{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:03:42Z","timestamp":1760148222032,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,9]],"date-time":"2023-04-09T00:00:00Z","timestamp":1680998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Growing evidence indicates that hepatocyte growth factor (HGF) possesses potent antifibrotic activity. Furthermore, macrophages migrate to inflamed sites and have been linked to the progression of fibrosis. In this study, we utilized macrophages as vehicles to express and deliver the HGF gene and investigated whether macrophages carrying the HGF expression vector (HGF-M) could suppress peritoneal fibrosis development in mice. We obtained macrophages from the peritoneal cavity of mice stimulated with 3% thioglycollate and used cationized gelatin microspheres (CGMs) to produce HGF expression vector-gelatin complexes. Macrophages phagocytosed these CGMs, and gene transfer into macrophages was confirmed in vitro. Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate (CG) for three weeks; seven days after the first CG injection, HGF-M was administered intravenously. Transplantation of HGF-M significantly suppressed submesothelial thickening and reduced type III collagen expression. Moreover, in the HGF-M-treated group, the number of \u03b1-smooth muscle actin- and TGF-\u03b2-positive cells were significantly lower in the peritoneum, and ultrafiltration was preserved. Our results indicated that the transplantation of HGF-M prevented the progression of peritoneal fibrosis and indicated that this novel gene therapy using macrophages may have potential for treating peritoneal fibrosis.<\/jats:p>","DOI":"10.3390\/ijms24086951","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T03:49:29Z","timestamp":1681098569000},"page":"6951","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Transfer of the Hepatocyte Growth Factor Gene by Macrophages Ameliorates the Progression of Peritoneal Fibrosis in Mice"],"prefix":"10.3390","volume":"24","author":[{"given":"Yoko","family":"Obata","sequence":"first","affiliation":[{"name":"Department of Nephrology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsushige","family":"Abe","sequence":"additional","affiliation":[{"name":"Abe Diabetes Clinic, 16-13 Nakakasuga-machi, Oita 870-0039, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanobu","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Miyazaki Clinic, 3-12 Shiratori-cho, Nagasaki 852-8042, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takehiko","family":"Koji","sequence":"additional","affiliation":[{"name":"Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiko","family":"Tabata","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Life and Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoya","family":"Nishino","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1001\/archinte.1980.00330200077024","article-title":"Sclerotic thickening of the peritoneal membrane in maintenance peritoneal dialysis patients","volume":"140","author":"Gandhi","year":"1980","journal-title":"Arch. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1159\/000188837","article-title":"Morphological changes in the peritoneal vasculature of patients on CAPD with ultrafiltration failure","volume":"72","author":"Honda","year":"1996","journal-title":"Nephron"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1681\/ASN.V132470","article-title":"Morphologic changes in the peritoneal membrane of patients with renal disease","volume":"13","author":"Williams","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/ndt\/17.suppl_3.12","article-title":"Morphological and functional changes in the dialysed peritoneal cavity: Impact of more biocompatible solutions","volume":"17","author":"Devuyst","year":"2002","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/342440a0","article-title":"Molecular cloning and expression of human hepatocyte growth factor","volume":"342","author":"Nakamura","year":"1989","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Motoi, S., Toyoda, H., Obara, T., Ohta, E., Arita, Y., Negishi, K., Moriya, K., Kuboi, Y., Soejima, M., and Imai, T. (2019). Anti-apoptotic effects of recombinant human hepatocyte growth factor on hepatocytes were associated with intrahepatic hemorrhage suppression indicated by the preservation of prothrombin time. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20081821"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1038\/aps.2018.14","article-title":"Anti-inflammatory activities of hepatocyte growth factor in post-ischemic heart failure","volume":"39","author":"Rong","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.etp.2012.03.003","article-title":"Plasmid pUDK-HGF encoding human hepatocyte growth factor gene attenuates gentamicin-induced kidney injury in rats","volume":"65","author":"Chen","year":"2013","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4357","DOI":"10.1073\/pnas.91.10.4357","article-title":"Hepatocyte growth factor prevents acute renal failure and accelerates renal regeneration in mice","volume":"91","author":"Kawaida","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1006\/cyto.1996.0053","article-title":"Preventive effect of hepatocyte growth factor on acute side effects of cyclosporin A in mice","volume":"8","author":"Amaike","year":"1996","journal-title":"Cytokine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/5593","article-title":"Hepatocyte growth factor gene therapy of liver cirrhosis in rats","volume":"5","author":"Ueki","year":"1999","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1172\/JCI1709","article-title":"Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease","volume":"101","author":"Mizuno","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.1164\/ajrccm.162.6.9908097","article-title":"Hepatocyte growth factor attenuates collagen accumulation in a murine model of pulmonary fibrosis","volume":"162","author":"Dohi","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1172\/JCI10226","article-title":"Myocardial protection from ischemia\/reperfusion injury by endogenous and exogenous HGF","volume":"106","author":"Nakamura","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1161\/01.CIR.0000065579.19126.B8","article-title":"Postinfarction treatment with an adenoviral vector expressing hepatocyte growth factor relieves chronic left ventricular remodeling and dysfunction in mice","volume":"107","author":"Li","year":"2003","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1182\/blood-2006-11-058933","article-title":"Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency","volume":"110","author":"Chinen","year":"2007","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1056\/NEJMoa0805817","article-title":"Gene therapy for immunodeficiency due to adenosine deaminase deficiency","volume":"360","author":"Aiuti","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1126\/science.1171242","article-title":"Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy","volume":"326","author":"Cartier","year":"2009","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1056\/NEJMoa1108046","article-title":"Adenovirus-associated virus vector-mediated gene transfer in hemophilia B","volume":"365","author":"Nathwani","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/S1474-4422(21)00251-9","article-title":"STR1VE-EU study group. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): An open-label, single-arm, multicentre, phase 3 trial","volume":"20","author":"Mercuri","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1056\/NEJMoa1709866","article-title":"Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia","volume":"378","author":"Maude","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1056\/NEJMoa1804980","article-title":"Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma","volume":"380","author":"Schuster","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S1474-4422(11)70039-4","article-title":"Feigin A AAV2-GAD gene therapy for advanced Parkinson\u2019s disease: A double-blind, sham-surgery controlled, randomised trial","volume":"10","author":"LeWitt","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1093\/brain\/awy331","article-title":"Gene therapy improves motor and mental function of aromatic L-amino acid decarboxylase deficiency","volume":"142","author":"Kojima","year":"2019","journal-title":"Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1038\/gt.2010.51","article-title":"Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia","volume":"17","author":"Shigematsu","year":"2010","journal-title":"Gene Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1016\/S0140-6736(16)31009-1","article-title":"Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): Two randomised, double-blind, placebo-controlled, dose-ranging trials","volume":"388","author":"Viney","year":"2016","journal-title":"Lancet"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1159\/000108759","article-title":"Suppression of renal tubulointerstitial fibrosis by small interfering RNA targeting heat shock protein 47","volume":"28","author":"Xia","year":"2008","journal-title":"Am. J. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2688","DOI":"10.1016\/j.actbio.2012.03.050","article-title":"HSP47 siRNA conjugated with cationized gelatin microspheres suppresses peritoneal fibrosis in mice","volume":"8","author":"Obata","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/B978-1-4831-6753-4.50010-7","article-title":"The physical chemistry of gelatin","volume":"3","author":"Veis","year":"1965","journal-title":"Int. Rev. Connect. Tissue Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0168-3659(03)00197-4","article-title":"In vivo release and gene expression of plasmid DNA by hydrogels of gelatin with different cationization extents","volume":"90","author":"Kushibiki","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1177\/089686080302300102","article-title":"Enhanced expression of heat shock protein 47 in rat model of peritoneal fibrosis","volume":"23","author":"Mishima","year":"2003","journal-title":"Perit. Dial. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1177\/0896860820981322","article-title":"An inhibitor of Kr\u00fcppel-like factor 5 suppresses peritoneal fibrosis in mice","volume":"41","author":"Muta","year":"2021","journal-title":"Perit. Dial. Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1056\/NEJM199411103311907","article-title":"Transforming growth factor beta in tissue fibrosis","volume":"331","author":"Border","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/sj.ki.5001661","article-title":"Hepatocyte growth factor: New arsenal in the fights against renal fibrosis?","volume":"70","author":"Liu","year":"2006","journal-title":"Kidney Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1053\/jhep.2000.9109","article-title":"Inhibition of transforming growth factor beta prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats","volume":"32","author":"Nakamura","year":"2000","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1161\/01.CIR.83.2.578","article-title":"Introduction of vascular smooth muscle cells expressing recombinant genes in vivo","volume":"83","author":"Plautz","year":"1991","journal-title":"Circulation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1126\/science.8047883","article-title":"Gene therapy for vascular smooth muscle cell proliferation after arterial injury","volume":"265","author":"Ohno","year":"1994","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1177\/1358836X0000500107","article-title":"Insights into the molecular pathogenesis of atherosclerosis and therapeutic strategies using gene transfer","volume":"5","author":"Hiltunen","year":"2000","journal-title":"Vasc. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1161\/01.CIR.93.2.301","article-title":"Enhanced in vivo antithrombotic effects of endothelial cells expressing recombinant plasminogen activators transduced with retroviral vectors","volume":"93","author":"Dichek","year":"1996","journal-title":"Circulation"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1161\/01.RES.70.2.348","article-title":"Genetically engineered endothelial cells remain adherent and viable after stent deployment and exposure to flow in vitro","volume":"70","author":"Flugelman","year":"1992","journal-title":"Circ. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/BFb0043062","article-title":"Phagocytosis of polymer microspheres by macrophages","volume":"94","author":"Tabata","year":"1990","journal-title":"Adv. Polym. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1161\/01.CIR.0000079161.56080.22","article-title":"Hybrid cell-gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells","volume":"108","author":"Nagaya","year":"2003","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0168-3659(02)00026-3","article-title":"Controlled release of plasmid DNA from cationized gelatin hydrogels based on hydrogel degradation","volume":"80","author":"Fukunaka","year":"2002","journal-title":"J. Control. Release"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/sj.gt.3302285","article-title":"Suppression of tumor metastasis by NK4 plasmid DNA released from cationized gelatin","volume":"11","author":"Kushibiki","year":"2004","journal-title":"Gene Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/0003-2697(75)90431-5","article-title":"An improved 2,4,6-trinitrobenzenesulfonic acid method for the determination of amines","volume":"64","author":"Snyder","year":"1975","journal-title":"Anal. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S1074-7613(00)80119-3","article-title":"Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components","volume":"11","author":"Takeuchi","year":"1999","journal-title":"Immunity"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1267\/ahc.13005","article-title":"Involvement of leptin in the progression of experimentally induced peritoneal fibrosis in mice","volume":"46","author":"Nakazawa","year":"2013","journal-title":"Acta Histochem. Cytochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/6951\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:12:40Z","timestamp":1760123560000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/6951"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,9]]},"references-count":47,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24086951"],"URL":"https:\/\/doi.org\/10.3390\/ijms24086951","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,4,9]]}}}