Transdifferentiation of Epithelial Glomerular Cells
Jean Bariéty,
Patrick Bruneval,
Gary S. Hill,
Chantal Mandet,
Christian Jacquot and
Alain Meyrier
University Paris VI, Hospital Georges Pompidou and INSERM U430, Paris, France.
Correspondence to Dr. Patrick Bruneval, Pathology Department, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75908 Paris Cedex 15, France; Phone: 33-1-56-09-38-60; Fax: 33-1-56-09-38-89; E-mail: patrick.bruneval{at}hop.egp.ap-hop-paris.fr
Cell transdifferentiation is characterized by loss of some phenotypesalong with acquisition of new phenotypes in differentiated cells.Differentiated cells are endowed with the capacity of transforminginto cells of a different type having other functions (1,2).Gene expression in differentiated cells has long been consideredan irreversible phenomenon that is established at the time ofreplication. Given that, although repressed, the same geneticframework is present in all cell types, a change in gene expressionamong differentiated cells was predictable in particular conditions.In fact, the differentiated state of a given cell is not irreversible.It depends on the up- and downregulation exerted by specificmolecules (3,4).
Apart from organogenesis, malignant cell development, and tumorprogression, the best documented examples of cell transdifferentiationconcern transdifferentiation of epithelial cells into mesenchymatouscells (EMT). Such a transdifferentiation of epithelial cellsinto myofibroblasts has been identified as a factor fosteringfibrosis in various organs such as the liver (5,6), the lung(7), and the kidney (8,9). Myofibroblasts exhibit features commonto both fibroblasts and myocytes and may be considered as activatedfibroblasts that express -smooth muscle actin (-SMA) (10). Theirability to proliferate and to synthesize extracellular matrix(interstitial type collagens) is remarkable (7,11,12). In thehuman kidney, we have been the first to describe transdifferentiationof glomerular epithelial cells into myofibroblastic or intomacrophagic cells (13–15).
EMT-Like Changes of Podocytes during Nephrogenesis
Apart from the collecting duct cells, all renal cells are derivedfrom the metanephrogenic mesenchyme, a stem cell populationthat has the capacity to differentiate in either epithelialor interstitial cells (2). Immature glomerular epithelial cellsoriginate from the metanephric mesenchyme after induction bythe ureteric bud. Glomerular development is divided into fourstages: renal vesicle, S-shaped stage, capillary loop stage,and maturing glomeruli. Glomerular parietal and visceral epithelium(podocytes) can be distinguished after the S-shaped stage. Duringnephrogenesis and in mature glomeruli, parietal epithelial cells(PEC) express desmosomal proteins and cytokeratin (CK), whichare markers of an epithelial phenotype. Conversely, the podocytedifferentiates from an epithelial to a mesenchymal phenotype(16,17). Immature podocyte precursor cells at the S-shaped bodystage are simple cuboidal cells expressing epithelial markers(desmosomal proteins and CK) with apical tight junctions. Theseprecursors cells, actively dividing, express Ki67 and proliferatingcell nuclear antigen (PCNA) proliferation markers. As the developingglomerulus evolves from the S-shaped body stage to the capillaryloop stage and finally to the mature glomerulus, podocytes acquiretheir characteristic architecture. Their features include footprocess formation and replacement of apical tight junctionsby basal slit diaphragms. Podocytes reorganize their actin cytoskeletonand extend the ordered array of actin-based foot processes.They lose their mitotic activity and no longer express proliferationmarkers. De novo expression of cyclin-dependent kinase inhibitors(CDKI) p21, p27, and p57, which prevent cell proliferation byinhibiting the activation of CDK, coincides with the cessationof podocyte proliferation (18,19). Transition from the S-shapedbody stage to the capillary loop stage represents the transdifferentiationof an epithelial to a mesenchymal phenotype that is characterizedby the disappearance of epithelial markers (desmosomal proteins,CK) and the reappearance of vimentin, a characteristic intermediatefilament protein of mesenchymal cells.
This maturation is associated with expression of mature podocytemarkers (14,16,20) including the Wilms tumor protein (WT-1),common acute lymphoblastic leukemia antigen, C3b receptor (CR1),glomerular epithelial protein-1 (GLEPP-1), podocalyxin, andsynaptopodin. WT-1, which was weakly expressed in all cellsat early stages, becomes restricted to podocyte nuclei. Synaptopodinassociated with actin filaments, linked to the formation offoot processes, is restricted to the sole of the podocytes.GLEPP-1 and podocalyxin, the latter being the major sialomucinof the glycocalyx, are located at the apical part of the podocytesand of the foot processes. Podocalyxin, complexed with ezrin,which mediates its link to the actin cytoskeleton, plays animportant role in maintaining the foot process architectureby virtue of its highly negatively charged ectodomain (21).From the capillary loop stage, podocyte proteins are detectedat the slit diaphragm level or in foot processes close to theslit diaphragm (22). Podocyte proteins consist of nephrin; podocin;CD2AP; P cadherin; Z0-1; -, -, and -catenin; and -actinin-4.They play a crucial role in the functions of the glomerularfiltration barrier. The fibroblast growth factor (FGF) (16,17)and Pod-1 (23) signalings seem to control EMT-like changes ofpodocytes during nephrogenesis.
Several cell types, including monocyte-macrophages, epithelialcells, and myofibroblasts, have been implicated in crescentformation and progression toward fibrosis. Crescents seem toevolve through three stages—cellular, fibrocellular, andfibrous—with much heterogeneity even in the same patient(24).
The nature and origin of myofibroblastic cells responsible foreliciting crescents have been debated. They might originatefrom mesangial cells (25), from periglomerular fibroblasts migratinginto Bowman’s space through a gap in Bowman’s capsule(26,27), or from transdifferentiated epithelial cells.
Glomerular EMT in Human Pauci-Immune Crescentic Glomerulonephritis
We tested the hypothesis that EMT is involved in human pauci-immunecrescentic glomerulonephritis (CGN) (15). We studied 18 pretreatmentand posttreatment renal biopsies from 11 patients with pauci-immuneCGN. In seven of them, a renal biopsy was carried out beforeand after treatment. All of these biopsies were studied for(1) the proliferation marker PCNA and CDKI p27 and p57 and (2)the cellular markers podocalyxin, synaptopodin, and GLEPP-1for podocytes; -SMA for myofibroblasts; and CK (C2562) for PEC(28). Vimentin, a mesenchymal marker, was considered as an additionalmarker for podocytes because vimentin is normally expressedon podocytes but not on PEC. Confocal laser microscopy was usedto assess colocalization of -SMA and CK.
On pretreatment biopsies, crescent cells expressed the proliferationmarker PCNA in 33 ± 10% of the cells, along with lackof CDKI expression in crescents, whereas p27 and p57 CDKI expressionpersisted in the sound areas of the glomerular tuft. Most—sometimesall—of the crescent cells were labeled with vimentin,as were endocapillary cells. Different cell phenotypes couldbe identified in the crescents (Figure 1): PEC positive forC2562 CK, their customer marker (26 ± 17%), dedifferentiatedepithelial cells that were not labeled by C2562 CK antibodiesor by any of the markers used except vimentin (an acquired phenotypeusually not observed in normal PEC), macrophagic cells (16 ±6%), myofibroblasts (9 ± 4%,) and fewer than 1% of cellscoexpressing CK and -SMA (Figure 2). That last coexpressionsuggests a transitional phase of the dynamic phenomenon in whichtransdifferentiating PEC still expressing epithelial CK markersacquire a myofibroblastic epitope in the crescent.
Figure 1. Immunohistochemistry can identify different phenotypes among crescent cells, although they exhibit the same pattern of spindle cells. These spindle-shaped cells are either cytokeratin (CK)-positive (a; arrows) or -smooth muscle actin (-SMA)-positive (b; arrows). Human pauci-immune crescentic glomerulonephritis in a Wegener patient. Initial pretreatment biopsy labeled by C2562 anti-CK antibody (a) or 1A4 anti–-SMA antibody. Magnification, x300.
Figure 2. Confocal laser microscopy analysis of immunofluorescent labeling on crescent cells. Rare crescent cells (arrow) show coexpression of -SMA and CK, suggesting a transitional phase of the dynamic phenomenon in which transdifferentiating parietal epithelial cells (PEC) still expressing epithelial CK markers acquire a myofibroblastic epitope (-SMA) in the crescent. Human pauci-immune crescentic glomerulonephritis in a Wegener patient. Initial pretreatment biopsy showing pseudotubule organization (*) in a fibrocellular crescent. Labeling by 1A4 anti–-SMA antibody (a; green cyanin-2 fluorescence) and C2562 anti-CK antibody (b; red cyanin-3 fluorescence). (c) Merged images. Magnification, x800.
Figure 3. Confocal laser microscopy analysis of immunofluorescent labeling on glomerular epithelial cells. Coexpression of the macrophagic epitope CD68 and of the epithelial maker AE1/AE3 CK on still-attached podocytes (arrows) and PEC (arrowhead) suggesting a transdifferentiation process from epithelial type into macrophagic type. Posttransplantation relapse of FSGS. Labeling by anti-CD68 antibody (a; green cyanin-2 fluorescence) and AE1/AE3 anti-CK antibody (b; red cyanin-3 fluorescence). (c) Merged images. Magnification, x250. (From Bariety et al. J Am Soc Nephrol 12: 261–274, 2001).
Figure 4. Confocal laser microscopy analysis of immunofluorescent labeling on glomerular epithelial cells. Coexpression of the macrophagic epitope CD68 and of the podocyte maker podocalyxin on glomerular cells (arrows) suggesting transdifferentiation of podocytes into macrophagic cells. Posttransplantation relapse of FSGS. Merged image of the labeling by anti-CD68 antibody (green cyanin-2 fluorescence) and by anti-podocalyxin antibody (red cyanin-3 fluorescence). Magnification, x800. (From Bariety et al. J Am Soc Nephrol 12: 261–274, 2001).
Figure 5. Immunohistochemical labeling of dysregulated podocytes expressing CD68 macrophagic epitope (arrow). Note that a few parietal epithelial cells express this marker, indicating that they are also involved in a process of epithelial to macrophagic transdifferentiation. The renal biopsy with collapsing glomerulopathy in an HIV-negative patient is labeled by the PGM1 anti-CD68 antibody. Magnification, x500
Crescents do not contain normal podocytes. However, the possibilitythat modified and/or hyperplastic podocytes might participatein crescent development cannot be ruled out. Thus, the podocytesthat proliferate are dysregulated (14,20,29) and no longer expresstheir normal phenotypes. Furthermore, they acquire new phenotypes(14), particularly CK expression. The possibility remains thatsome CD68-positive cells might be transdifferentiated podocytes,as has recently been described (14). However, in our cases ofpauci-immune CGN, no cells coexpressed synaptopodin and C68on confocal microscopy. In crescents, PEC were intermingledwith a major component of epithelial cells that had lost theirCK customary epitopes, with cells coexpressing CK and -SMA andwith mature myofibroblasts. Therefore, PEC could be a possiblecellular source for myofibroblasts originating from EMT. Inaddition, EMT was observed in rare tubular epithelial cellsthat coexpressed C2562 CK and -SMA.
Posttreatment lesions were qualitatively similar to the pretreatmentlesions, but there was a marked shift toward fibrotic lesionswith increased -SMA and decreased CK labeled cells. No cellcoexpressed CK and -SMA in the crescents.
Glomerular EMT in Rat Crescentic Glomerulonephritis
The correlate of these human phenomena was described in twoexperimental types of CGN, one related to nephron reductionand the other to anti–glomerular basement membrane (GBM)antibody glomerulonephritis (30). In these experiments, immunohistochemistryand in situ hybridization labelings demonstrated de novo expressionof -SMA by PEC. Some PEC no longer expressed E-cadherin, a ratepithelial cell marker, and others coexpressed both E-cadherinand -SMA. There was a marked increase in both TGF-1 and FGF-2expression by PEC in association with glomerular crescent formation.Cellular crescents showed either no disruption or only localareas of disruption in the basal lamina of Bowman’s capsule,suggesting that the myofibroblasts in the crescents are derivedfrom transdifferentiation of proliferating glomerular epithelialcells rather than by migration of interstitial myofibroblastsinto Bowman’s space.
Mechanisms of EMT
The mechanisms that lead to EMT are still poorly understoodand are probably diverse. In the kidney, EMT was essentiallystudied experimentally on tubular epithelial cells.
EMT can be achieved by changes in the extracellular matrix composition:tubular epithelial cells grown in three-dimensional collagentype I promotes EMT (2,3,31–33) with loss of CK expressionand acquisition of mesenchymal morphology and phenotype, includingfibroblast-specific protein-1 (FSP-1) and vimentin. This suggeststhat direct interaction between epithelial cells and the interstitialextracellular matrix could induce EMT.
Type IV collagen contributes to the maintenance of the epithelialphenotype of cultured proximal tubular cells, whereas type Icollagen promotes EMT. Inhibition of type IV collagen assemblyby the 1-NC1 domain upregulated the production of TGF- in proximaltubular cells and induced EMT (34,35). The transdifferentiatedepithelial cells exhibited fibroblast-like morphology, increasedexpression of FSP-1 and vimentin, decreased CK expression, andincreased synthesis of collagen I, which stabilizes the mesenchymephenotype of the transdifferentiated cells. EMT could be blockedby anti–TGF-1 antibodies. These data suggest that changesin the basement membrane architecture can lead to upregulationof TGF-1, which contributes to EMT that accompanies renal fibrosis.
Cytokines, growth factors, and adhesion molecules are involvedin EMT. In tubular epithelial cells, FGF (36), TGF- (37–39),and FGF associated with TGF- (33) induced de novo expressionof -SMA, loss of the epithelial marker E-cadherin, change froman epithelial (cuboidal) appearance to a myofibroblastic (spindleshaped) morphology, along with build-up of interstitial matrix.The typical cobblestone pattern of cultured epithelial cellswas replaced by a spindle-shaped fibroblast-like appearancewith cytoplasmic projections at the front end, large bundlesof actin microfilaments, and dense bodies. All of these effectswere blocked in NRK-52 E cells, a normal rat kidney epithelialcell line, by a neutralizing antibody to TGF-1 (38). Similarresults were obtained using IL-1. Addition of a neutralizingantibody to TGF- blocked the effects of IL-1 on EMT, suggestinga TGF- dependence (40).
EMT in tubular epithelial cells has been demonstrated in vivo.In DBA/2-pcy mice, a model of polycystic kidney disease (41),epithelial cells in remnant tubules lost expression of CK butexpressed FSP-1 and HSP47, a marker for collagen synthesis.In unilateral renal obstruction, epithelial cells exhibitedfeatures of EMT (39,42). In the same experimental model, TGF-1receptor expression was increased in renal tubules. Hepatocytegrowth factor blocked EMT and prevented interstitial fibrosisin the obstructed kidney. In vitro hepatocyte growth factorabrogated EMT-induced TGF-1 expression in tubular epithelialcells (43).
Loss of epithelial cell adhesion may also promote the EMT process.E-cadherin, an adhesion receptor found within adherens-typejunctions, plays a role in maintaining the polarity and thestructural integrity of renal epithelial cells. The additionof antibodies to E-cadherin induced disaggregation of the MDCKkidney epithelial cell line and their reversion to fibroblast-likecells (44,45). TGF-1 rapidly suppressed E-cadherin expressionin cultured tubular epithelial cells before all of the majorevents that characterize EMT (39). All of these human and experimentalstudies on EMT suggest that EMT may participate in the developmentand the progression of glomerular and tubulointerstitial fibrosis.
Transdifferentiation of Glomerular Epithelial Cells into Macrophagic Cells
Transdifferentiation of Glomerular Epithelial Cells in Posttransplantation Relapse of Primary FSGS
Relapse of primary FSGS on transplanted kidneys offers a privilegedmodel for studying the early and later lesions that characterizethis glomerulopathy. We studied 18 renal biopsies from 6 casesof primary nephrotic FSGS that had relapsed after transplantation(14). The glomerular lesions comprised the cellular, the collapsing,and the scar variants of FSGS and showed shedding of large roundcells into Bowman’s space and within the tubular lumens.With the use of immunohistochemical identification of glomerularcells and of free migrating cells, some phenotypic changes suggestingtransdifferentiation were found. Some podocytes identified bypodocyte markers (podocalyxin, synaptopodin, GLEPP-1) were detachedfrom the tuft and were free in the urinary spaces. Loss of normalpodocyte epitopes (podocalyxin, synaptopodin, GLEPP-1, WT1,CR1) was observed on the podocytes in the cellular variant andon the cobblestone-like epithelial cells that covered the scarlesions outside the synechiae. Podocytes acquired expressionof various CK (identified by the AE1/AE3, C2562, CK22, and AEL-KS2monoclonal antibodies) that were not found in the podocytesof normal glomeruli. However, PEC expressed AE1/AE3 CK thatwere rarely found on the PEC of normal glomeruli. Expressionof macrophagic epitopes, identified by the PGM1 (CD68) and theHAM56 monoclonal antibodies, was observed on numerous cellslocated at the periphery of the tuft or free in the urinaryspace. That these cells that express epitopes specific for themonocyte-macrophage lineage were endowed with macrophagic attributeswas shown by expression of 25F9, which characterizes macrophagematuration, and even more convincingly by expression of HLA-DRand CD16, which characterize macrophagic cell activation. Thebest argument for a process of cell transdifferentiation occurringin the glomerular epithelial cells stems from confocal lasermicroscopic examination. Using this technique, we observed coexpressionof (1) CD68 + AE1/AE3 CK (Figure 3) (2), podocalyxin + CD68(Figure 4), and (3) podocalyxin + AE1/AE3 CK on cells that werestill attached to the glomerular tuft or that drifted in Bowman’sspace and within the tubular lumens.
These findings strongly suggest that some "dysregulated" podocytes,occasionally some PEC, and possibly some tubular epithelialcells undergo a process of transdifferentiation. This processof transdifferentiation was especially striking in podocytesthat acquired macrophagic and CK epitopes, which are not expressedin normal adult and fetal podocytes.
Transdifferentiation of Podocytes in Idiopathic Collapsing Glomerulopathy
Collapsing glomerulopathy, a severe variant of FSGS, is characterizedby collapse of most, if not all, of the glomerular tufts withproliferation of modified podocytes. In the most damaged glomeruli,the hyperplastic podocytes show swelling, vacuolization, multinucleation,cobblestone alignment around the glomerular tuft, and pseudocrescentformation in Bowman’s space. Some of these podocytes areseparated from the GBM and seem to be drifting in Bowman’sspace.
We studied eight cases of idiopathic collapsing glomerulopathy.There were five black and three white patients. All were HIVnegative (13). Podocytes were identified by the presence ofpodocalyxin, of vimentin, a protein of the podocyte cytoskeleton,and of CR1. To characterize further the phenotypic expressionof swollen, vacuolated, cobblestone-like, or detached podocytes,we used three anti-human monoclonal antibodies with differentspecificities for macrophage-associated epitopes: an anti-CD68monoclonal antibody (clone PGM1,) an anti-CD68 monoclonal antibody(clone KP1), and an anti-human macrophage antibody (clone M18).Along with dislodging, podocytes exhibited phenotypic transformation.Most of those still attached to the GBM still expressed podocalyxin,CR1, and vimentin, whereas some expressed CD68 (Figure 5). Onceassuming cobblestone-like alignment or detachment from the tuftand moving free in the urinary space, they lost normal podocyteepitopes and acquired a macrophage-associated phenotype.
Our findings are substantiated by experiments based on normalrat glomerular cell cultures. Glomerular epithelial cells areable to acquire in vitro the ability to process and presentantigens (46). Whole glomeruli in culture were isolated by agraded sieving technique. Cells identified as being derivedfrom podocytes changed into macrophages that migrated from theglomeruli. Once cultured, podocytes lost both the ultrastructuralappearance and some immunohistochemical podocyte markers, andthey acquired morphologic and functional characteristics ofmacrophages (47).
The significance and the consequences of such intriguing phenomenaregarding transdifferentiation of glomerular epithelial cellsinto macrophagic cells are a matter of obvious interest. Thereis no doubt that these observations should—and will—fosterfurther studies that hopefully will unravel their implicationsin the still elusive pathophysiology of FSGS and of other glomerulopathies.
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Introduction
EMT-Like Changes of Podocytes...
-smooth muscle actin (
-, and 
-catenin; and 
