethally injured cells and dead cells (9) can obstruct the tubular lumen, leading to increased intratubular pressure that along with "backleak" of filtrate may contribute to dysfunction (2,7,8). Conversely, the epithelial lining of the tubule has remarkable capacity to recover. In animal models, the rate of recovery depends strictly on the replacement of damaged and/or dead epithelium with a new functioning one. Growth factors, such as IGF-1, hepatocyte growth factor, and epidermal growth factor, have been used consistently to potentiate tubular regeneration in experimental ARF (10,11). Protection may relate both to stimulatory actions on the regenerative potential of surviving tubular cells and to cell "rescue." One major limit to such healing is the requirement for a critical number of surviving cells to restore structural integrity. An alternative or additional strategy should consider the local supply of new cells to direct the replacement of damaged cells.
Tissue-based stem cells have traditionally been viewed as multipotential precursor cells that are capable of generating tissue-specific differentiated cells (12). In recent years, it has become clear that adult stem cells have remarkable plasticity to the extent that they can differentiate into lineages other than the tissue of origin. After mesenchymal or hematopoietic stem cell transplantation, donor cells have been shown to differentiate into cardiac myoblasts, hepatic epithelium, and neuroectodermal cells (13–19). Adult bone marrow–derived cells can also contribute to renal remodeling (20–22). Chimeric rats carrying enhanced green fluorescence protein bone marrow cells responded to anti-Thy1 antibody-induced mesangiolysis with a dramatic repopulation of the mesangium by enhanced green fluorescence protein cells, mainly of nonhematopoietic lineages (20). Furthermore, female mice recipients of male bone marrow grafts carried the Y chromosome in up to 7.9% of cortical tubular epithelial cells, indicating that bone marrow cells participated in the normal tubular turnover (21). The possibility that extrarenal cells of bone marrow origin may take part in tubular regeneration in humans rests on findings of Y chromosome–positive epithelial cells in sex-mismatched kidney transplants that sustain damage as a consequence of acute tubular necrosis (21,22). Moreover, recent studies have reported on the role of bone marrow–derived hematopoietic stem cells in the regeneration of the renal tubular epithelium after ischemia/reperfusion in mice (23,24). This newly described pathway of tubular regeneration provides opportunities for therapeutic intervention.
Here we tested the hypothesis that the treatment with mesenchymal stem cells or hematopoietic stem cells of adult bone marrow origin could improve renal function and attenuate tubular injury in ARF induced in mice by injection of cisplatin. As the regenerative process takes place, events that occur during renal development are reactivated as shown by reappearance of mesenchymal molecules (25–28), but the role of extrarenal stem cells has not been fully appreciated. We found that mesenchymal stem cells but not hematopoietic stem cells contributed to restore renal tubule structure and ameliorated renal function.
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Materials and Methods |
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Female C57BL6/J mice were divided in two groups and 1 d after cisplatin received an intravenous (i.v.) injection as follows: group 1, saline (n = 27); group 2, mesenchymal stem cells (MSC; 2 x 105 cells) derived from bone marrow of male C57BL6/J mice (n = 23). Mice were killed at different time intervals (4, 7, 11, and 29 d after cisplatin), and blood samples for blood urea nitrogen (BUN) determination were collected at all times until the animals were killed. Two additional groups of female mice on day 1 after cisplatin were treated as follows: group 3 (n = 12) received an i.v. injection of Lin– c-kitPOS hematopoietic stem cells (HSC; 2 x 105 cells) derived from the bone marrow of male mice; group 4 (n = 12) received an injection of saline. Mice were killed at 4, 11, and 29 d after cisplatin, and blood samples for BUN determination were collected. Renal function was assessed as BUN in heparinized blood by the Reflotron test (Roche Diagnostics, Indianapolis, IN). BUN levels that exceeded 30 mg/dl were considered abnormal (normal range in our laboratory: 14 to 29 mg/dl). Kidneys were taken for histologic and ultrastructural analysis and for Y-chromosome examination by in situ hybridization (groups 1, 2, and 3). The expression of Ki-67, a proliferation marker, was also evaluated. Normal mice served as controls. A group of mice that received cisplatin were killed after 1 d for light and electron microscopy studies. At this time, BUN levels were within the normal range. An additional group of mice (n = 12) 1 d after cisplatin received an i.v. injection of MSC immunodepleted of hematopoietic precursor CD45-positive cells (2 x 105 cells). Renal function was evaluated before (day 0) and at day 4 after cisplatin and compared with BUN of mice that received saline (n = 10) or MSC (n = 8). Renal histology was assessed at day 4.
Isolation and Purification of MSC and HSC
Bone marrow (BM) was obtained from 2-mo-old male C57BL6/J mice. Briefly, mice were killed, and femurs and tibias were aseptically removed. BM was flushed from the shaft of the bone with DMEM medium (Sigma) containing 5% FCS (Invitrogen, Paisley, Scotland) plus penicillin/streptomycin (100 U/ml to 0.1 mg/ml; Invitrogen) and then filtered through a 100-µm sterile filter (Falcon) to produce a single-cell suspension. MSC were recovered from BM by their tendency to adhere tightly to plastic culture dishes, as described previously (29). Filtered BM cells were plated in DMEM plus 10% FCS and penicillin-streptomycin (100 U/ml to 0.1 mg/ml) and allowed to adhere for 6 h. Nonadherent cells were then removed. Medium was changed regularly every 3 d; after 2 to 3 wk, adherent cells were detached by trypsin-EDTA (0.5 to 0.2 g/L; Invitrogen), washed with PBS, and used for the in vivo experiments.
In additional experiments, MSC were immunodepleted of CD45-positive cells (CD45– MSC). Briefly, after blocking with PBS that contained 0.5% BSA (Sigma), cells were incubated for 20 min with rat anti-mouse CD45 antibody, 0.2 µg/106 cells (Caltag Laboratories, Burlingame, CA). After washing, cells were incubated with magnetic microbeads coated with goat anti-rat IgG (Miltenyi Biotec, Caldara di Reno, Bologna, Italy), and CD45– MSC were isolated by magnetic cell-sorting separation system.
For isolating HSC (30,31), total BM cells were suspended in PBS that contained 1% FCS and incubated on ice with rat anti-mouse mAb specific for the following lineage markers: CD4 (0.125 µg/106 cells) and CD8 (0.5 µg/106 cells; T lymphocytes), CD45R (0.05 µg/106 cells; B-lymphocytes), CD11b (0.5 µg/106 cells; macrophages), Gr-1 (0.125 µg/106 cells; granulocytes), and Ter-119 (0.5 µg/106 cells; erythrocytes; Caltag Laboratories). After washings, cells were incubated with magnetic microbeads and magnetically cell sorted as described above. The obtained lineage negative cells (Lin–), which represented 10% of the total BM cells, were incubated with rat mAb against mouse CD117 (c-kit) PE conjugate (Caltag Laboratories). A wavelength of 488 nm was used to excite c-kit–PE–labeled cells. The c-kitPOS cells were sorted on a FACS Vantage cytofluorimeter (Becton Dickinson, BD Bioscience, Milan, Italy) to obtain purified HSC preparations. For the in vivo experiments, 2 x 105 MSC, CD45– MSC, or Lin– c-kitPOS HSC, isolated from BM of male mice, were washed with PBS, suspended in 500 µl of saline and then injected intravenously into syngeneic female mice.
Fibroblast-Like Colony-Forming Unit Assay
Fibroblast colony growth was evaluated on primary cells grown on tissue culture six-well dishes (32). Total BM-derived cells were plated at the density of 25 x 106 cells/well. After 7 d, the capability of MSC to form fibroblast-like colonies was assessed. Images that showed MSC morphology were acquired by contrast-phase microscope.
In Vitro Differentiation Assays
BM-derived cells obtained by plastic adhesion, as described above, were studied to verify their mesenchymal potential to differentiate toward osteoblasts, adipocytes, and chondroblasts. MSC were grown until confluence, and the growth medium was replaced with the inductive medium consisting of Iscove’s modified Dulbecco’s medium (Invitrogen), 20% FCS, 100 U/ml penicillin, 100 µg/ml streptomycin, and 0.05 mM 
-mercaptoethanol supplemented with specific differentiation reagents as follows.
Osteogenesis.
Cultures were fed twice a week for 3 wk with 10 mM -glycero-phosphate, 50 µg/ml ascorbic acid 2-phosphate, and 10–9 M dexamethasone (33). Then cells were fixed with 10% formalin for 20 min at room temperature and mineralization—presence of calcium-rich hydroxyapatite—of the extracellular matrix was assessed by staining for 20 min with 2% wt/vol Alizarin Red S, adjusted to pH 4.1 with ammonium hydroxide (all reagents were from Sigma) (34).
Adipogenesis.
Cells were incubated for 3 wk with 5 µg/ml insulin (Sigma) and 10–9 M dexamethasone. Adipogenic differentiation was visualized in phase-contrast microscopy by the presence of highly refractive intracellular lipid vacuoles (33). Oil Red O (Sigma) staining was used to assay the accumulation of lipid droplets in these vacuoles (34).
Chondrogenesis.
MSC were harvested and 6 x 105 cells were centrifuged to form a pellet on the bottom of a 15-ml polypropylene tube (Falcon). The micromass was cultured in 500 µl of chondrogenic medium that consisted of 50 µg/ml ascorbic acid 2-phosphate and 1 ng/ml TGF-1 (Sigma) (33). After 3 wk of culture, cell clumps were harvested, embedded in paraffin, cut into 3-µm sections, and stained for glycosaminoglycans using 0.1% safranin O (Sigma).
Renal morphology.
Light microscopy.
Fragments of renal cortex were fixed overnight in Dubosq-Brazil, dehydrated in alcohol, and embedded in paraffin. Sections of 3-µm thickness were stained with hematoxylin and eosin, Masson’s trichrome, or periodic acid-Schiff (PAS) reagent. Slides were scored for the following changes: luminal hyaline casts, tubular cell degenerative changes (cytoplasmic vacuolization, swelling, cell flattening, PAS-positive droplets, nuclear fragmentation, cell debris), and cell loss (denudation of the tubular basement membrane). Nonoverlapping fields of the entire section (up to 28 fields for each mouse) were analyzed at high magnification using a x40 objective (high-power field [HPF]). Lesions were focal in distribution, and the scores ranged from 0 to 3+ as follows: 0, no changes; 1+, very occasional tubular profiles (usually <3/section and <2/HPF) affected by lesion; 2+, more evident lesions affecting a minor percentage of tubuli in each affected area; 3+, lesions in most tubuli within affected areas. Sections were analyzed by the same pathologist, in a single-blind manner.
Electron microscopy.
Fragments of kidney tissue were fixed for 4 h in 2.5% glutaraldehyde in 0.1 M cacodylate buffer (pH 7.4) and washed repeatedly in the same buffer. After postfixation in 1% OsO4, specimens were dehydrated through ascending grades of alcohol and embedded in Epon resin. Ultrathin sections were stained with uranyl acetate and lead citrate and examined using a Philips Morgagni electron microscope.
Immunohistochemistry and In Situ Hybridization
To verify the presence of male mesenchymal or hematopoietic stem cells and to characterize their phenotype in the kidney of female recipients, we stained sections for lectin Lens culinaris binding sites in the brush border of proximal tubuli and further processed for Y-chromosome detection using in situ hybridization. Renal biopsies were fixed in Dubosq-Brazil, routinely processed, and paraffin wax embedded. Slides were dewaxed by xylene, taken through graded alcohols (100, 90, 70, and 50%) to PBS, and incubated with trypsin (0.1% in CaCl2 0.1%) at 37°C for 15 min. After washing with PBS, slides were incubated with biotinylated lectin (Vector Laboratories, Burlingame, CA) for 30 min (1:200), followed by treatment with streptavidin-alkaline phosphatase (1:50). Vector Red substrate (Vector Laboratories) was then applied for 15 min at room temperature. After washing in PBS, the slides were processed using the in situ hybridization protocol as described previously (21). Sections were washed again in PBS and digested with 0.4% wt/vol pepsin (Sigma) in 0.1 M HCl for 10 min at 37°C. For quenching the reaction, 0.2% glycine was used and then sections were postfixed with 4% paraformaldehyde and dehydrated through graded alcohols. Samples were air dried and incubated with FITC-labeled mouse Y-chromosome paint (Star-FISH; Cambio, Cambridge, UK). The probe was added to the sections, and a 10-min incubation at 60°C was performed followed by overnight incubation at 37°C. Slides were washed with 50% formamide/2x SSC and then 0.1x SSC followed by PBS. The sections were incubated with 1/50 peroxidase-conjugated antifluorescein antibody (Boehringer Mannheim), developed in 3,3'-diaminobenzidine, counterstained with hematoxylin, and mounted with either an aqueous mounting medium (Bio Optica) or 60% glycerol. Slides were analyzed under a light microscope. In additional experiments, sections were further stained with PAS reagent after initial examination and removal of the coverslip to stain tubular basement membrane structures for more precise localization of Y chromosome—positive cells.
Proliferating tubular cells were immunohistochemically identified by labeling with mAb against the proliferating cell nuclear antigen Ki-67 (Novocastra Laboratories, Newcastle, UK) as follows (35). Sections fixed in Dubosq-Brazil were deparaffinized and dehydrated. For obtaining an adequate signal with Ki-67 antibody, the sections were microwaved twice for 5 min in citrate buffer, and for reducing background, they were blocked for 30 min in 1% BSA (Sigma). The sections were incubated overnight with anti–Ki-67 Ab (1:100) at 4°C. After rinsing with PBS, sections were incubated with biotinylated sheep anti-mouse IgG (Chemicon International, Temecula, CA), 1:100 for 30 min at room temperature. Then streptavidin-alkaline phosphatase conjugate (Roche Diagnostic) was applied at a dilution of 1:100 for 30 min. The reaction product was visualized by incubation with Fast Red substrate (Vector Laboratories). Counterstaining was performed by using Harris hematoxylin (Bio-Optica, Milan, Italy). For establishing whether MSC may be proliferating, serial sections of kidneys of selected female mice at 4 d were stained as above for Y chromosome and Ki-67, respectively. In control experiments, the first antibody was omitted or replaced by normal serum. Signals in negative control sections were negative. Ki-67–positive cells within tubuli were counted in 10 randomly selected HPF (x400) for each animal (n = 5 mice for each group).
Statistical Analyses
The results are expressed as mean ± SEM. ANOVA with Tukey-Cicchetti test for multiple comparisons was used to analyze BUN data. Histology and immunohistochemistry data were analyzed using the nonparametric Kruskal-Wallis test or Mann-Whitney test, as appropriate. Statistical significance level was defined as P < 0.05.
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Results |
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HSC Fail to Protect Cisplatin-Treated Mice against ARF
To examine whether HSC may have the same protective potential as MSC against renal injury, we assessed the effect of Lin– c-kitPOS HSC purified from BM of male mice. Injection of HSC into female cisplatin-treated mice (2 x 105 cells given intravenously on day 1) did not ameliorate renal function, as indicated by serum BUN levels that were similar to those of cisplatin-treated mice that were given saline, at any time points considered (Figure 2). By histology, at day 4 after cisplatin, mice that received HSC had severe tubular changes comparable to those of mice that received saline (Table 1, Figures 3f and 8a
). As shown in Figure 8b, occasional Y chromosome–positive cells were localized, mostly in the least severely damaged tubular structures, at day 4 in kidneys of cisplatin-treated mice that received HSC.
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Discussion |
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From adult male mouse BM, we established a cell population with morphologic and functional characteristics of multipotent mesenchymal progenitors. The transplantation of MSC attenuated severe epithelial cell injury in mice with ARF and improved function. This is to the best of our knowledge the first report to show that MSC accelerate the structural recovery of the kidney after ARF and, more importantly, that they confer therapeutic benefit. Functional protection by MSC can possibly be the consequence of the capacity of MSC to engraft the damaged kidney and integrate/differentiate within tubuli. Consistent with this possibility are the present data documenting that Y chromosome–containing MSC were recruited into the kidney. Detection of MSC at day 4 and at day 29 in the context of the well-differentiated tubular epithelial lining indicates that MSC repopulate the tubule, most presumably by recruitment at peritubular sites in which the Y-chromosome MSC were also visualized. MSC exploit their potential to generate tubular epithelial cells, as shown by the simultaneous evidence of specific lectin-binding sites in the proximal tubular brush border. In support of our interpretation, adult BM-derived cells can indeed traffic into the kidney, contributing to tubular renewal in a sex-mismatched mouse model of BM transplantation (21). Moreover, in the setting of acute tubular damage Y chromosome–positive cells are detectable in human biopsy specimens taken from female kidneys upon grafting into male recipients (21,22).
Recently, cell fusion between transplanted donor BM cells and recipient tissue has been claimed as an alternative novel mechanism to transdifferentiation, which can occur in vivo (41) and produce functional cells in liver (42) and brain (43). This is, however, a controversial issue, because in other experimental systems—skeletal muscle and pancreatic islets of Langerhans—the cell fusion process has been excluded as a way to explain BM stem cell plasticity (44,45). Whether in our setting MSC-driven regeneration of tubular cells might also occur by steps that suggest cell fusion of MSC with resident cells is an issue that at present cannot be completely ruled out.
Another significant finding of the present work is that MSC engrafting the kidney accelerated to a remarkable extent tubular cell proliferation in response to cisplatin-induced damage as shown by high numbers of Ki-67–positive cells within the tubuli at day 4, time at which renal function was ameliorated. The evidence of nuclear colocalization of Y-chromosome and Ki-67 staining in tubuli indicates that at least some MSC may proliferate and directly reconstitute the tubular epithelium. We also suggest that the functional benefit of MSC could be due to their ability to produce growth and trophic factors (46–49). That the local production of factors by stem cells may occur and play a role in tissue repair has been suggested by data in a mouse model of pancreatic regeneration (50). Among those factors, in vitro MSC express hepatocyte growth factor and bone morphogenetic proteins acting to promote mitogenic, antiapoptotic, and morphogenic activities of renal tubular epithelial cells (46,48).
HSC have a clearly defined therapeutic potential in liver, heart, and brain reconstitution (14,16,19). Actually, highly purified HSC can differentiate into mature hepatocytes, restoring biochemical function of the liver in a murine model of tyrosinemia type I (16). In mice with infarcted myocardium, locally delivered Lin– c-kitPOS HSC generated de novo cells exhibiting markers and morphology of myocytes, endothelial cells, and smooth muscle cells, thus ameliorating heart function (14). In keeping with such kinds of differentiation plasticity, we wanted to assess whether purified HSC may have a renoprotective effect in cisplatin-induced ARF. Systemic injection of Lin– c-kitPOS HSC failed to protect cisplatin-treated mice against renal function impairment and tubular damage. Notably, scattered HSC were detected by staining for Y chromosome in tubular structures of cisplatin-treated mice after injection of male HSC, indicating that HSC can localize to the injured renal tissue. However, in the cisplatin model, this occurred to a much lesser extent than with MSC. The rarity of Y chromosome–positive cells in the kidney of mice that received HSC injections could simply reflect that donor HSC cannot survive in the host, possibly because of lack of engraftment in nonirradiated mice. If so, then the clinical application of HSC, albeit considered important, seems to be less relevant in respect to MSC that did not require irradiation to engraft and to exert beneficial effect. One can also speculate that HSC may be more susceptible to the cytotoxic effect of cisplatin or that the kidney exposed to cisplatin may generate chemoattractants with more specific activity toward MSC.
Recent studies have reported that Lin– Sca-1POSc-kitPOS cells engrafting the BM of irradiated mice were mobilized by renal ischemia/reperfusion into the circulation and homed specifically to injured regions of the tubule, where they differentiated into tubular epithelial cells (23,24). Consistent with our data, injection of Lin– BM cells had no protective effect on renal function impairment of ischemic mice (24). However, such manipulation limited further worsening of BUN induced by BM ablation in mice with ischemic ARF, suggesting that BM stem cells contributed to spontaneous repair after ischemia.
In summary, our findings indicate that MSC contribute to the recovery of the kidney during ARF. In the context of regenerative therapies, renotropic preparations of autologous adult stem cells can be proposed as a safe strategy in humans. Combined administration with growth factors or molecular engineering of MSC to deliver specific factors to the site of injury would hopefully aid in maximizing their therapeutic potential.
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Acknowledgments |
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Part of this work was presented at the 35th Annual Meeting of the American Society of Nephrology, November 1–4, 2002, Philadelphia, PA.
We are deeply indebted to Dr. Arrigo Schieppati for contribution in writing the manuscript and Professor Richard Poulsom (Histopathology Unit, Imperial Cancer Research Fund, London, UK) for great help in setting up the Y chromosome in situ hybridization. We gratefully acknowledge Sergio Bernasconi (Department of Immunology and Cell Biology, Mario Negri Institute for Pharmacologic Research, Milano, Italy) for providing us excellent technical assistance with the cell sorting. Reproduction of Figures in color was made possible by the generous sponsorship of Merck Sharp & Dohme Italia, (Rome, Italy) through the courtesy of Dr. Luigi Caratelli.
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), MSC (
), or HSC (
). Data are mean ± SE. °P < 0.01 versus day 0 (basal) and cisplatin+saline at 7, 11, and 29 d; *P < 0.01 versus cisplatin+saline at the same time.
