title: Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats.
abstract: Bone marrow-derived cells (BMDC) have been proposed to exert beneficial effects after renal ischemia/reperfusion injury (IRI) by engraftment in the tubular epithelium. However, BMDC can give rise to myofibroblasts and may contribute to fibrosis. BMDC contribution to the renal interstitial myofibroblast population in relation to fibrotic changes after IRI in rats was investigated. A model of unilateral renal IRI (45 min of ischemia) was used in F344 rats that were reconstituted with R26-human placental alkaline phosphatase transgenic BM to quantify BMDC contribution to the renal interstitial myofibroblast population over time. After IRI, transient increases in collagen III transcription and interstitial protein deposition were observed, peaking on days 7 and 28, respectively. Interstitial infiltrates of BMDC and myofibroblasts reached a maximum on day 7 and gradually decreased afterward. Over time, an average of 32% of all interstitial alpha-smooth muscle actin-positive myofibroblasts coexpressed R26-human placental alkaline phosphatase and, therefore, were derived from the BM. BMD myofibroblasts produced procollagen I protein and therefore were functional. The postischemic kidney environment was profibrotic, as demonstrated by increased transcription of TGF-beta and decreased transcription of bone morphogenic protein-7. TGF-beta protein was present predominantly in interstitial myofibroblasts but not in BMD myofibroblasts. In conclusion, functional BMD myofibroblasts infiltrate in the postischemic renal interstitium and are involved in extracellular matrix production.
authors.affiliation: Department of Pathology & Laboratory Medicine, University Medical Center Groningen, University of Groningen, The Netherlands. m.broekema@med.umcg.nl
authors.forename: Martine
authors.initials: M
authors.lastname: Broekema
authors.forename: Martin C
authors.initials: MC
authors.lastname: Harmsen
authors.forename: Marja J A
authors.initials: MJ
authors.lastname: van Luyn
authors.forename: Jasper A
authors.initials: JA
authors.lastname: Koerts
authors.forename: Arjen H
authors.initials: AH
authors.lastname: Petersen
authors.forename: Theo G
authors.initials: TG
authors.lastname: van Kooten
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Eliane R
authors.initials: ER
authors.lastname: Popa
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D016026:Bone Marrow Transplantation; D024042:Collagen Type I / Q000096:biosynthesis*; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008297:Male; D012313:RNA / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016212:Transforming Growth Factor beta / Q000378:metabolism; D018183:Transplantation Chimera
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D016212:Transforming Growth Factor beta; D012313:RNA; D003404:Creatinine