Original Article
Neointimal and Tubulointerstitial Infiltration by Recipient Mesenchymal Cells in Chronic Renal-Allograft Rejection
N Engl J Med 2001; 345:93-97July 12, 2001
- Abstract
Background
Tissue remodeling depends on mesenchymal cells (fibroblasts and myofibroblasts) and is a prominent feature of chronic renal-transplant rejection. It is not known whether the mesenchymal cells that participate in remodeling originate locally or from circulating precursor cells.
Methods
We obtained biopsy specimens of renal allografts from six male recipients of an allograft from a female donor, four female recipients of an allograft from a male donor, two male recipients of an allograft from a male donor, and two female recipients of an allograft from a female donor. All the allografts were undergoing chronic rejection. We used immunohistochemical methods to identify mesenchymal cells with smooth-muscle α-actin and in situ hybridization to identify mesenchymal cells with Y-chromosome DNA.
Results
No Y-chromosome bodies were identified in the case of the two renal-allograft specimens in which both the donor and the recipient were female. In the case of the two renal-allograft specimens in which both the donor and the recipient were male, approximately 40 percent of mesenchymal cells contained a Y-chromosome body. In the case of the six specimens in which the donor was female and the recipient was male, a mean (±SD) of 34±16 percent of mesenchymal cells in the neointima, 38±12 percent of such cells in the adventitia, and 30±7 percent of such cells in the interstitium contained the Y-chromosomal marker, indicating that they originated from the recipient rather than the donor. In the case of the four renal-allograft specimens in which the donor was male and the recipient was female, the respective values were 24±15 percent, 33±9 percent, and 23±8 percent, indicating a persistent population of donor mesenchymal cells.
Conclusions
The presence of mesenchymal cells of host origin in the vascular and interstitial compartments of renal allografts undergoing chronic rejection provides evidence that a circulating mesenchymal precursor cell has the potential to migrate to areas of inflammation.
Media in This Article
Figure 2
Results of Combined Immunostaining for Smooth-Muscle α-Actin and in Situ Hybridization for the Y-Chromosome Body in Tubulointerstitium (×400).Figure 1
Results of Combined Immunostaining for Smooth-Muscle α-Actin (Red Cytoplasm) and in Situ Hybridization for the Y-Chromosome Body (Black Nuclear Signal) (×325).Article Activity
- Article
Tissue remodeling is central to the pathogenesis of many chronic illnesses. In the vascular narrowing of atherosclerosis,1 the proliferation of smooth-muscle cells and the synthesis of matrix lead to the formation of a neointima. The same events in the adventitia2 cause a constrictive fibrosis that prevents the vessel from dilating in response to the encroachment of the neointima into the vascular lumen.1 Tissue remodeling is also important in chronic allograft rejection, which is the chief limitation to the long-term success of organ transplantation. The principal lesions in chronic rejection are vascular fibrointimal hyperplasia and interstitial fibrosis.3 The mesenchymal cells that synthesize matrix in the vascular neointima are smooth-muscle cells, whereas in the interstitium they are myofibroblasts.4-6
It is commonly accepted that in allograft rejection the mononuclear inflammatory cells derive from the recipient,7 whereas the mesenchymal cells that participate in remodeling originate in the graft itself. However, it has been shown that collagen vascular grafts are rapidly infiltrated and remodeled by smooth-muscle cells into physiologically responsive neovessels, suggesting that circulating smooth-muscle cells (or their mesenchymal precursors) migrate to areas of tissue remodeling and take part in the process.8 Moreover, studies in animal models9-11 indicate that mesenchymal cells involved in chronic rejection may originate from the recipient.
To investigate the origin of mesenchymal cells in tissue remodeling, we studied the infiltrating mesenchymal cells in sex-mismatched renal allografts that were undergoing chronic rejection. We used combined immunohistochemical techniques to identify mesenchymal cells with smooth-muscle α-actin and in situ hybridization to determine whether Y-chromosome DNA was present in biopsy specimens of renal allografts.
Methods
Patients and Biopsies
Our group routinely performs renal-allograft biopsies 1, 2, 3, 6, and 12 months after transplantation; the characteristics of 76 patients who were studied under this protocol have been described previously.12,13 All patients received cyclosporine, azathioprine, and prednisone for immunosuppression after renal transplantation and were in clinically stable condition at the time of biopsy. The biopsy protocol was approved by the faculty committee on the use of human subjects in research at the University of Manitoba, and all patients gave written informed consent to participate.
Changes in the tubules, interstitium, glomeruli, and vessels were assessed by a pathologist who was unaware of the clinical condition of the patients. The pathologist assigned semiquantitative scores for these changes using the standardized Banff classification.14 The Banff criteria have accepted validity and reproducibility and are widely used in the histologic analysis of transplants. We scanned our data base of renal biopsies and selected samples from all sex-mismatched grafts with a Banff grade of CV2 (indicating the presence of chronic rejection with a moderately vascular neointima) or CV3 (indicating the presence of chronic rejection with severe vascular changes, including narrowing of the vascular lumen by more than 50 percent) and adequate tissue available for study. We identified such biopsy specimens from six male recipients who had received an allograft from a female donor and four female recipients who had received an allograft from a male donor.
We then selected biopsy specimens from two female recipients of an allograft from a female donor as a negative control and biopsy specimens from two male recipients of an allograft from a male donor as a positive control. As an additional control, we studied nine sex-mismatched biopsy specimens with no evidence of rejection (from five male recipients of an allograft from a female donor and four female recipients of an allograft from a male donor). In no case did we study biopsy specimens that had been obtained from a single patient at more than one time.
Combined Immunohistochemical Analysis and in Situ Hybridization
We performed all immunohistochemical procedures using the Microprobe apparatus (Fisher Scientific) with semiautomated capillary staining to ensure that the results of staining were consistent and reproducible. Formalin-fixed, paraffin-embedded blocks were cut into sections that were 4 μm thick, and the sections were placed on microscope slides (ProbeOn Plus, Fisher Scientific) and incubated. Immunohistochemical analysis with use of an antibody against smooth-muscle α-actin (M0851, Dako) as a marker for smooth-muscle cells15 was performed essentially as described previously.16 DNA in situ hybridization for the human Y chromosome was immediately performed with use of pHY2.1, a Y-chromosome repeat marker labeled with digoxigenin (1558196, Boehringer Mannheim). The pHY2.1 fragment hybridizes with a 2000-copy tandem repeat on the long arm of the Y chromosome.17 The slides were dehydrated in ethanol, air dried, then incubated with hybridization solution containing 2× saline sodium citrate (1× saline sodium citrate is 0.15 M sodium chloride and 0.015 M sodium citrate), 50 percent formamide, 10 percent dextran sulfate, 1 mg of salmon-sperm DNA per milliliter, and 1 μg of digoxigenin-labeled probe per milliliter. Denaturation for 10 minutes at 72°C was followed by incubation overnight at 37°C. The following morning, unbound probe was washed off with 2× saline sodium citrate at 37°C. Subsequent detection steps were performed as described previously.18 Nuclei were counterstained with methyl green, then the slides were cover-slipped with light mineral oil in order to preserve both solvent-soluble and water-soluble components.
Statistical Analysis
Each blue-stained nucleus was interpreted as indicating a mesenchymal cell (myofibroblast or smooth-muscle cell) if it was surrounded by red-stained smooth-muscle α-actin. Staining for the Y chromosome was considered to be positive if a clear dark blue–black signal in the nucleus could be detected. The analysis was performed by an observer who was unaware of the patients' histories. The presence or absence of smooth-muscle α-actin and the Y chromosome was recorded for each nucleus counted in the neointima, perivascular adventitia, and peritubular interstitium, for a total of up to 1000 cells. Differences between groups were analyzed with use of a two-tailed unpaired t-test.
Results
We studied 14 renal-biopsy specimens with the typical vascular and interstitial changes of chronic rejection. Two specimens each were from female recipients of an allograft from a female donor and from male recipients of an allograft from a male donor, four specimens were from female recipients of an allograft from a male donor, and six specimens from male recipients of an allograft from a female donor. The underlying reason or reasons for transplantation were diabetes mellitus in six patients, glomerulonephritis in six, polycystic kidney disease in four, hypertensive nephrosclerosis in three, chronic pyelonephritis in two, obstructive uropathy in one, and unknown disease in one.
The results are summarized in Table 1Table 1
Percentage of Mesenchymal Cells That Were Positive for the Y-Chromosome Body.. In renal-allograft specimens from the four female patients with male donors, we found clear evidence of infiltration of the neointima, adventitia, and interstitium by mesenchymal cells of donor (male) origin. These allografts also demonstrated a population of male mesenchymal cells.The Y-chromosome body was clearly distinguishable in approximately 40 percent of the tubular, interstitial, and neointimal mesenchymal cells in the grafts from male donors that had been transplanted into male recipients (Figure 1AFigure 1
Results of Combined Immunostaining for Smooth-Muscle α-Actin (Red Cytoplasm) and in Situ Hybridization for the Y-Chromosome Body (Black Nuclear Signal) (×325). and Table 1). Although the analysis was performed in a blinded fashion, a kidney-biopsy specimen from a male donor was immediately obvious on cursory inspection of the tubular-cell nuclei. In renal-allograft specimens in which both the donor and the recipient were female, the Y-chromosome body was always absent (Figure 1B and Table 1).In cases in which the donor was female and the recipient was male, the presence of Y-chromosome bodies in cells infiltrating the renal-allograft specimen was also obvious. In such cases, a mean (±SD) of 34±16 percent of the neointimal smooth-muscle cells in the renal-allograft specimens clearly expressed the Y-chromosomal signal (Figure 1C and Table 1). In cases in which the donor was male and the recipient was female, a mean of 24±15 percent of neointimal smooth-muscle cells in the renal-allograft specimens were of male origin (Figure 1D and Table 1).
In cases in which the donor was female and the recipient was male, a mean of 38±12 percent of perivascular interstitial smooth-muscle cells in the renal-allograft specimens were of male origin, whereas in cases in which the donor was male and the recipient was female, a mean of 33±9 percent were of male origin (Table 1). In specimens from male recipients of allografts from female donors, the Y-chromosome body was present in a mean of 30±7 percent of the smooth-muscle cells in the renal interstitium (Figure 2AFigure 2
Results of Combined Immunostaining for Smooth-Muscle α-Actin and in Situ Hybridization for the Y-Chromosome Body in Tubulointerstitium (×400). and Table 1). In cases in which the donor was male and the recipient was female, a mean of 23±8 percent of mesenchymal cells in the interstitium of the renal-allograft specimens showed the Y-chromosomal signal (Figure 2B).In cases in which both the donor and the recipient were male or were female and in cases in which the donor was male and the recipient was female, the tubular cells in the renal-allograft specimens reflected the sex of the donor. In cases in which the donor was female and the recipient was male, a small number of male cells (4±2 percent) were seen within the confines of the tubular basement membrane in the renal-allograft specimens. These cells were not positive for smooth-muscle α-actin and resembled mononuclear inflammatory cells morphologically. This result probably represents invasion of the tubule by the recipient's immune cells (tubulitis).
In biopsy specimens obtained from patients without chronic rejection, there was no vascular neointima to examine. In cases in which the donor was male and the recipient was female, 30 percent of smooth-muscle cells in the interstitium of the renal-allograft specimens demonstrated a Y-chromosome body. In cases in which the donor was female and the recipient was male, 10 percent of the smooth-muscle cells in the interstitium of the renal-allograft specimens demonstrated a Y-chromosome body; this value was significantly less than the value found in the corresponding group with chronic rejection (10 percent vs. 30 percent, P<0.001).
Discussion
We found that recipient-derived mesenchymal cells infiltrated the neointima, adventitia, and tubulointerstitial compartments of renal transplants undergoing chronic rejection. These results provide evidence that a circulating mesenchymal cell has the potential to colonize an allograft. This information may lead to the development of ways to prevent and treat chronic rejection.
In chronic renal-allograft rejection, the vascular neointima consists of an infiltrate of lymphoid and mesenchymal (smooth-muscle) cells. As is the case in atherosclerosis in native organs, medial smooth-muscle cells are thought to migrate through breaks in the internal elastic lamina to the neointima.19 In animal models of aortic and femoral-artery transplants, the neointimal smooth-muscle cells found during chronic rejection of these grafts are of host origin.10,11 Our study shows that in humans with chronic rejection, smooth-muscle cells of host origin are also present in the vascular neointima of the renal allograft. Whether these cells derive from precursors that migrate directly into the neointima or initially colonize the adventitia or perivascular interstitium before they migrate through the media to the neointima is unknown.
Another critical lesion in chronic rejection is interstitial fibrosis, the development and progression of which require smooth muscle thought to derive from local sources.5,20 Our data show that mesenchymal cells of host origin infiltrate not only the neointima but also the perivascular and interstitial components of an allograft undergoing chronic rejection.
Whether the mesenchymal cells of the donor are entirely replaced by those of the recipient over time, as has been shown in untreated animal allografts,21 is unknown. We found that a large proportion of the mesenchymal cells in allografts undergoing chronic rejection were of donor origin. The persistence of donor mesenchymal cells may be due to immunosuppression with cyclosporine.21 In our study, all but two of the biopsy specimens were obtained within six months after transplantation, at which time cyclosporine levels are relatively high. Alternatively, the persistence of donor cells in the vessels and interstitium may be related to the short interval between transplantation and the biopsy.
Our findings suggest the existence of a circulating mesenchymal precursor cell. Indeed, Bucala et al. have provided evidence of the existence of a circulating fibroblastic stem cell.22 In their study, subcutaneous wound-viewing chambers became colonized with a circulating population of CD34+ fibrocytes. Moreover, other investigators have shown that smooth-muscle cells can be generated by human stromal cell lines derived from bone marrow,23 and human mesenchymal progenitor cells have been transferred by bone marrow transplantation.24 Myofibroblasts that appear soon after the onset of an episode of asthma are thought to originate from a circulating pool25 or to be the result of the activation or proliferation of a local precursor cell.26
Our study raises the question whether controlling the migration of smooth-muscle cells may prevent or ameliorate chronic rejection. An interesting possibility in this regard is the inhibition of local signaling of hyaluronan to smooth-muscle cells. These signals control proliferation and motility mediated through CD44 and the receptor for hyaluronan-mediated motility in smooth-muscle cells.27,28 This receptor is widely expressed in renal allografts undergoing chronic rejection, and in these allografts, the sequestration of hyaluronan alters the fibrotic response that follows tissue injury.29,30 These mesenchymal signaling molecules may represent targets for the blockade of smooth-muscle–dependent remodeling processes.
Supported by grants from the Baxter Extramural Grant Program of the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases [R21 DK53610-01] and National Institute of Allergy and Infectious Diseases [RO1-AI43655-02]) and by the Children's Hospital of Winnipeg Research Foundation. Dr. Nickerson is the recipient of a Medical Research Council of Canada Scholarship.
We are indebted to Stacey Benzick, B.Sc., and Mr. John Tutt for invaluable and creative technical assistance.
Source Information
From the Department of Pediatrics, University of California at San Diego, San Diego (P.C.G.); the Departments of Internal Medicine (P.N., J.J., R.M.M., E.S., D.N.R.) and Pathology (J.G.), University of Manitoba, Winnipeg, Canada; and the Department of Pediatrics, University of Pennsylvania, Philadelphia (R.C.S.).
Address reprint requests to Dr. Grimm at the Department of Pediatrics, UCSD, 9500 Gilman Dr., MC 0831, La Jolla, CA 92093-0831, or at pgrimm@ucsd.edu.
- References
References
1
Pethig K ,Heublein B ,Wahlers T ,Haverich A . Mechanism of luminal narrowing in cardiac allograft vasculopathy: inadequate vascular remodeling rather than intimal hyperplasia is the major predictor of coronary artery stenosis. Am Heart J 1998;135:628-633
CrossRef | Web of Science | Medline2
Shi Y ,Pieniek M ,Fard A ,O'Brien J ,Mannion JD ,Zalewski A . Adventitial remodeling after coronary arterial injury. Circulation 1996;93:340-348
Web of Science | Medline3
Solez K . International standardization of criteria for histologic diagnosis of chronic rejection in renal allografts. Clin Transplant 1994;8:345-350
Web of Science | Medline4
Katoh Y ,Periasamy M . Growth and differentiation of smooth muscle cells during vascular development. Trends Cardiovasc Med 1996;6:100-106
CrossRef | Web of Science | Medline5
Pedagogos E ,Hewitson TD ,Walker RG ,Nicholis KM ,Becker GJ . Myofibroblast involvement in chronic transplant rejection. Transplantation 1997;64:1192-1197
CrossRef | Web of Science | Medline6
Salomon RN ,Hughes CC ,Schoen FJ ,Payne DD ,Pober JS ,Libby P . Human coronary transplantation-associated arteriosclerosis: evidence for a chronic immune reaction to activated graft endothelial cells. Am J Pathol 1991;138:791-798
Web of Science | Medline7
Andersen CB ,Ladefoged SD ,Larsen S . Cellular inflammatory infiltrates and renal cell turnover in kidney allografts: a study using in situ hybridization and combined in situ hybridization and immunohistochemistry with a Y-chromosome-specific DNA probe and monoclonal antibodies. APMIS 1991;99:645-652
CrossRef | Web of Science | Medline8
Huynh T ,Abraham G ,Murray J ,Brockbank K ,Hagen PO ,Sullivan S . Remodeling of an acellular collagen graft into a physiologically responsive neovessel. Nat Biotechnol 1999;17:1083-1086
CrossRef | Web of Science | Medline9
Akyurek LM ,Paul LC ,Funa K ,Larsson E ,Fellstrom BC . Smooth muscle cell migration into intima and adventitia during development of transplant vasculopathy. Transplantation 1996;62:1526-1529
CrossRef | Web of Science | Medline10
Brazelton T ,Adams B ,Shorthouse R ,Morris R . Chronic rejection: the result of uncontrolled remodelling of graft tissue by recipient mesenchymal cells? Data from two rodent models and the effects of immunosuppressive therapies. Inflamm Res 1999;48:Suppl 2:S134-S135
CrossRef | Web of Science | Medline11
Plissonnier D ,Nochy D ,Poncet P , et al. Sequential immunological targeting of chronic experimental arterial allograft. Transplantation 1995;60:414-424
CrossRef | Web of Science | Medline12
Rush DN ,Henry SF ,Jeffery JR ,Schroeder TJ ,Gough J . Histological findings in early routine biopsies of stable renal allograft recipients. Transplantation 1994;57:208-211
CrossRef | Web of Science | Medline13
Rush DN ,Nickerson P ,Gough J , et al. Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 1998;9:2129-2134
Web of Science | Medline14
Solez K ,Axelsen RA ,Benediktsson H , et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int 1993;44:411-422
CrossRef | Web of Science | Medline15
Skalli O ,Vandekerckhove J ,Gabbiani G . Actin-isoform pattern as a marker of normal or pathological smooth-muscle and fibroblastic tissues. Differentiation 1987;33:232-238
CrossRef | Web of Science | Medline16
Grimm PC ,McKenna R ,Nickerson P , et al. Clinical rejection is distinguished from subclinical rejection by increased infiltration by a population of activated macrophages. J Am Soc Nephrol 1999;10:1582-1589
Web of Science | Medline17
Cooke HJ ,Schmidtke J ,Gosden JR . Characterisation of a human Y chromosome repeated sequence and related sequences in higher primates. Chromosoma 1982;87:491-502
CrossRef | Web of Science | Medline18
Grimm PC ,McKenna RM ,Gospodarek EM ,Jeffery JR ,Rush DN . Low frequency of infiltrating cells intensely expressing T cell cytokine mRNA in human renal allograft rejection. Transplantation 1995;59:579-584
Web of Science | Medline19
Geraghty JG ,Stoltenberg RL ,Sollinger HW ,Hullett DA . Vascular smooth muscle cells and neointimal hyperplasia in chronic transplant rejection. Transplantation 1996;62:502-509
CrossRef | Web of Science | Medline20
Ng YY ,Huang TP ,Yang WC , et al. Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int 1998;54:864-876
CrossRef | Web of Science | Medline21
Brazelton T ,Shorthouse R ,Huang X ,Morris R . Efficacy of immunosuppressive agents corresponds to their ability to maintain donor tissue phenotype in allografted tracheas. J Heart Lung Transplant 1997;16:72-7222
Bucala R ,Spiegel LA ,Chesney J ,Hogan M ,Cerami A . Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1994;1:71-81
Web of Science | Medline23
Li J ,Sensebe L ,Herve P ,Charbord P . Nontransformed colony-derived stromal cell lines from normal human marrows. II. Phenotypic characterization and differentiation pathway. Exp Hematol 1995;23:133-141
Web of Science | Medline24
Horwitz EM ,Prockop DJ ,Fitzpatrick LA , et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999;5:309-313
CrossRef | Web of Science | Medline25
Gizycki MJ ,Adelroth E ,Rogers AV ,O'Byrne PM ,Jeffery PK . Myofibroblast involvement in the allergen-induced late response in mild atopic asthma. Am J Respir Cell Mol Biol 1997;16:664-673
Web of Science | Medline26
Elias JA ,Zhu Z ,Chupp G ,Homer RJ . Airway remodeling in asthma. J Clin Invest 1999;104:1001-1006
CrossRef | Web of Science | Medline27
Jain M ,He Q ,Lee W-S , et al. Role of CD44 in the reaction of vascular smooth muscle cells to arterial wall injury. J Clin Invest 1996;97:596-603
CrossRef | Web of Science | Medline28
Savani RC ,Wang C ,Yang B , et al. Migration of bovine aortic smooth muscle cells following wounding injury: the role of hyaluronan and RHAMM. J Clin Invest 1995;95:1158-1168
CrossRef | Web of Science | Medline29
Routledge MW ,Rush D ,McKenna R , et al. The receptor for hyaluronan-mediated motility is expressed in human renal allografts and is correlated with Banff chronic rejection scores. Transplant Proc 1997;29:2603-2604
CrossRef | Web of Science | Medline30
Savani RC ,Khalil N ,Turley EA . Hyaluronan receptor antagonists alter skin inflammation and fibrosis following injury. Proc West Pharmacol Soc 1995;38:131-136
Medline
- Citing Articles (95)
Citing Articles
1
S.-m. Song, C.-c. Wang, S.-h. Qi, L. Xing, B.-f. Yang, T. Oite, B. Li. (2011) Angiotensin receptor blockade attenuates glomerulosclerosis progression by promoting VEGF expression and bone marrow-derived cells recruitment. Nephrology Dialysis Transplantation
CrossRef2
Nicolas Roux, Ebba Brakenhielm, Caroline Freguin-Bouillant, Françoise Lallemand, Jean-Paul Henry, Olivier Boyer, Christian Thuillez, Didier Plisonnier. (2011) Progenitor Cell Mobilizing Treatments Prevent Experimental Transplant Arteriosclerosis. Journal of Surgical Research
CrossRef3
Peter J Nelson, Christine von Toerne, Hermann-Josef Gröne. (2011) Wnt-signaling pathways in progressive renal fibrosis. Expert Opinion on Therapeutic Targets 15:9, 1073-1083
CrossRef4
Barry Kahan. (2011) Toxicity spectrum of inhibitors of mammalian target of rapamycin in organ transplantation: etiology, pathogenesis and treatment. Expert Opinion on Drug Safety 10:5, 727-749
CrossRef5
Paola Campagnolo, Mei Mei Wong, Qingbo Xu. (2011) Progenitor Cells in Arteriosclerosis: Good or Bad Guys?. Antioxidants & Redox Signaling 15:4, 1013-1027
CrossRef6
Caroline Freguin-Bouilland, Bassam Alkhatib, Nathalie David, Françoise Lallemand, Jean Paul Bessou, Olivier Boyer, Christian Thuillez, Didier Plissonnier. (2011) Syngeneic Bone Marrow Cell Therapy Prevents Intimal Proliferation in Allogeneic Vascular Transplantation. Journal of Surgical Research 168:1, 143-148
CrossRef7
Soma Meran, Robert Steadman. (2011) Fibroblasts and myofibroblasts in renal fibrosis. International Journal of Experimental Pathology 92:3, 158-167
CrossRef8
William R Otto, Nicholas A Wright. (2011) Mesenchymal stem cells: from experiment to clinic. Fibrogenesis & Tissue Repair 4:1, 20
CrossRef9
Niloufar Safinia, Behdad Afzali, Kerem Atalar, Giovanna Lombardi, Robert I Lechler. (2010) T-cell alloimmunity and chronic allograft dysfunction. Kidney International 78, S2-S12
CrossRef10
Mathilde Soulez, Isabelle Sirois, Nathalie Brassard, Marc-André Raymond, Frédéric Nicodème, Nicolas Noiseux, Yves Durocher, Alexei V. Pshezhetsky, Marie-Josée Hébert. (2010) Epidermal Growth Factor and Perlecan Fragments Produced by Apoptotic Endothelial Cells Co-Ordinately Activate ERK1/2-Dependent Antiapoptotic Pathways in Mesenchymal Stem Cells. STEM CELLS 28:4, 810-820
CrossRef11
Hong Zebger-Gong, Jan Kampmann, Linghua Kong, Jan Roigas, Kerstin Sommer, Uwe Hoff, Stephanie Krämer, Harm Peters, Dominik Müller, Duska Dragun, Uwe Querfeld. (2010) Decreased Transplant Arteriosclerosis in Endothelial Nitric Oxide Synthase-Deficient Mice. Transplantation 89:5, 518-526
CrossRef12
Gary S Hill, Dominique Nochy, Alexandre Loupy. (2010) Accelerated arteriosclerosis: a form of transplant arteriopathy. Current Opinion in Organ Transplantation 15:1, 11-15
CrossRef13
Michael Hart-Matyas, Sara Nejat, Julie L. Jordan, Gregory M. Hirsch, Timothy D.G. Lee. (2010) IFN-γ and Fas/FasL pathways cooperate to induce medial cell loss and neointimal lesion formation in allograft vasculopathy. Transplant Immunology 22:3-4, 157-164
CrossRef14
Sophie Ferlicot, Amélia Vernochet, Serge Romana, Monique Ortin-Serrano, Alexia Letierce, Olivier Brégerie, Antoine Durrbach, Catherine Guettier. (2010) Microchimerism in renal allografts: clinicopathological associations according to the type of chimeric cells. Histopathology 56:2, 188-197
CrossRef15
Elizabeth Ingulli. (2010) Mechanism of cellular rejection in transplantation. Pediatric Nephrology 25:1, 61-74
CrossRef16
Miriam Boersema, Heleen Rienstra, Marius van den Heuvel, Harry van Goor, Marja J. A. van Luyn, Gerjan J. Navis, Eliane R. Popa, Jan-Luuk Hillebrands. (2009) Donor and Recipient Contribution to Transplant Vasculopathy in Chronic Renal Transplant Dysfunction. Transplantation 88:12, 1386-1392
CrossRef17
Amr M. Zaki, Gregory M. Hirsch, Timothy D.G. Lee. (2009) Contribution of pre-existing vascular disease to allograft vasculopathy in a murine model. Transplant Immunology 22:1-2, 93-98
CrossRef18
Bryan N Becker, Sean B Fain, Elizabeth A Sadowski, Arjang Djamali, Jonathan B Jaffery, Lynn M Jacobson. (2009) Endothelium in the allograft. Kidney International
CrossRef19
I. Stroo, G. Stokman, G. J. D. Teske, S. Florquin, J. C. Leemans. (2009) Haematopoietic stem cell migration to the ischemic damaged kidney is not altered by manipulating the SDF-1/CXCR4-axis. Nephrology Dialysis Transplantation 24:7, 2082-2088
CrossRef20
Rachel Zubko, William Frishman. (2009) Stem Cell Therapy for the Kidney?. American Journal of Therapeutics 16:3, 247-256
CrossRef21
Achal S. Achrol, Raphael Guzman, Marco Lee, Gary K. Steinberg. (2009) Pathophysiology and genetic factors in moyamoya disease. Neurosurgical FOCUS 26:4, E4
CrossRef22
Meindert Crop, Carla Baan, Willem Weimar, Martin Hoogduijn. (2009) Potential of mesenchymal stem cells as immune therapy in solid-organ transplantation. Transplant International 22:4, 365-376
CrossRef23
H. Rienstra, M. Boersema, G. Onuta, M. W. Boer, A. Zandvoort, M. van Riezen, J. Rozing, H. van Goor, G. J. Navis, E. R. Popa, J. L. Hillebrands. (2009) Donor and Recipient Origin of Mesenchymal and Endothelial Cells in Chronic Renal Allograft Remodeling. American Journal of Transplantation 9:3, 463-472
CrossRef24
Richard N. Mitchell. (2009) Graft Vascular Disease: Immune Response Meets the Vessel Wall. Annual Review of Pathology: Mechanisms of Disease 4:1, 19-47
CrossRef25
David Wu, Quynh Vu, Anhthu Nguyen, James R Stone, Hannah Stubbs, Georgiana Kuhlmann, Lynette M Sholl, A John Iafrate. (2009) In situ genetic analysis of cellular chimerism. Nature Medicine 15:2, 215-219
CrossRef26
Kuniko KIMURA, Masayuki IWANO. (2009) Molecular mechanisms of tissue fibrosis. Japanese Journal of Clinical Immunology 32:3, 160-167
CrossRef27
Shuei-Liong Lin, Tatiana Kisseleva, David A. Brenner, Jeremy S. Duffield. (2008) Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney. The American Journal of Pathology 173:6, 1617-1627
CrossRef28
Sharon D. Ricardo, Harry van Goor, Allison A. Eddy. (2008) Macrophage diversity in renal injury and repair. Journal of Clinical Investigation 118:11, 3522-3530
CrossRef29
M Refik Gökmen, Giovanna Lombardi, Robert I Lechler. (2008) The importance of the indirect pathway of allorecognition in clinical transplantation. Current Opinion in Immunology 20:5, 568-574
CrossRef30
Kathleen D. Liu, Paul R. Brakeman. (2008) Renal repair and recovery. Critical Care Medicine 36:Suppl, S187-S192
CrossRef31
Antonia Loverre, Carmen Capobianco, Pasquale Ditonno, Michele Battaglia, Giuseppe Grandaliano, Francesco Paolo Schena. (2008) Increase of Proliferating Renal Progenitor Cells in Acute Tubular Necrosis Underlying Delayed Graft Function. Transplantation 85:8, 1112-1119
CrossRef32
Wey-Ran Lin, Mairi Brittan, Malcolm R. Alison. (2008) The Role of Bone Marrow-Derived Cells in Fibrosis. Cells Tissues Organs 188:1-2, 178-188
CrossRef33
Brian J. Nankivell. 2008. Chronic Allograft Nephropathy. , 416-438.
CrossRef34
T D Hewitson. (2007) Collecting duct epithelium and injury: Not all cells are created equal. Kidney International 72:8, 914-915
CrossRef35
Martine Broekema, Martin C. Harmsen, Jasper A. Koerts, Theo G. van Kooten, Gerjan Navis, Marja J. A. van Luyn, Eliane R. Popa. (2007) Tubular Engraftment and Myofibroblast Differentiation of Recipient-Derived Cells After Experimental Kidney Transplantation. Transplantation 84:8, 1003-1011
CrossRef36
S. François, M. Mouiseddine, A. Semont, J. Frick, A. Saché, D. Thierry, P. Voisin, N.-C. Gorin, P. Gourmelon, A. Chapel. (2007) Thérapie cellulaire par cellules souches mésenchymateuses d’une atteinte multi-organes induite par une irradiation gamma : un modèle expérimental. Radioprotection 42:3, 351-367
CrossRef37
Caroline Fr??guin-Bouilland, Bassam Alkhatib, Nathalie David, Fran??oise Lallemand, Jean-Paul Henry, Michel Godin, Christian Thuillez, Didier Plissonnier. (2007) Low Molecular Weight Fucoidan Prevents Neointimal Hyperplasia After Aortic Allografting. Transplantation 83:9, 1234-1241
CrossRef38
T.-H. Yen, M. R. Alison, H. T. Cook, R. Jeffery, W. R. Otto, N. A. Wright, R. Poulsom. (2007) The cellular origin and proliferative status of regenerating renal parenchyma after mercuric chloride damage and erythropoietin treatment. Cell Proliferation 40:2, 143-156
CrossRef39
Jinhua Li, James A. Deane, Naomi V. Campanale, John F. Bertram, Sharon D. Ricardo. (2007) The Contribution of Bone Marrow-Derived Cells to the Development of Renal Interstitial Fibrosis. STEM CELLS 25:3, 697-706
CrossRef40
Shi-ping Luh, Chi-huei Chiang. (2007) Acute lung injury/acute respiratory distress syndrome (ALI/ARDS): the mechanism, present strategies and future perspectives of therapies. Journal of Zhejiang University SCIENCE B 8:1, 60-69
CrossRef41
O. Cheng, R. Thuillier, E. Sampson, G. Schultz, P. Ruiz, X. Zhang, P.S.T. Yuen, R.B. Mannon. (2006) Connective Tissue Growth Factor is a Biomarker and Mediator of Kidney Allograft Fibrosis. American Journal of Transplantation 6:10, 2292-2306
CrossRef42
G. Wieczorek, M. Bigaud, K. Menninger, S. Riesen, V. Quesniaux, H.-J. Schuurman, M. Audet, A. Blancher, M. J. Mihatsch, V. Nickeleit. (2006) Acute and Chronic Vascular Rejection in Nonhuman Primate Kidney Transplantation. American Journal of Transplantation 6:6, 1285-1296
CrossRef43
Pekka Häyry, Serdar Yilmaz, Joannis Vamvakopoulos, Einari Aavik. (2006) Pathology and pathophysiology of chronic rejection. Current Opinion in Organ Transplantation 11:3, 296-303
CrossRef44
T. Q. Nguyen, H. Chon, F. A. Nieuwenhoven, B. Braam, M. C. Verhaar, R. Goldschmeding. (2006) Myofibroblast progenitor cells are increased in number in patients with type 1 diabetes and express less bone morphogenetic protein 6: a novel clue to adverse tissue remodelling?. Diabetologia 49:5, 1039-1048
CrossRef45
R. B. Mannon. (2006) Therapeutic Targets in the Treatment of Allograft Fibrosis. American Journal of Transplantation 6:5p1, 867-875
CrossRef46
Tetsufumi Yamamoto, Masataka Sata, Daiju Fukuda, Shinichi Takamoto. (2006) The Angiotensin II Type 1 Receptor Blocker Candesartan Attenuates Graft Vasculopathy. Journal of Surgical Research 132:1, 62-68
CrossRef47
Sabine François, Morad Bensidhoum, Moubarak Mouiseddine, Christelle Mazurier, Bénédicte Allenet, Alexandra Semont, Johanna Frick, Amandine Saché, Sandrine Bouchet, Dominique Thierry, Patrick Gourmelon, Norbert-Claude Gorin, Alain Chapel. (2006) Local Irradiation Not Only Induces Homing of Human Mesenchymal Stem Cells at Exposed Sites but Promotes Their Widespread Engraftment to Multiple Organs: A Study of Their Quantitative Distribution After Irradiation Damage. Stem Cells 24:4, 1020-1029
CrossRef48
Yichao Wu, Zhihong Liu, Shuming Ji, Jingsong Chen, Caihong Zeng, Leishi Li. (2006) Recipient-Derived Cells in the Tissue Repair of Renal Allografts. Transplantation 81:5, 756-759
CrossRef49
B Li, T Morioka, M Uchiyama, T Oite. (2006) Bone marrow cell infusion ameliorates progressive glomerulosclerosis in an experimental rat model. Kidney International 69:2, 323-330
CrossRef50
James F. George, Laura J. Pinderski, Silvio Litovsky, James K. Kirklin. (2005) Of Mice and Men: Mouse Models and the Molecular Mechanisms of Post-transplant Coronary Artery Disease. The Journal of Heart and Lung Transplantation 24:12, 2003-2014
CrossRef51
SIMONE A JOOSTEN, YVO W J SIJPKENS, CEES VAN KOOTEN, LEENDERT C PAUL. (2005) Chronic renal allograft rejection: Pathophysiologic considerations. Kidney International 68:1, 1-13
CrossRef52
Masataka Sata, Daiju Fukuda, Kimie Tanaka, Yukari Kaneda, Hisako Yashiro, Ibuki Shirakawa. (2005) The role of circulating precursors in vascular repair and lesion formation. Journal of Cellular and Molecular Medicine 9:3, 557-568
CrossRef53
SHARON D RICARDO, JAMES A DEANE. (2005) Adult stem cells in renal injury and repair (Review Article). Nephrology 10:3, 276-282
CrossRef54
Björn Hegner, Manfred Weber, Duska Dragun, Eckhard Schulze-Lohoff. (2005) Differential regulation of smooth muscle markers in human bone marrow-derived mesenchymal stem cells. Journal of Hypertension 23:6, 1191-1202
CrossRef55
Marije Koopmans, Idske C. L. Kremer Hovinga, Hans J. Baelde, Rosette J. Fernandes, Emile de Heer, Jan A. Bruijn, Ingeborg M. Bajema. (2005) Chimerism in Kidneys, Livers and Hearts of Normal Women: Implications for Transplantation Studies. American Journal of Transplantation 5:6, 1495-1502
CrossRef56
Shunya Matsuo, Jesus M. Lopez-Guisa, Xiaohe Cai, Daryl M. Okamura, Charles E. Alpers, Roger E. Bumgarner, Mette A. Peters, Guoqiang Zhang, Allison A. Eddy. (2005) Multifunctionality of PAI-1 in fibrogenesis: Evidence from obstructive nephropathy in PAI-1-overexpressing mice1. Kidney International 67:6, 2221-2238
CrossRef57
Yuichi Tanaka, Hironori Haga, Hiroto Egawa, Tomoko Okuno, Aya Miyagawa-Hayashino, Tatsuaki Tsuruyama, Michiyo Kambe, Hiroyuki Marusawa, Tsutomu Chiba, Toshiaki Manabe. (2005) Intragraft expression of recipient-type ABO blood group antigens: Long-term follow-up and histological features after liver transplantation. Liver Transplantation 11:5, 547-554
CrossRef58
Winson Y. Cheung, Ian W. Gibson, David Rush, John Jeffery, Martin Karpinski. (2005) Late Recurrence of Scleroderma Renal Crisis in a Renal Transplant Recipient Despite Angiotensin II Blockade. American Journal of Kidney Diseases 45:5, 930-934
CrossRef59
Benedicte Puissant, Corinne Barreau, Philippe Bourin, Cyril Clavel, Jill Corre, Christine Bousquet, Christine Taureau, Beatrice Cousin, Michel Abbal, Patrick Laharrague, Luc Penicaud, Louis Casteilla, Antoine Blancher. (2005) Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. British Journal of Haematology 129:1, 118-129
CrossRef60
Anton I. Skaro, Robert S. Liwski, Jennifer O'Neill, Ellen L. Vessie, Juan Zhou, Gregory M. Hirsch, Timothy D.G. Lee. (2005) Impairment of recipient cytolytic activity attenuates allograft vasculopathy. Transplant Immunology 14:1, 27-35
CrossRef61
Toshio Heike, Tatsutoshi Nakahata. (2005) Stem cell plasticity in hematopoietic system. Ensho Saisei 25:2, 90-101
CrossRef62
Michael Mengel, Danny Jonigk, Ludwig Wilkens, Jörg Radermacher, Reinhard von Wasielewski, Ulrich Lehmann, Hermann Haller, Michael Mihatsch, Hans Kreipe. (2004) Chimerism of Metanephric Adenoma but Not of Carcinoma in Kidney Transplants. The American Journal of Pathology 165:6, 2079-2085
CrossRef63
F. Anglani, M. Forino, D. Del Prete, E. Tosetto, R. Torregrossa, A. D'Angelo. (2004) In search of adult renal stem cells. Journal of Cellular and Molecular Medicine 8:4, 474-487
CrossRef64
Michael Mengel, Ulrich Lehmann, Danny Jonigk, Wolfram Kleeberger, Hans Kreipe. (2004) Role of stem cell trafficking and donor???recipient cellular chimerism in lung transplantation. Current Opinion in Organ Transplantation 9:3, 332-336
CrossRef65
Te-Chao Fang, Malcolm R. Alison, Nicholas A. Wright, Richard Poulsom. (2004) Adult stem cell plasticity: will engineered tissues be rejected?. International Journal of Experimental Pathology 85:3, 115-124
CrossRef66
Simone A Joosten, Yvo W.J Sijpkens, Cees van Kooten, Leendert C Paul. (2004) Chronic rejection in renal transplantation. Transplantation Reviews 18:2, 86-95
CrossRef67
C.A Roufosse, N.C Direkze, W.R Otto, N.A Wright. (2004) Circulating mesenchymal stem cells. The International Journal of Biochemistry & Cell Biology 36:4, 585-597
CrossRef68
Aya Miyagawa-Hayashino, Tatsuaki Tsuruyama, Hironori Haga, Fimitaka Oike, Kim Il-Deok, Hiroto Egawa, Hiroshi Hiai, Koichi Tanaka, Toshiaki Manabe. (2004) Arteriopathy in chronic allograft rejection in liver transplantation. Liver Transplantation 10:4, 513-519
CrossRef69
Matthew R Weir. (2004) Blood pressure management in the kidney transplant recipient. Advances in Chronic Kidney Disease 11:2, 172-183
CrossRef70
Masataka Sata. (2004) Circulating progenitor cells contribute to vascular repair, remodeling and lesion formation. Ensho Saisei 24:1, 27-34
CrossRef71
Toshio Heike, Tatsutoshi Nakahata. (2004) Stem Cell Plasticity in the Hematopoietic System. International Journal of Hematology 79:1, 7-14
CrossRef72
Juan A Oliver. (2004) Adult renal stem cells and renal repair. Current Opinion in Nephrology and Hypertension 13:1, 17-22
CrossRef73
Daniel J Mollura, Joshua M Hare, Hamid Rabb. (2003) Stem-cell therapy for renal diseases. American Journal of Kidney Diseases 42:5, 891-905
CrossRef74
Te-Chao Fang, Richard Poulsom. (2003) Cell-based therapies for birth defects: A role for adult stem cell plasticity?. Birth Defects Research Part C: Embryo Today: Reviews 69:3, 238-249
CrossRef75
Gordon D. Wu, Tai-Lan Tuan, Michael E. Bowdish, Yang-Sun Jin, Vaughn A. Starnes, Donald V. Cramer, Mark L. Barr. (2003) Evidence for recipient derived fibroblast recruitment and activation during the development of chronic cardiac allograft rejection1. Transplantation 76:3, 609-614
CrossRef76
Christopher R. Cogle, Steven M. Guthrie, Ronald C. Sanders, William L. Allen, Edward W. Scott, Bryon E. Petersen. (2003) An Overview of Stem Cell Research and Regulatory Issues. Mayo Clinic Proceedings 78:8, 993-1003
CrossRef77
C. R. Cogle, S. M. Guthrie, R. C. Sanders, W. L. Allen, E. W. Scott, B. E. Petersen. (2003) An Overview of Stem Cell Research and Regulatory Issues. Mayo Clinic Proceedings 78:8, 993-1003
CrossRef78
Sujata Kale, Anil Karihaloo, Paul R. Clark, Michael Kashgarian, Diane S. Krause, Lloyd G. Cantley. (2003) Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. Journal of Clinical Investigation 112:1, 42-49
CrossRef79
Heinz Regele, Georg A. Böhmig. (2003) Tissue injury and repair in allografts: novel perspectives. Current Opinion in Nephrology and Hypertension 12:3, 259-266
CrossRef80
Koichi Shimizu, Richard N. Mitchell. (2003) Stem cell origins of intimal cells in graft arterial disease. Current Atherosclerosis Reports 5:3, 230-237
CrossRef81
Peter S. Heeger. (2003) T-Cell Allorecognition and Transplant Rejection: A Summary and Update. American Journal of Transplantation 3:5, 525-533
CrossRef82
Shigeru Horita, Kosaku Nitta, Kazunari Tanabe, Hirosha Nihei, Hiroshi Toma, Yutaka Yamaguchi. (2003) Endothelial chimerism in association with vascular rejection in patients after kidney transplantation. Kidney International 63:5, 1960-1960
CrossRef83
Gordon D. Wu, Jan A. Nolta, Yang-Sun Jin, Mark L. Barr, Hong Yu, Vaughn A. Starnes, Donald V. Cramer. (2003) Migration of mesenchymal stem cells to heart allografts during chronic rejection. Transplantation 75:5, 679-685
CrossRef84
Koichi Shimizu, Richard N. Mitchell. (2003) Chemokine-mediated recruitment of inflammatory and smooth muscle cells in transplant-associated arteriosclerosis. Current Opinion in Organ Transplantation 8:1, 55-63
CrossRef85
Masataka Sata. (2003) Molecular Strategies to Treat Vascular Diseases. Circulation Journal 67:12, 983-991
CrossRef86
Masataka Sata, Ryozo Nagai. (2003) Bone marrow-derived vascular progenitor cells contribute to vascular remodeling.. Ensho Saisei 23:1, 44-50
CrossRef87
Koutaro Yokote, Ayako Take, Chiaki Nakaseko, Kazuki Kobayashi, Masaki Fujimoto, Harukiyo Kawamura, Yoshiro Maezawa, Miki Nishimura, Seijiro Mori, Yasushi Saito. (2003) Bone Marrow-derived Vascular Cells in Response to Injury.. Journal of Atherosclerosis and Thrombosis 10:4, 205-210
CrossRef88
G. V. Ramesh Prasad, Dushanthi Pinnaduwage, Robert K. Parkes, Julian Midgley, J. Williamson Balfe, Robert A. Hegele, Shelley B. Bull, Edward H. Cole, Alexander G. Logan. (2003) Angiotensinogen M235T genotype predicts progression in chronic renal allograft dysfunction1. Transplantation 75:2, 209-216
CrossRef89
Piotr Religa, Krzysztof Bojakowski, Michal Maksymowicz, Maria Bojakowska, Allan Sirsj??, Zbigniew Gaciong, Waldemar Olszewski, Ulf Hedin, Johan Thyberg. (2002) Smooth-muscle progenitor cells of bone marrow origin contribute to the development of neointimal thickenings in rat aortic allografts and injured rat carotid arteries1. Transplantation 74:9, 1310-1315
CrossRef90
Sandeep Gupta, Catherine Verfaillie, David Chmielewski, Youngki Kim, Mark E. Rosenberg. (2002) A role for extrarenal cells in the regeneration following acute renal failure. Kidney International 62:4, 1285-1290
CrossRef91
Richard Poulsom, Malcolm R. Alison, Stuart J. Forbes, Nicholas A. Wright. (2002) Adult stem cell plasticity. The Journal of Pathology 197:4, 441-456
CrossRef92
A.L Lobashevsky, R.W Senkbeil, J.L Shoaf, A.K Stephenson, S.B Skelton, R.M Burke, M.H Deierhoi, J.M Thomas. (2002) The number of amino acid residues mismatches correlates with flow cytometry crossmatching results in high PRA renal patients. Human Immunology 63:5, 364-374
CrossRef93
William M. Baldwin, Nicholas A. Flavahan, Robert L. Fairchild. (2002) Integration of complement and leukocytes in response to allotransplantation. Current Opinion in Organ Transplantation 7:1, 92-99
CrossRef94
Leendert C. Paul. (2002) New insights in chronic allograft rejection. Current Opinion in Urology 12:2, 89-93
CrossRef95
Frank Strutz. (2001) Potential methods to prevent interstitial fibrosis in renal disease. Expert Opinion on Investigational Drugs 10:11, 1989-2001
CrossRef
