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• W3010922633 abstract "Tumor necrosis factor receptor 2 (TNFR2) is strongly upregulated on renal tubular epithelial cells by acute cell-mediated rejection (ACR. In human kidney organ culture, TNFR2 signaling both upregulates TNFR2 expression and promotes cell cycle entry of tubular epithelial cells. We find significantly more cells express CD133 mRNA and protein, a putative stem cell marker, in allograft biopsy samples with ACR compared to acute tubular injury without rejection or pretransplant “normal kidney” biopsy samples. Of CD133+ cells, ~85% are within injured tubules and ~15% are interstitial. Both populations express stem cell marker TRA-1-60 and TNFR2, but only tubular CD133+ cells express proximal tubular markers megalin and aquaporin-1. TNFR2+CD133+ cells in tubules express proliferation marker phospho-histone H3S10 (pH3S10). Tubular epithelial cells in normal kidney organ cultures respond to TNFR2 signaling by expressing CD133 mRNA and protein, stem cell marker TRA-1-60, and pH3S10 within 3 hours of treatment. This rapid response time suggests that CD133+ cells in regenerating tubules of kidneys undergoing ACR represent proliferating tubular epithelial cells with TNFR2-induced stem cell markers rather than expansion of resident stem cells. Infiltrating host mononuclear cells are a likely source of TNF as these changes are absent in acute tubular injury . Tumor necrosis factor receptor 2 (TNFR2) is strongly upregulated on renal tubular epithelial cells by acute cell-mediated rejection (ACR. In human kidney organ culture, TNFR2 signaling both upregulates TNFR2 expression and promotes cell cycle entry of tubular epithelial cells. We find significantly more cells express CD133 mRNA and protein, a putative stem cell marker, in allograft biopsy samples with ACR compared to acute tubular injury without rejection or pretransplant “normal kidney” biopsy samples. Of CD133+ cells, ~85% are within injured tubules and ~15% are interstitial. Both populations express stem cell marker TRA-1-60 and TNFR2, but only tubular CD133+ cells express proximal tubular markers megalin and aquaporin-1. TNFR2+CD133+ cells in tubules express proliferation marker phospho-histone H3S10 (pH3S10). Tubular epithelial cells in normal kidney organ cultures respond to TNFR2 signaling by expressing CD133 mRNA and protein, stem cell marker TRA-1-60, and pH3S10 within 3 hours of treatment. This rapid response time suggests that CD133+ cells in regenerating tubules of kidneys undergoing ACR represent proliferating tubular epithelial cells with TNFR2-induced stem cell markers rather than expansion of resident stem cells. Infiltrating host mononuclear cells are a likely source of TNF as these changes are absent in acute tubular injury . Acute cell-mediated rejection (ACR) is the major cause of transplant organ failure in the first posttransplant year.1Sellarés J de Freitas DG Mengel M et al.Inflammation lesions in kidney transplant biopsies: association with survival is due to the underlying diseases.Am J Transplant. 2011; 11: 489-499Crossref PubMed Scopus (68) Google Scholar About 15% of patients experience ACR in the first 3 months after a transplant in the UK.2National Kidney Federation. What is transplant rejection? kidney.org.uk/what-is-transplant-rejection. Accessed April 3, 2020.Google Scholar One of the hallmarks of rejecting kidney is severe damage to tubular epithelial cells.3Havasi A Dong Z. Autophagy and tubular cell death in the kidney.Semin Nephrol. 2016; 36: 174-188Abstract Full Text Full Text PDF Google Scholar On treatment of ACR, the kidney typically undergoes a regenerative response leading in most cases to recovery of renal function.4Lazzeri E Mazzinghi B Romagnani P. Regeneration and the kidney.Curr Opin Nephrol Hypertens. 2010; 19: 248-253Crossref Scopus (25) Google Scholar, 5Little MH. Tracing the life of the kidney tubule- re-establishing dogma and redirecting the options.Cell Stem Cell. 2008; 2: 191-192Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 6Nony PA Schnellmann RG. Mechanisms of renal cell repair and regeneration after acute renal failure.J Pharmacol Exp Ther. 2003; 304: 905-912Crossref Scopus (142) Google Scholar However, the source of the cells that repopulate the injured nephron is unclear. Some studies support the existence and homing (engraftment) of a stem/progenitor cells in adult kidney for ameliorating injury,5Little MH. Tracing the life of the kidney tubule- re-establishing dogma and redirecting the options.Cell Stem Cell. 2008; 2: 191-192Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 6Nony PA Schnellmann RG. Mechanisms of renal cell repair and regeneration after acute renal failure.J Pharmacol Exp Ther. 2003; 304: 905-912Crossref Scopus (142) Google Scholar, 7Gurtner GC Werner S Barrandon Y Longaker MT. Wound repair and regeneration.Nature. 2008; 453: 314-321Crossref PubMed Scopus (3751) Google Scholar, 8Humphreys BD Valerius MT Kobayashi A et al.Intrinsic epithelial cells repair the kidney after injury.Cell Stem Cell. 2008; 2: 284-291Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 9Romagnani P Lasagni L Remuzzi G. Renal progenitors: an evolutionary conserved strategy for kidney regeneration.Nat Rev Nephrol. 2013; 9: 137-146Crossref Scopus (136) Google Scholar, 10Sagrinati C Netti GS Mazzinghi B et al.Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult human kidneys.J Am Soc Nephrol. 2006; 17: 2443-2456Crossref PubMed Scopus (0) Google Scholar whereas other studies support an indirect involvement of circulating cells that mediate paracrine effects on injured epithelial cells to promote repair.11Buzhor E Omer D Harari-Steinberg O et al.Reactivation of NCAM1 defines a subpopulation of human adult kidney epithelial cells with clonogenic and stem/progenitor properties.Am J Pathol. 2013; 183: 1621-1633Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 12Deregibus MC Cantaluppi V Calogero R et al.Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA.Blood. 2007; 110: 2440-2448Crossref PubMed Scopus (764) Google Scholar, 13Kusaba T Lalli M Kramann R Kobayashi A Humphreys BD. Differentiated kidney epithelial cells repair injured proximal tubule.Proc Natl Acad Sci U S A. 2014; 111: 1527-1532Crossref PubMed Scopus (305) Google Scholar, 14Ranghino A Bruno S Bussolati B et al.The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury.Stem Cell Res Ther. 2017; 8: 24Crossref Scopus (91) Google Scholar, 15Ratajczak MZ Zuba-Surma E Kucia M Reca R Wojakowski W Ratajczak J. The pleiotropic effects of the SDF-1-CXCR4 axis in organogenesis, regeneration and tumorigenesis.Leukemia. 2006; 20: 1915-1924Crossref PubMed Scopus (0) Google Scholar, 16Santeramo I Herrera Perez Z Illera A et al.Human kidney-derived cells ameliorate acute kidney injury without engrafting into renal tissue.Stem Cells Transl Med. 2017; 6: 1373-1384Crossref Scopus (22) Google Scholar If stem/progenitor cells are involved, a key issue is how to identify them. Multiple studies have used CD133 as a marker for progenitor cells in various organs including the human adult kidney.14Ranghino A Bruno S Bussolati B et al.The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury.Stem Cell Res Ther. 2017; 8: 24Crossref Scopus (91) Google Scholar,17Al-Lamki RS Wang J Yang J et al.Tumor necrosis factor receptor 2-signaling in CD133-expressing cells in renal clear cell carcinoma.Oncotarget. 2016; 7: 24111-24124Crossref Scopus (15) Google Scholar, 18Angelotti ML Ronconi E Ballerini L et al.Characterization of renal progenitors committed toward tubular lineage and their regenerative potential in renal tubular injury.Stem Cells. 2012; 30: 1714-1725Crossref PubMed Scopus (0) Google Scholar, 19Bruno S Bussolati B Grange C et al.CD133+ renal progenitor cells contribute to tumor angiogenesis.Am J Pathol. 2006; 169: 2223-2235Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 20Lindgren D Boström A-K Nilsson K et al.Isolation and characterization of progenitor-like cells from human renal proximal tubules.Am J Pathol. 2011; 178: 828-837Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 21Ye Y Wang B Jiang X et al.Proliferative capacity of stem/progenitor-like cells in the kidney may associate with the outcome of patients with acute tubular necrosis.Hum Pathol. 2011; 42: 1132-1141Crossref PubMed Scopus (0) Google Scholar CD133+ cells have been implicated in repair/dedifferentiation of injured proximal and distal tubular epithelia in acute kidney injury (AKI) in human adults22Weigmann A Corbeil D Hellwig A Huttner WB. Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells.Proc Natl Acad Sci USA. 1997; 94: 12425-12430Crossref PubMed Scopus (0) Google Scholar and in a mouse model of kidney injury.8Humphreys BD Valerius MT Kobayashi A et al.Intrinsic epithelial cells repair the kidney after injury.Cell Stem Cell. 2008; 2: 284-291Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar It is assumed that progenitor cells are in a quiescent state until new stimuli activate their proliferation, differentiation, or migration. Tumor necrosis factor (TNF) can cause survival and invasion of CD133+ cells in human colon cancer,23Wei X Li X Kong F et al.TNF-alpha activates Wnt signaling pathway to promote the invasion of human colon cancer stem cells.Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2018; 34: 982-988Google Scholar and a link between TNF and CD133 has been reported in human pancreas.24Thole AA Rodrigues-Cunha A Carvalho SN et al.Progenitor cells and TNF-alpha involvement during morphological changes in pancreatic islets of obese mice.Tissue Cell. 2012; 44: 238-248Crossref PubMed Scopus (0) Google Scholar Our laboratory has previously shown that the effects of TNF on graft outcome may vary due to a diverse range of cellular responses that are triggered via the 2 distinct TNF receptors: TNFR1 and TNFR2.25Al-Lamki RS Wang J Skepper JN Thiru S Pober JS Bradley JR. Expression of tumor necrosis factor receptors in normal kidney and rejecting renal transplants.Lab Invest. 2001; 81: 1503-1515Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In control renal tissue, TNFR1 is expressed primarily on glomerular and microvascular endothelial cells. TNFR2 is minimally expressed, primarily on tubular epithelial cells. In transplant biopsy samples with ACR that show morphological evidence of tubular injury, TNFR1 is lost on the endothelium and this receptor is largely confined to infiltrating leukocytes. TNFR2 is concomitantly upregulated on endothelial cells and much more prominently on tubular epithelium. Furthermore, selective ligation of TNFR2 in a short-term organ culture of human kidney with a mutein form of TNF (R2-TNF) demonstrates receptor signalling, assessed by phosphorylation of endothelial/epithelial tyrosine kinase, and mediates both upregulation of TNFR2 and entry into cell cycle of tubular epithelial cells.26Al-Lamki RS Wang J Vandenabeele P et al.TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury.FASEB J. 2005; 19: 1637-1645Crossref Scopus (128) Google Scholar These observations suggest an important role for TNFR2 in tubular regeneration. Our subsequent studies in human renal clear cell carcinoma has revealed a coassociation of TNFR2 with CD133+ cancer stem cell–like cells (CSCs) and CD133+CD45− small round cells in the interstitium of normal kidney from the same tissues. In both cases, these cells express stem cell markers and TNFR2 ligation initiated cell cycle entry.17Al-Lamki RS Wang J Yang J et al.Tumor necrosis factor receptor 2-signaling in CD133-expressing cells in renal clear cell carcinoma.Oncotarget. 2016; 7: 24111-24124Crossref Scopus (15) Google Scholar The present study was designed to answer the question of whether CD133+ renal stem cells participate in tubular repair associated with ACR. Specifically, we investigated the localization and distribution of CD133 in posttransplant biopsy samples of ACR (histologically categorized as Banff-IA, -IB, -IIA, and –IIB) by immunofluorescence and in situ hybridization, determined their association with TNFR2, and used short-term organ culture of human renal biopsy samples to examine the effect of TNFR2 ligation on CD133+ cells within regenerating renal tubules. Our data here are most consistent with a model in which TNFR2 signaling, likely in response to lymphocyte-derived TNF, stimulates tubular epithelial cells to express stem cell markers as part of the reparative process rather than one in which resident stem cells are activated to repair injured tubules in ACR. Cases of renal biopsy ACR with tubular injury (tubulitis) categorized according to Banff 2017 classification (Banff-IA, -IB, -IIA, and -IIB)27Haas M Loupy A Lefaucheur C et al.The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials.Am J Transplant. 2018; 18: 293-307Crossref PubMed Scopus (627) Google Scholar,28Roufosse C Simmonds N Clahsen-van Groningen M et al.A 2018 reference guide to the banff classification of renal allograft pathology.Transplantation. 2018; 102: 1795-1814Crossref PubMed Scopus (292) Google Scholar and cases of acute tubular injury (ATI; without evidence of rejection) were identified by renal pathologists (ST, VBD, and VBR; n = 5 each case) from archives reported between 2015 and 2019. Corresponding normal kidney tissue taken at the time of transplantation (NK) was used for comparative studies with approval of the local research ethics committee. Histological cross sections of 3- to 5-μm thickness were stained with hematoxylin and eosin (H&E) and reviewed by the pathologists. Additional paraffin-wax sections were placed on polyl-lysine–coated glass slides (BDH Merck Ltd) for IF and in situ hybridization studies. Antibodies/reagents used included mouse monoclonal anti-CD133 (AC133, cat. W6B3C1; Miltenyi Biotec), rabbit polyclonal anti-CD133 (cat. E90032; Enogene Biotech Ltd.), goat-polyclonal anti-TNFR2 (cat. AP-226-PB; R&D Systems), mouse anti-CD45 (cat. M0701; Dakocytomation), mouse anti-CD24 (cat. MAB248; R&D Systems), goat anti-CD24 (cat. sc-7034; Insight Biotechnology), anti–TRA-1-60 (cat. MA1-023X; ThermoFischer; stem cell markers), and mouse anti–phospho-histone H3S10 (cat. ab14955; Abcam). Rabbit polyclonal anti-megalin (anti-LRP2; cat. AP6154A-ABG; Stratech). Rabbit anti-aquaporin-1 (AQP-1; cat. Ab134695; Abcam) and Hoechst 33342 (cat. LSH3570; Molecular Probes) were used for nuclei detection. Renal tissue for organ culture was obtained from kidney allograft biopsy samples (n = 5) taken immediately after reperfusion of renal transplants (NK) or from the uninvolved pole of kidney specimens (n = 6) excised because of renal tumors as previously described.26Al-Lamki RS Wang J Vandenabeele P et al.TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury.FASEB J. 2005; 19: 1637-1645Crossref Scopus (128) Google Scholar To assess the reliability and reproducibility of these assays, multiple samples of cross sections from the medulla through to the cortex were taken from each patient to obtain randomized samples, and all samples were incubated in duplicate. Approximately 1-mm3 fragments of tissue were immersed in M199 (medium containing 10% heat-inactivated FCS, antibiotics, and 2.2 mmol/L glutamine) and incubated for 0, 1.5, 3, 6, and 18 hours at 37°C with either culture media alone (without TNF) or with 10 ng/mL recombinant human TNF (wtTNF; AMS Biotechnology, Europe, Ltd.) or with 1 μg/mL recombinant mutations of the wild-type TNF sequence, which enable the mutated protein (“mutein”) to bind selectively to either of the TNFR subtypes.17Al-Lamki RS Wang J Yang J et al.Tumor necrosis factor receptor 2-signaling in CD133-expressing cells in renal clear cell carcinoma.Oncotarget. 2016; 7: 24111-24124Crossref Scopus (15) Google Scholar,25Al-Lamki RS Wang J Skepper JN Thiru S Pober JS Bradley JR. Expression of tumor necrosis factor receptors in normal kidney and rejecting renal transplants.Lab Invest. 2001; 81: 1503-1515Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,26Al-Lamki RS Wang J Vandenabeele P et al.TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury.FASEB J. 2005; 19: 1637-1645Crossref Scopus (128) Google Scholar,29Van Ostade X Vandenabeele P Tavernier J Fiers W. Human tumor necrosis factor mutants with preferential binding to and activity on either the R55 or R75 receptor.Eur J Biochem. 1994; 220: 771-779Crossref Scopus (49) Google Scholar The specific double mutation of R32W, S86T (here termed R1TNF) allows selective activation of TNFR1, whereas the D143N, A145R (termed R2TNF) double mutation allows selective activation of the TNFR2 subtype only. Cultures were harvested, fixed in 4% formaldehyde, and processed for paraffin-wax embedding. We subjected 5-μm-thick formalin-fixed paraffin-embedded sections of NK, ACR, ATI, and organ cultures to IF as previously described25Al-Lamki RS Wang J Skepper JN Thiru S Pober JS Bradley JR. Expression of tumor necrosis factor receptors in normal kidney and rejecting renal transplants.Lab Invest. 2001; 81: 1503-1515Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,26Al-Lamki RS Wang J Vandenabeele P et al.TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury.FASEB J. 2005; 19: 1637-1645Crossref Scopus (128) Google Scholar with 1:50; anti-CD133 alone or in combination with stem cell marker; anti–TRA-1-6030Hishikawa K Takase O Yoshikawa M Tsujimura T Nangaku M Takato T. Adult stem-like cells in kidney.World J Stem Cells. 2015; 7: 490-494Crossref Google Scholar,31Sallustio F Serino G Schena FP. Potential reparative role of resident adult renal stem/progenitor cells in acute kidney injury.Biores Open Access. 2015; 4: 326-333Crossref Google Scholar or anti-TNFR2 or anti-CD45 (detects leukocytes), or anti-megalin or anti–aquaporin-1 or anti–phospho-histone-H3S10 (pH3S10; detects replicating cells) or anti-CD24.10Sagrinati C Netti GS Mazzinghi B et al.Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult human kidneys.J Am Soc Nephrol. 2006; 17: 2443-2456Crossref PubMed Scopus (0) Google Scholar,18Angelotti ML Ronconi E Ballerini L et al.Characterization of renal progenitors committed toward tubular lineage and their regenerative potential in renal tubular injury.Stem Cells. 2012; 30: 1714-1725Crossref PubMed Scopus (0) Google Scholar,32Ronconi E Sagrinati C Angelotti ML et al.Regeneration of glomerular podocytes by human renal progenitors.J Am Soc Nephrol. 2009; 20: 322-332Crossref PubMed Scopus (427) Google Scholar, 33Sallustio F Costantino V Cox SN et al.Human renal stem/progenitor cells repair tubular epithelial cell injury through TLR2-driven inhibin-A and microvesicle-shuttled decorin.Kidney Int. 2013; 83: 392-403Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 34Smeets B Boor P Dijkman H et al.Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration.J Pathol. 2013; 229: 645-659Crossref Scopus (160) Google Scholar In addition, parallel sections were subjected to triple-IF staining with anti-CD133, -TNFR2, and -pH3S10. Primary antibodies were then detected using species-specific secondary antibodies; conjugated to Alexa Fluo-488 or -568 (Vector Laboratories) and nuclei detected with Hoechst 33342. For triple-IF staining, secondary antibodies used were anti-rabbit NL-405, anti-mouse NL-557, and anti-goat NL-498. Sections were mounted in Vectashield Mountant (Vector Laboratories) and examined with use of a TCS-NT confocal laser scanning microscope (Leica Microsystems). No signal was observed when primary antibody was replaced by either nonimmune serum or isotype-matched nonbinding immunoglobulin. Nonradioactive in situ hybridization was carried out on 5-μm-thick formalin-fixed paraffin-embedded sections of kidney organ cultures as described previously.17Al-Lamki RS Wang J Yang J et al.Tumor necrosis factor receptor 2-signaling in CD133-expressing cells in renal clear cell carcinoma.Oncotarget. 2016; 7: 24111-24124Crossref Scopus (15) Google Scholar,25Al-Lamki RS Wang J Skepper JN Thiru S Pober JS Bradley JR. Expression of tumor necrosis factor receptors in normal kidney and rejecting renal transplants.Lab Invest. 2001; 81: 1503-1515Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,26Al-Lamki RS Wang J Vandenabeele P et al.TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury.FASEB J. 2005; 19: 1637-1645Crossref Scopus (128) Google Scholar,35Al-Lamki RS Lu W Manalo P et al.Tubular epithelial cells in renal clear cell carcinoma express high RIPK1/3 and show increased susceptibility to TNF receptor 1-induced necroptosis.Cell Death Dis. 2016; 7: e2287Crossref Scopus (25) Google Scholar, 36Al-Lamki RS Lu W Wang J et al.TNF, acting through inducibly expressed TNFR2, drives activation and cell cycle entry of c-Kit+ cardiac stem cells in ischemic heart disease.Stem Cells. 2013; 31: 1881-1892Crossref PubMed Scopus (0) Google Scholar, 37Al-Lamki RS Wang J Thiru S et al.Expression of silencer of death domains and death-receptor-3 in normal human kidney and in rejecting renal transplants.Am J Pathol. 2003; 163: 401-411Abstract Full Text Full Text PDF PubMed Google Scholar Single-stranded antisense DNA oligonucleotide probes 5′-end labeled with digoxigenin specific for human CD133 (GenBank: HQ628627.1; MWG-Biotech AG) were used. Negative controls included incubation of sections with a sense probe to CD133 (MW Biotech-AG). Gene expression was visualized using alkaline-phosphatase/BCIP/NBT substrate (Sigma-Aldrich). All data represent mean ± SEM of the number of positive cells (n = 30) presented as percentage of positive cells/total number of cells (×100), counted in 10 random regions from 3 random biopsy samples from NK, each ACR grade, and ATI unless otherwise stated. The number of pH3S10-positive cells were counted in 10 representative fields at ×40 magnification on 5 random biopsy samples from 5 cases of NK, each ACR grade, and each ATI. Differences between 2 groups were analyzed with a 2-tailed Student t test assuming unequal variance and between >2 groups by 1-way ANOVA followed by a Bonferroni post hoc t test in GraphPad Prism version v8.1. P < .05 was regarded as significant. H&E-stained sections of NK biopsy samples showed intact tubules lined by epithelial cells and absence of inflammatory cells (Figure 1A). In contrast, biopsy samples with ACR showed either foci of moderate tubulitis (t2; Banff-IA) or severe tubulitis (t3; Banff-IB) with interstitial inflammation involving >25% of nonsclerotic cortical parenchyma with edema (i2/i3) or mild to moderate intimal arteritis (v1/v2; Banff-IIA/IIB) with tubulitis (Figure 1B-E). Although Banff grade II rejections involved arteries as well as tubules, the extent of tubular injury was at least equivalent to that in grade I biopsy samples. Periodic acid–Schiff silver stain38Yang S Wang J Chen Y et al.Concurrent Kidney Glomerular and Interstitial Lesions Associated with Kimura’s Disease.Nephron. 2019; 143: 92-99Crossref Scopus (3) Google Scholar clearly shows marked injury in tubules with lymphocytic infiltration in ACR (insets, Figure 1B-D). In contrast, H&E-stained sections of ATI showed tubules with epithelial injury, luminal dilatation, nuclear loss, and nuclear pyknosis with no obvious mononuclear cell infiltration (Figure 1F). We first examined the expression of CD133 protein and mRNA in NK, ACR, and ATI using IF and ISH. We found CD133 protein expression in isolated cells in glomeruli and interstitium (<4% mean) but rarely in tubules (Figure 2A). In contrast, a significantly higher number of CD133+ cells was evident in all grades of ACR compared with ATI and NK, and these were mainly confined to tubules with morphological evidence of injury (breach of epithelial membrane and infiltration of lymphocytes). These changes were more pronounced in Banff-IB (32.3% ± 0.2%) and Banff-IIB (30.1% ± 0.1%) graded biopsy samples (Figure 2A-E, quantified in Table 1). In comparison, a significantly fewer number of CD133+ cells were seen on sections with ATI (12.6% ± 0.4%; Figure 2F). No signal was seen in sections incubated with nonimmune serum isotype-matched nonbinding immunoglobulin (data not shown). Of note, tubular CD133+ cells in ACR also expressed stem cell–associated marker TRA-1-60 (Figure 2G), which was rare in sections with ATI (data not shown). A majority of the CD133+ tubular cells in ACR were also positive for another stem cell marker CD24,10Sagrinati C Netti GS Mazzinghi B et al.Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult human kidneys.J Am Soc Nephrol. 2006; 17: 2443-2456Crossref PubMed Scopus (0) Google Scholar,18Angelotti ML Ronconi E Ballerini L et al.Characterization of renal progenitors committed toward tubular lineage and their regenerative potential in renal tubular injury.Stem Cells. 2012; 30: 1714-1725Crossref PubMed Scopus (0) Google Scholar,32Ronconi E Sagrinati C Angelotti ML et al.Regeneration of glomerular podocytes by human renal progenitors.J Am Soc Nephrol. 2009; 20: 322-332Crossref PubMed Scopus (427) Google Scholar, 33Sallustio F Costantino V Cox SN et al.Human renal stem/progenitor cells repair tubular epithelial cell injury through TLR2-driven inhibin-A and microvesicle-shuttled decorin.Kidney Int. 2013; 83: 392-403Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 34Smeets B Boor P Dijkman H et al.Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration.J Pathol. 2013; 229: 645-659Crossref Scopus (160) Google Scholar with only a few of these tubular cells not coexpressing CD24 (Figure S1). Costaining for CD133 and CD24 was also seen in a few tubular cells in ATI and in some interstitial cells in NK. These immunostaining results were supported by ISH for mRNA localization. In comparison to sections of NK, which showed only a few CD133+ cells mainly in isolated cells in glomerular, specific strong signal for CD133 mRNA was evident in injured tubules and in isolated cells in interstitium (Figure 2H), similar to the distribution of CD133 protein. No signal was observed in negative controls after hybridization with sense probe.TABLE 1Quantification of the percentage of CD133+ cells in renal tissue from pretransplant (NK), acute cellular rejection grades, and in biopsy samples with acute tubular injury (ATI)Tissue typeTECINTGLOMNK1.3% ± 0.2%3.6% ± 1.2%3.1% ± 0.7%Banff-IA26.6% ± 0.3%**P < .001 vs NK.13.3% ± 0.3%*P < .05 vs NK.3.1% ± 0.3%Banff-IB32.3% ± 0.2%***P < .0001 vs NK.,+P < .01 vs Banff-IA/-IIA/-IIB.19.6% ± 0.4%**P < .001 vs NK.4.2% ± 0.8%Banff-IIA27.1% ± 0.4%**P < .001 vs NK.,ψP < .05 vs Banff-IA.16.6% ± 0.6%*P < .05 vs NK.2.6% ± 0.4%Banff-IIB30.1% ± 0.1%**P < .001 vs NK.,ψP < .05 vs Banff-IA.23.3% ± 0.3%**P < .001 vs NK.2.3% ± 0.2%ATI12.6% ± 0.4%*P < .05 vs NK.6.6% ± 0.3%2.4% ± 0.7%Abbreviations: GLOM, glomerular; INT, isolated cells in interstitium; TEC, tubular epithelial cells.Note: All values are mean ± SEM.* P < .05 vs NK.** P < .001 vs NK.*** P < .0001 vs NK.+ P < .01 vs Banff-IA/-IIA/-IIB.ψ P < .05 vs Banff-IA. Open table in a new tab Abbreviations: GLOM, glomerular; INT, isolated cells in interstitium; TEC, tubular epithelial cells. Note: All values are mean ± SEM. We previously reported that TNFR2 protein and mRNA are induced in injured tubular cells in ACR.25Al-Lamki RS Wang J Skepper JN Thiru S Pober JS Bradley JR. Expression of tumor necrosis factor receptors in normal kidney and rejecting renal transplants.Lab Invest. 2001; 81: 1503-1515Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Our subsequent studies in human renal clear cell carcinoma demonstrated localization of TNFR2 to CSCs and that selective engagement of TNFR2 in these cells promoted cell cycle entry and sensitization to killing by a cell cycle–dependent cytotoxic agent.17Al-Lamki RS Wang J Yang J et al.Tumor necrosis factor receptor 2-signaling in CD133-expressing cells in renal clear cell carcinoma.Oncotarget. 2016; 7: 24111-24124Crossref Scopus (15) Google Scholar Here we examined whether there is an association between CD133 and TNFR2 in ACR and ATI by double-IF. Consistent with our previous findings,26Al-Lamki RS Wang J Vandenabeele P et al.TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury.FASEB J. 2005; 19: 1637-1645Crossref Scopus (128) Google Scholar TNFR2 expression was not detected in NK (Figure 3A). In contrast, a strong colocalization of CD133 and TNFR2 expression was seen in all ACR grades, mainly confined to tubules and in isolated cells within interstitium but rarely in glomerular (Figure 3B-E). In comparison, significantly fewer double-positive cells were detected in sections with ATI (Figure 3F). Table 2 is a quantitative assessment of the double-staining with the highest tubula" @default.
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• W3010922633 title "Signaling through tumor necrosis receptor 2 induces stem cell marker in CD133+ regenerating tubular epithelial cells in acute cell-mediated rejection of human renal allografts" @default.
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