{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T16:57:07Z","timestamp":1787763427164,"version":"build-2784847793"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>\n                      No effective therapy is currently available to directly address a key feature of CKD progression: interstitial fibrosis leading to a loss of peritubular capillaries (PTCs). One potential antifibrotic candidate, hepatocyte growth factor (HGF), cannot be applied in clinical settings owing to its short\n                      <jats:italic toggle=\"yes\">t<\/jats:italic>\n                      <jats:sub>1\/2<\/jats:sub>\n                      in blood and elimination by other organs, such as the liver. The authors describe use of a novel HGF therapy using cell sheet technology: transplantation of transgenic HGF-secreting mesothelial cell sheets to the kidney in a CKD rat model. The HGF-secreting cell sheet directly suppresses interstitial fibrosis for 28 days and prevents loss of peritubular capillaries. Inhibition of CKD progression requires long-term suppression of fibrosis, and cell sheet therapy represents a promising strategy for achieving that goal.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Although hepatocyte growth factor (HGF) has antifibrotic effects and is involved in angiogenesis and vasodilation, systemic administration of HGF to prevent kidney fibrosis is not a feasible strategy for suppressing interstitial fibrosis in patients with CKD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated a novel therapy involving HGF transgenic cell sheets grown in culture from human mesothelial cells and administered to rats with unilateral ureteral obstruction (UUO). We compared progression of fibrosis in rats with UUO that received one of five interventions: HGF-transgenic mesothelial cell sheets transplanted to the kidney surface, HGF-transgenic mesothelial cell sheets transplanted to thigh, mesotherial cell sheets transplanted to kidney, no sheets, or HGF injections.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HGF transgenic cell sheets transplanted to the kidney strongly suppressed the induction of myofibroblasts and collagen in the kidney for 28 days; other interventions did not. Additionally, the HGF-secreting cell sheets ameliorated loss of peritubular capillaries and maintained renal blood flow.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest that cell sheet therapy is a novel and promising strategy for inhibiting progressive fibrosis in CKD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2018050556","type":"journal-article","created":{"date-parts":[[2019,1,11]],"date-time":"2019-01-11T17:35:16Z","timestamp":1547228116000},"page":"261-276","source":"Crossref","is-referenced-by-count":33,"title":["Hepatocyte Growth Factor\u2013Secreting Mesothelial Cell Sheets Suppress Progressive Fibrosis in a Rat Model of CKD"],"prefix":"10.1681","volume":"30","author":[{"given":"Masatoshi","family":"Oka","sequence":"first","affiliation":[{"name":"Department of Medicine, Kidney Center,"},{"name":"Institute of Advanced Biomedical Engineering and Science, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Sekiya","sequence":"additional","affiliation":[{"name":"Institute of Advanced Biomedical Engineering and Science, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoichi","family":"Sakiyama","sequence":"additional","affiliation":[{"name":"Department of Clinical Engineering, Tokyo Women\u2019s Medical University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Institute of Advanced Biomedical Engineering and Science, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosaku","family":"Nitta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Kidney Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,1,11]]},"reference":[{"key":"B1-20230829","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/S0140-6736(13)60687-X","article-title":"Chronic kidney disease: Global dimension and perspectives.","volume":"382","author":"Jha","year":"2013","journal-title":"Lancet"},{"key":"B2-20230829","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1681\/ASN.V561273","article-title":"Experimental insights into the tubulointerstitial disease accompanying primary glomerular lesions.","volume":"5","author":"Eddy","year":"1994","journal-title":"J Am Soc Nephrol"},{"key":"B3-20230829","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0272-6386(12)80312-X","article-title":"Tubulointerstitial changes as a major determinant in the progression of renal damage.","volume":"20","author":"Nath","year":"1992","journal-title":"Am J Kidney Dis"},{"key":"B4-20230829","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/ki.2008.183","article-title":"The role of capillary density, macrophage infiltration and interstitial scarring in the pathogenesis of human chronic kidney disease.","volume":"74","author":"Eardley","year":"2008","journal-title":"Kidney Int"},{"key":"B5-20230829","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1097\/01.ASN.0000018408.51388.57","article-title":"Peritubular capillary regression during the progression of experimental obstructive nephropathy.","volume":"13","author":"Ohashi","year":"2002","journal-title":"J Am Soc Nephrol"},{"key":"B6-20230829","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1681\/ASN.2010111143","article-title":"Noninvasive evaluation of kidney hypoxia and fibrosis using magnetic resonance imaging.","volume":"22","author":"Inoue","year":"2011","journal-title":"J Am Soc Nephrol"},{"key":"B7-20230829","first-page":"3810","article-title":"Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition.","volume":"117","author":"Higgins","year":"2007","journal-title":"J Clin Invest"},{"key":"B8-20230829","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1097\/01.ASN.0000128047.13396.48","article-title":"Hypoperfusion of peritubular capillaries induces chronic hypoxia before progression of tubulointerstitial injury in a progressive model of rat glomerulonephritis.","volume":"15","author":"Matsumoto","year":"2004","journal-title":"J Am Soc Nephrol"},{"key":"B9-20230829","doi-asserted-by":"crossref","first-page":"F1187","DOI":"10.1152\/ajprenal.00425.2014","article-title":"Hypoxia as a key player in the AKI-to-CKD transition.","volume":"307","author":"Tanaka","year":"2014","journal-title":"Am J Physiol Renal Physiol"},{"key":"B10-20230829","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1681\/ASN.2005070757","article-title":"Chronic hypoxia and tubulointerstitial injury: A final common pathway to end-stage renal failure.","volume":"17","author":"Nangaku","year":"2006","journal-title":"J Am Soc Nephrol"},{"key":"B11-20230829","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1172\/JCI114359","article-title":"Epidermal growth factor enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic acute renal failure.","volume":"84","author":"Humes","year":"1989","journal-title":"J Clin Invest"},{"key":"B12-20230829","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/nm888","article-title":"BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.","volume":"9","author":"Zeisberg","year":"2003","journal-title":"Nat Med"},{"key":"B13-20230829","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1046\/j.1523-1755.2001.0590041304.x","article-title":"Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy.","volume":"59","author":"Mizuno","year":"2001","journal-title":"Kidney Int"},{"issue":"Suppl","key":"B14-20230829","first-page":"11301","article-title":"Potential role of hepatocyte growth factor, a novel angiogenic growth factor, in peripheral arterial disease: Downregulation of HGF in response to hypoxia in vascular cells.","volume":"100","author":"Hayashi","year":"1999","journal-title":"Circulation"},{"key":"B15-20230829","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1161\/01.HYP.0000136394.08900.ed","article-title":"Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease.","volume":"44","author":"Morishita","year":"2004","journal-title":"Hypertension"},{"key":"B16-20230829","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.vph.2012.02.002","article-title":"Hepatocyte growth factor stimulated angiogenesis without inflammation: Differential actions between hepatocyte growth factor, vascular endothelial growth factor and basic fibroblast growth factor.","volume":"57","author":"Kaga","year":"2012","journal-title":"Vascul Pharmacol"},{"key":"B17-20230829","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1042\/bj20030326","article-title":"Hepatocyte growth factor activates endothelial nitric oxide synthase by Ca(2+)- and phosphoinositide 3-kinase\/Akt-dependent phosphorylation in aortic endothelial cells.","volume":"374","author":"Makondo","year":"2003","journal-title":"Biochem J"},{"key":"B18-20230829","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nature14407","article-title":"MET is required for the recruitment of anti-tumoural neutrophils.","volume":"522","author":"Finisguerra","year":"2015","journal-title":"Nature"},{"key":"B19-20230829","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1681\/ASN.V13196","article-title":"Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis.","volume":"13","author":"Yang","year":"2002","journal-title":"J Am Soc Nephrol"},{"key":"B20-20230829","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1038\/nm.3218","article-title":"Origin and function of myofibroblasts in kidney fibrosis.","volume":"19","author":"LeBleu","year":"2013","journal-title":"Nat Med"},{"key":"B21-20230829","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.2353\/ajpath.2009.090096","article-title":"Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice.","volume":"175","author":"Li","year":"2009","journal-title":"Am J Pathol"},{"key":"B22-20230829","doi-asserted-by":"crossref","first-page":"22910","DOI":"10.1074\/jbc.M703597200","article-title":"Differentiation of human circulating fibrocytes as mediated by transforming growth factor-\u03b2 and peroxisome proliferator-activated receptor \u03b3.","volume":"282","author":"Hong","year":"2007","journal-title":"J Biol Chem"},{"key":"B23-20230829","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1046\/j.1523-1755.1998.00092.x","article-title":"Potential role of hepatocyte growth factor in the maintenance of renal structure: Anti-apoptotic action of HGF on epithelial cells.","volume":"54","author":"Yo","year":"1998","journal-title":"Kidney Int"},{"key":"B24-20230829","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1681\/ASN.2006020185","article-title":"Anti-inflammatory effect of hepatocyte growth factor in chronic kidney disease: Targeting the inflamed vascular endothelium.","volume":"17","author":"Gong","year":"2006","journal-title":"J Am Soc Nephrol"},{"key":"B25-20230829","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 U S A"},{"key":"B26-20230829","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.hepres.2004.09.002","article-title":"Pharmacokinetic study of recombinant human hepatocyte growth factor administered in a bolus intravenously or via portal vein.","volume":"30","author":"Ido","year":"2004","journal-title":"Hepatol Res"},{"key":"B27-20230829","first-page":"270","article-title":"Hepatocyte growth factor, blood clearance, organ uptake, and biliary excretion in normal and partially hepatectomized rats.","volume":"68","author":"Appasamy","year":"1993","journal-title":"Lab Invest"},{"key":"B28-20230829","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/0142-9612(95)93257-E","article-title":"Mechanism of cell detachment from temperature-modulated, hydrophilic-hydrophobic polymer surfaces.","volume":"16","author":"Okano","year":"1995","journal-title":"Biomaterials"},{"key":"B29-20230829","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1016\/S0142-9612(03)00110-8","article-title":"Cell sheet engineering for myocardial tissue reconstruction.","volume":"24","author":"Shimizu","year":"2003","journal-title":"Biomaterials"},{"key":"B30-20230829","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s00595-011-0106-4","article-title":"Tissue engineered myoblast sheets improved cardiac function sufficiently to discontinue LVAS in a patient with DCM: Report of a case.","volume":"42","author":"Sawa","year":"2012","journal-title":"Surg Today"},{"key":"B31-20230829","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1056\/NEJMoa040455","article-title":"Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium.","volume":"351","author":"Nishida","year":"2004","journal-title":"N Engl J Med"},{"key":"B32-20230829","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1089\/biores.2012.0296","article-title":"Hormone supplying renal cell sheet in vivo produced by tissue engineering technology.","volume":"2","author":"Sekiya","year":"2013","journal-title":"Biores Open Access"},{"key":"B33-20230829","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1002\/term.1860","article-title":"Peritoneal cell sheets composed of mesothelial cells and fibroblasts prevent intra-abdominal adhesion formation in a rat model.","volume":"10","author":"Kawanishi","year":"2016","journal-title":"J Tissue Eng Regen Med"},{"key":"B34-20230829","doi-asserted-by":"crossref","first-page":"e19161","DOI":"10.1371\/journal.pone.0019161","article-title":"hHGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure.","volume":"6","author":"Siltanen","year":"2011","journal-title":"PLoS One"},{"key":"B35-20230829","doi-asserted-by":"crossref","first-page":"F406","DOI":"10.1152\/ajprenal.00099.2004","article-title":"TNF-\u03b1 mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling.","volume":"288","author":"Misseri","year":"2005","journal-title":"Am J Physiol Renal Physiol"},{"key":"B36-20230829","doi-asserted-by":"crossref","first-page":"189","DOI":"10.5489\/cuaj.1338","article-title":"A simple method to estimate renal volume from computed tomography.","volume":"7","author":"Breau","year":"2013","journal-title":"Can Urol Assoc J"},{"key":"B37-20230829","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.kint.2016.07.038","article-title":"Regardless of etiology, progressive renal disease causes ultrastructural and functional alterations of peritubular capillaries.","volume":"91","author":"B\u00e1b\u00ed\u010dkov\u00e1","year":"2017","journal-title":"Kidney Int"},{"key":"B38-20230829","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1007\/s10157-018-1559-1","article-title":"Association between exercise intensity and renal blood flow evaluated using ultrasound echo.","volume":"22","author":"Kawakami","year":"2018","journal-title":"Clin Exp Nephrol"},{"key":"B39-20230829","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1681\/ASN.2015020204","article-title":"Quantitative micro-computed tomography imaging of vascular dysfunction in progressive kidney diseases.","volume":"27","author":"Ehling","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"B40-20230829","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/(SICI)1097-4636(19990615)45:4<355::AID-JBM10>3.0.CO;2-7","article-title":"Decrease in culture temperature releases monolayer endothelial cell sheets together with deposited fibronectin matrix from temperature-responsive culture surfaces.","volume":"45","author":"Kushida","year":"1999","journal-title":"J Biomed Mater Res"},{"key":"B41-20230829","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1089\/ten.tea.2010.0659","article-title":"Cardiac cell sheet transplantation improves damaged heart function via superior cell survival in comparison with dissociated cell injection.","volume":"17","author":"Sekine","year":"2011","journal-title":"Tissue Eng Part A"},{"key":"B42-20230829","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1053\/j.gastro.2009.12.059","article-title":"Characterization and functional analyses of hepatic mesothelial cells in mouse liver development.","volume":"138","author":"Onitsuka","year":"2010","journal-title":"Gastroenterology"}],"container-title":["Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/00001751-201902000-00009","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T19:31:12Z","timestamp":1786131072000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/00001751-201902000-00009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,11]]},"references-count":42,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019]]}},"URL":"https:\/\/doi.org\/10.1681\/asn.2018050556","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.734849403.793557502","asserted-by":"object"}]},"ISSN":["1046-6673","1533-3450"],"issn-type":[{"value":"1046-6673","type":"print"},{"value":"1533-3450","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,11]]}}}