title: Instructive Role of the Microenvironment in Preventing Renal Fibrosis.
abstract: Accumulation of myofibroblasts is a hallmark of renal fibrosis. A significant proportion of myofibroblasts has been reported to originate via endothelial-mesenchymal transition. We initially hypothesized that exposing myofibroblasts to the extract of endothelial progenitor cells (EPCs) could reverse this transition. Indeed, in vitro treatment of transforming growth factor-β1 (TGF-β1)-activated fibroblasts with EPC extract prevented expression of α-smooth muscle actin (α-SMA); however, it did not enhance expression of endothelial markers. In two distinct models of renal fibrosis-unilateral ureteral obstruction and chronic phase of folic acid-induced nephropathy-subcapsular injection of EPC extract to the kidney prevented and reversed accumulation of α-SMA-positive myofibroblasts and reduced fibrosis. Screening the composition of EPC extract for cytokines revealed that it is enriched in leukemia inhibitory factor (LIF) and vascular endothelial growth factor. Only LIF was capable of reducing fibroblast-to-myofibroblast transition of TGF-β1-activated fibroblasts. In vivo subcapsular administration of LIF reduced the number of myofibroblasts and improved the density of peritubular capillaries; however, it did not reduce the degree of fibrosis. A receptor-independent ligand for the gp130/STAT3 pathway, hyper-interleukin-6 (hyper-IL-6), not only induced a robust downstream increase in pluripotency factors Nanog and c-Myc but also exhibited a powerful antifibrotic effect. In conclusion, EPC extract prevented and reversed fibroblast-to-myofibroblast transition and renal fibrosis. The component of EPC extract, LIF, was capable of preventing development of the contractile phenotype of activated fibroblasts but did not eliminate TGF-β1-induced collagen synthesis in cultured fibroblasts and models of renal fibrosis, whereas a receptor-independent gp130/STAT3 agonist, hyper-IL-6, prevented fibrosis. In summary, these studies, through the evolution from EPC extract to LIF and then to hyper-IL-6, demonstrate the instructive role of microenvironmental cues and may provide in the future a facile strategy to prevent and reverse renal fibrosis. Stem Cells Translational Medicine 2017;6:992-1005.
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.|Renal Research Institute, New York Medical College, Valhalla, New York, USA.|Showa University, Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.|Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Xavier
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.|Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.|Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Kida
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.|Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lipphardt
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.|Renal Research Institute, New York Medical College, Valhalla, New York, USA.|Okayama University, Okayama, Japan.
authors.forename: Reina
authors.initials: R
authors.lastname: Ikeda
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.|Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Gevertz
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.|Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Caviris
authors.affiliation: Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Antonis K
authors.initials: AK
authors.lastname: Hatzopoulos
authors.affiliation: University of Connecticut Health Center, Farmington, Connecticut, USA.
authors.forename: Ivo
authors.initials: I
authors.lastname: Kalajzic
authors.affiliation: Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: James
authors.initials: J
authors.lastname: Dutton
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.|Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Ratliff
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.|Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.|Renal Research Institute, New York Medical College, Valhalla, New York, USA.
authors.forename: Zbygniew
authors.initials: Z
authors.lastname: Darzynkiewicz
authors.affiliation: Institute of Biochemistry, Christian-Albrechts University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Department of Medicine, New York Medical College, Valhalla, New York, USA.|Department of Pharmacology, New York Medical College, Valhalla, New York, USA.|Department of Physiology, New York Medical College, Valhalla, New York, USA.|Department of Pathology, New York Medical College, Valhalla, New York, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
mesh_terms: D016475:3T3 Cells; D000818:Animals; D060833:Cellular Microenvironment / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005355:Fibrosis; D015850:Interleukin-6 / Q000494:pharmacology; D007668:Kidney / Q000473:pathology*; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014517:Ureteral Obstruction / Q000473:pathology
chemical_list: D018925:Chemokines; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D050822:Cytokine Receptor gp130
keywords: Green fluorescent protein; Hyper-interleukin-6; Leukemia inhibitory factor; Transforming growth factor-β1; α-Smooth muscle actin