title: Microencapsulated human mesenchymal stem cells decrease liver fibrosis in mice.
abstract: OBJECTIVE
  Mesenchymal stem cell (MSC) transplantation was shown to be effective for the treatment of liver fibrosis, but the mechanisms of action are not yet fully understood. We transplanted encapsulated human MSCs in two mouse models of liver fibrosis to determine the mechanisms behind the protective effect.
  
  
  METHODS
  Human bone marrow-derived MSCs were microencapsulated in novel alginate-polyethylene glycol microspheres. In vitro, we analyzed the effect of MSC-conditioned medium on the activation of hepatic stellate cells and the viability, proliferation, cytokine secretion, and differentiation capacity of encapsulated MSCs. The level of fibrosis induced by bile duct ligation (BDL) or carbon tetrachloride (CCl4) was assessed after intraperitoneal transplantation of encapsulated MSCs, encapsulated human fibroblasts, and empty microspheres.
  
  
  RESULTS
  MSC-conditioned medium inhibited hepatic stellate cell activation and release of MSC secreted anti-apoptotic (IL-6, IGFBP-2) and anti-inflammatory (IL-1Ra) cytokines. Viability, proliferation, and cytokine secretion of microencapsulated MSCs were similar to those of non-encapsulated MSCs. Within the microspheres, MSCs maintained their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. 23% (5/22) of the MSC clones were able to produce anti-inflammatory IL-1Ra in vitro. Microencapsulated MSCs significantly delayed the development of BDL- and CCl4-induced liver fibrosis. Fibroblasts had an intermediate effect against CCl4-induced fibrosis. Mice transplanted with encapsulated MSCs showed lower mRNA levels of collagen type I, whereas levels of matrix metalloproteinase 9 were significantly higher. Human IL-1Ra was detected in the serum of 36% (4/11) of the mice transplanted with microencapsulated MSCs.
  
  
  CONCLUSIONS
  MSC-derived soluble molecules are responsible for an anti-fibrotic effect in experimental liver fibrosis.
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and Medical School, Geneva, Switzerland. Electronic address: Raphael.meier@hcuge.ch.
authors.forename: Raphael P H
authors.initials: RP
authors.lastname: Meier
authors.affiliation: Institut d'Ingénierie Biologique et Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Redouan
authors.initials: R
authors.lastname: Mahou
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and Medical School, Geneva, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Morel
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and Medical School, Geneva, Switzerland.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Meyer
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and Medical School, Geneva, Switzerland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Montanari
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and Medical School, Geneva, Switzerland.
authors.forename: Yannick D
authors.initials: YD
authors.lastname: Muller
authors.affiliation: Orthopedic Surgery, Department of Surgery, Geneva University Hospitals and Medical School, Geneva, Switzerland.
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Christofilopoulos
authors.affiliation: Institut d'Ingénierie Biologique et Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Wandrey
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and Medical School, Geneva, Switzerland.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gonelle-Gispert
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and Medical School, Geneva, Switzerland.
authors.forename: Leo H
authors.initials: LH
authors.lastname: Bühler
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000637:transplantation; D000410:Alanine Transaminase / Q000097:blood; D000464:Alginates; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001652:Bile Ducts; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation; D002470:Cell Survival; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D006801:Humans; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008811:Mice, Inbred DBA; D008863:Microspheres; D011092:Polyethylene Glycols; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000464:Alginates; D017077:Culture Media, Conditioned; D016207:Cytokines; D012333:RNA, Messenger; D011092:Polyethylene Glycols; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Alginate; Cell transplantation; Inflammation; Interleukin 1 receptor antagonist; Liver fibrosis; Mesenchymal stem cells; Mice; Microencapsulation