{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:22:09Z","timestamp":1787318529478,"version":"build-2736575974"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,1,29]],"date-time":"2015-01-29T00:00:00Z","timestamp":1422489600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,1,29]],"date-time":"2015-01-29T00:00:00Z","timestamp":1422489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Stem Cell Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The immunomodulatory properties of human amnion epithelial cells (hAECs) have been previously described in several disease models. We previously reported on the ability of hAECs to influence macrophage phenotype and chemotaxis. In this study, we aim to elucidate the contribution of regulatory T cells (Tregs) to macrophage polarisation and downstream effects on inflammation and fibrosis in a bleomycin model of lung injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Either CD45\n                      <jats:sup>+<\/jats:sup>\n                      \/FoxP3\n                      <jats:sup>+<\/jats:sup>\n                      <jats:italic>Tregs<\/jats:italic>\n                      or CD45\n                      <jats:sup>+<\/jats:sup>\n                      \/FoxP3\n                      <jats:sup>\n                        <jats:italic>-<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>non-Tregs<\/jats:italic>\n                      were adoptively transferred into\n                      <jats:italic>Rag1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>-\/-<\/jats:italic>\n                      <\/jats:sup>\n                      mice immediately prior to bleomycin challenge. Four million hAECs were administered 24\u00a0hours later. Outcomes were measured 7 or 14\u00a0days later.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Mitigation of lung inflammation and fibrosis was observed only in animals that received both hAECs and Tregs. hAEC treatment also induced the maturation of non-Tregs into FoxP3-expressing Tregs. This event was found to be transforming growth factor-beta (TGF\u03b2)-dependent. Furthermore, polarisation of macrophages from M1 to M2 occurred only in animals that received hAECs and Tregs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides the first evidence that Tregs are required for hAEC-mediated macrophage polarisation and consequential mitigation of bleomycin-induced lung injury. Uncovering the interactions between hAECs, macrophages, and T-cell subsets is central to understanding the mechanisms by which hAECs elicit lung repair.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/scrt542","type":"journal-article","created":{"date-parts":[[2015,6,18]],"date-time":"2015-06-18T00:22:29Z","timestamp":1434586949000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Amnion cell-mediated immune modulation following bleomycin challenge: controlling the regulatory T cell response"],"prefix":"10.1186","volume":"6","author":[{"given":"Jean L","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siow T","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camden Y","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A","family":"Deane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney A","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude CA","family":"Bernard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Euan M","family":"Wallace","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,1,29]]},"reference":[{"key":"424_CR1","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.humimm.2008.10.016","volume":"70","author":"DL Roelen","year":"2009","unstructured":"Roelen DL, van der Mast BJ, In\u2019t Anker PS, Kleijburg C, Eikmans M, van Beelen E, et al.: Differential immunomodulatory effects of fetal versus maternal multipotent stromal cells.\n                           Hum Immunol 2009, 70:16\u201323. 10.1016\/j.humimm.2008.10.016","journal-title":"Hum Immunol"},{"key":"424_CR2","first-page":".","volume":".","author":"M Magatti","year":"2014","unstructured":"Magatti M, Caruso M, De Munari S, Vertua E, De D, Manuelpillai U, et al.: Human amniotic membrane-derived mesenchymal and epithelial cells exert different effects on monocyte-derived dendritic cell differentiation and function.\n                           Cell Transplant 2014, .:.. [Epub ahead of print]","journal-title":"Cell Transplant"},{"key":"424_CR3","doi-asserted-by":"publisher","first-page":"909","DOI":"10.3727\/096368910X543385","volume":"20","author":"S Murphy","year":"2011","unstructured":"Murphy S, Lim R, Dickinson H, Acharya R, Rosli S, Jenkin G, et al.: Human amnion epithelial cells prevent bleomycin-induced lung injury and preserve lung function.\n                           Cell Transplant 2011, 20:909\u201323. 10.3727\/096368910X543385","journal-title":"Cell Transplant"},{"key":"424_CR4","doi-asserted-by":"publisher","first-page":"405","DOI":"10.3727\/096368909788809857","volume":"18","author":"A Cargnoni","year":"2009","unstructured":"Cargnoni A, Gibelli L, Tosini A, Signoroni PB, Nassuato C, Arienti D, et al.: Transplantation of allogeneic and xenogeneic placenta-derived cells reduces bleomycin-induced lung fibrosis.\n                           Cell Transplant 2009, 18:405\u201322. 10.3727\/096368909788809857","journal-title":"Cell Transplant"},{"key":"424_CR5","doi-asserted-by":"crossref","first-page":"448.e8","DOI":"10.1016\/j.ajog.2012.02.038","volume":"206","author":"RJ Hodges","year":"2012","unstructured":"Hodges RJ, Jenkin G, Hooper SB, Allison B, Lim R, Dickinson H, et al.: Human amnion epithelial cells reduce ventilation-induced preterm lung injury in fetal sheep.\n                           Am J Obstet Gynecol 2012, 206:448.e8\u2013448.e15.","journal-title":"Am J Obstet Gynecol"},{"key":"424_CR6","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1016\/j.jcyt.2013.03.004","volume":"15","author":"P Vosdoganes","year":"2013","unstructured":"Vosdoganes P, Lim R, Koulaeva E, Chan ST, Acharya R, Moss TJM, et al.: Human amnion epithelial cells modulate hyperoxia-induced neonatal lung injury in mice.\n                           Cytotherapy 2013, 15:1021\u20139. 10.1016\/j.jcyt.2013.03.004","journal-title":"Cytotherapy"},{"key":"424_CR7","doi-asserted-by":"publisher","first-page":"156.e26","DOI":"10.1016\/j.ajog.2011.03.054","volume":"205","author":"P Vosdoganes","year":"2011","unstructured":"Vosdoganes P, Hodges RJ, Lim R, Westover AJ, Acharya RY, Wallace EM, et al.: Human amnion epithelial cells as a treatment for inflammation-induced fetal lung injury in sheep.\n                           Am J Obstet Gynecol 2011, 205:156.e26\u201333. 10.1016\/j.ajog.2011.03.054","journal-title":"Am J Obstet Gynecol"},{"key":"424_CR8","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.3727\/096368912X657657","volume":"22","author":"P Vosdoganes","year":"2013","unstructured":"Vosdoganes P, Wallace EM, Chan ST, Acharya R, Moss TJ, Lim R: Human amnion epithelial cells repair established lung injury.\n                           Cell Transplant 2013, 22:1337\u201349. 10.3727\/096368912X657657","journal-title":"Cell Transplant"},{"key":"424_CR9","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.3727\/096368910X504496","volume":"19","author":"U Manuelpillai","year":"2010","unstructured":"Manuelpillai U, Tchongue J, Lourensz D, Vaghjiani V, Samuel CS, Liu A, et al.: Transplantation of human amnion epithelial cells reduces hepatic fibrosis in immunocompetent CCl\n                           \n                              4\n                           \n                           -treated mice.\n                           Cell Transplant 2010, 19:1157\u201368. 10.3727\/096368910X504496","journal-title":"Cell Transplant"},{"key":"424_CR10","doi-asserted-by":"publisher","first-page":"319","DOI":"10.3727\/096368912X661409","volume":"23","author":"JL Tan","year":"2013","unstructured":"Tan JL, Chan ST, Wallace EM, Lim R: Human amnion epithelial cells mediate lung repair by directly modulating macrophage recruitment and polarization.\n                           Cell Transplant 2013, 23:319\u201328.","journal-title":"Cell Transplant"},{"key":"424_CR11","doi-asserted-by":"publisher","first-page":"e35758","DOI":"10.1371\/journal.pone.0035758","volume":"7","author":"YH Liu","year":"2012","unstructured":"Liu YH, Vaghjiani V, Tee JY, To K, Cui P, Oh DY, et al.: Amniotic epithelial cells from the human placenta potently suppress a mouse model of multiple sclerosis.\n                           PLoS One 2012, 7:e35758. 10.1371\/journal.pone.0035758","journal-title":"PLoS One"},{"key":"424_CR12","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1159\/000346683","volume":"35","author":"T Yawno","year":"2013","unstructured":"Yawno T, Schuilwerve J, Moss TJM, Vosdoganes P, Westover AJ, Afandi E, et al.: Human amnion epithelial cells reduce fetal brain injury in response to intrauterine inflammation.\n                           Dev Neurosci 2013, 35:272\u201382. 10.1159\/000346683","journal-title":"Dev Neurosci"},{"key":"424_CR13","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1038\/nprot.2007.258","volume":"2","author":"MC Fantini","year":"2007","unstructured":"Fantini MC, Dominitzki S, Rizzo A, Neurath MF, Becker C: In vitro generation of CD4+ CD25+ regulatory cells from murine naive T cells.\n                           Nat Protoc 2007, 2:1789\u201394. 10.1038\/nprot.2007.258","journal-title":"Nat Protoc"},{"key":"424_CR14","first-page":"Unit 1E.6","volume":"Chapter 1","author":"S Murphy","year":"2010","unstructured":"Murphy S, Rosli S, Acharya R, Mathias L, Lim R, Wallace E, et al.: Amnion epithelial cell isolation and characterization for clinical use.\n                           Curr Protoc Stem Cell Biol 2010, Chapter 1:Unit 1E.6.","journal-title":"Curr Protoc Stem Cell Biol"},{"key":"424_CR15","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1164\/rccm.200812-1936OC","volume":"179","author":"I Kotsianidis","year":"2009","unstructured":"Kotsianidis I, Nakou E, Bouchliou I, Tzouvelekis A, Spanoudakis E, Steiropoulos P, et al.: Global impairment of CD4\u2009+\u2009CD25\u2009+\u2009FOXP3+ regulatory T cells in idiopathic pulmonary fibrosis.\n                           Am J Respir Crit Care Med 2009, 179:1121\u201330. 10.1164\/rccm.200812-1936OC","journal-title":"Am J Respir Crit Care Med"},{"key":"424_CR16","doi-asserted-by":"crossref","first-page":"873","DOI":"10.18632\/aging.100391","volume":"3","author":"A Schellenberg","year":"2011","unstructured":"Schellenberg A, Lin Q, Sch\u00fcler H, Koch CM, Joussen S, Denecke B, et al.: Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks.\n                           Aging (Albany NY) 2011, 3:873\u201388.","journal-title":"Aging (Albany NY)"},{"key":"424_CR17","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.imbio.2012.05.020","volume":"218","author":"D Boveda-Ruiz","year":"2013","unstructured":"Boveda-Ruiz D, D\u2019Alessandro-Gabazza CN, Toda M, Takagi T, Naito M, Matsushima Y, et al.: Differential role of regulatory T cells in early and late stages of pulmonary fibrosis.\n                           Immunobiology 2013, 218:245\u201354. 10.1016\/j.imbio.2012.05.020","journal-title":"Immunobiology"},{"key":"424_CR18","doi-asserted-by":"publisher","first-page":"e950","DOI":"10.1038\/cddis.2013.480","volume":"4","author":"Y Wang","year":"2013","unstructured":"Wang Y, Zhang Z, Chi Y, Zhang Q, Xu F, Yang Z, et al.: Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation.\n                           Cell Death Dis 2013, 4:e950. 10.1038\/cddis.2013.480","journal-title":"Cell Death Dis"},{"key":"424_CR19","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1016\/j.jcyt.2014.01.005","volume":"14","author":"A Hodge","year":"2014","unstructured":"Hodge A, Lourensz D, Vaghjiani V, Nguyen H, Tchongue J, Wang B, et al.: Soluble factors derived from human amniotic epithelial cells suppress collagen production in human hepatic stellate cells.\n                           Cytotherapy 2014, 14:1132\u201344.","journal-title":"Cytotherapy"},{"key":"424_CR20","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.3727\/096368911X601028","volume":"21","author":"SV Murphy","year":"2012","unstructured":"Murphy SV, Shiyun SC, Tan JL, Chan S, Jenkin G, Wallace EM, et al.: Human amnion epithelial cells do not abrogate pulmonary fibrosis with impaired macrophage function.\n                           Cell Transplant 2012, 21:1477\u201392. 10.3727\/096368911X601028","journal-title":"Cell Transplant"},{"key":"424_CR21","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1084\/jem.20121849","volume":"210","author":"P Soroosh","year":"2013","unstructured":"Soroosh P, Doherty TA, Duan W, Mehta AK, Choi H, Adams YF, et al.: Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance.\n                           J Exp Med 2013, 210:775\u201388. 10.1084\/jem.20121849","journal-title":"J Exp Med"},{"key":"424_CR22","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1038\/icb.2010.70","volume":"89","author":"G Liu","year":"2011","unstructured":"Liu G, Ma H, Qiu L, Li L, Cao Y, Ma J, et al.: Phenotypic and functional switch of macrophages induced by regulatory CD4(+)CD25(+) T cells in mice.\n                           Immunol Cell Biol 2011, 89:130\u201342. 10.1038\/icb.2010.70","journal-title":"Immunol Cell Biol"},{"key":"424_CR23","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1164\/rccm.201303-0522WS","volume":"188","author":"MA Matthay","year":"2013","unstructured":"Matthay MA, Anversa P, Bhattacharya J, Burnett BK, Chapman HA, Hare JM, et al.: Cell therapy for lung diseases: report from an NIH-NHLBI workshop November 13\u201314, 2012.\n                           Am J Respir Crit Care Med 2013, 188:370\u20135. 10.1164\/rccm.201303-0522WS","journal-title":"Am J Respir Crit Care Med"},{"key":"424_CR24","unstructured":"Therapeutics Goods Administration: Australian Regulatory Guidelines for Biologicals. Appendix 2 - Guidelines on Class 3 Biological dossier requirements. Version 1.0. 2011"},{"key":"424_CR25","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1165\/rcmb.2012-0198OC","volume":"48","author":"BT Garibaldi","year":"2013","unstructured":"Garibaldi BT, D\u2019Alessio FR, Mock JR, Files DC, Chau E, Eto Y, et al.: Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment.\n                           Am J Respir Cell Mol Biol 2013, 48:35\u201343. 10.1165\/rcmb.2012-0198OC","journal-title":"Am J Respir Cell Mol Biol"},{"key":"424_CR26","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1152\/physiolgenomics.00131.2009","volume":"41","author":"NR Aggarwal","year":"2009","unstructured":"Aggarwal NR, D\u2019Alessio FR, Tsushima K, Sidhaye VK, Cheadle C, Grigoryev DN, et al.: Regulatory T cell-mediated resolution of lung injury: Identification of potential target genes via expression profiling.\n                           Physiol Genomics 2009, 41:109\u201319.","journal-title":"Physiol Genomics"},{"key":"424_CR27","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1095\/biolreprod52.4.839","volume":"52","author":"CA Jones","year":"1995","unstructured":"Jones CA, Williams KA, Finlay-Jones JJ, Hart PH: Interleukin 4 production by human amnion epithelial cells and regulation of its activity by glycosaminoglycan binding.\n                           Biol Reprod 1995, 52:839\u201347. 10.1095\/biolreprod52.4.839","journal-title":"Biol Reprod"},{"key":"424_CR28","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.1084\/jem.20030152","volume":"198","author":"W Chen","year":"2003","unstructured":"Chen W, Jin W, Hardegen N, Lei K-J, Li L, Marinos N, et al.: Conversion of peripheral CD4\u2009+\u2009CD25- naive T cells to CD4\u2009+\u2009CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.\n                           J Exp Med 2003, 198:1875\u201386. 10.1084\/jem.20030152","journal-title":"J Exp Med"},{"key":"424_CR29","doi-asserted-by":"publisher","first-page":"2040","DOI":"10.1182\/blood-2006-05-024547","volume":"109","author":"J LeMaoult","year":"2007","unstructured":"LeMaoult J, Caumartin J, Daouya M, Favier B, Le Rond S, Gonzalez A, et al.: Immune regulation by pretenders: cell-to-cell transfers of HLA-G make effector T cells act as regulatory cells.\n                           Blood 2007, 109:2040\u20138. 10.1182\/blood-2006-05-024547","journal-title":"Blood"},{"key":"424_CR30","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1002\/jlb.64.4.528","volume":"64","author":"RE Smith","year":"1998","unstructured":"Smith RE, Strieter RM, Phan SH, Lukacs N, Kunkel SL: TNF and IL-6 mediate MIP-1alpha expression in bleomycin-induced lung injury.\n                           J Leukoc Biol 1998, 64:528\u201336.","journal-title":"J Leukoc Biol"},{"key":"424_CR31","doi-asserted-by":"publisher","first-page":"L1255","DOI":"10.1152\/ajplung.00303.2002","volume":"285","author":"MJ Segel","year":"2003","unstructured":"Segel MJ, Izbicki G, Cohen PY, Or R, Christensen TG, Wallach-Dayan SB, et al.: Role of interferon-gamma in the evolution of murine bleomycin lung fibrosis.\n                           Am J Physiol Lung Cell Mol Physiol 2003, 285:L1255\u201362. 10.1152\/ajplung.00303.2002","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"424_CR32","doi-asserted-by":"publisher","first-page":"2898","DOI":"10.1172\/JCI36498","volume":"119","author":"FR D\u2019Alessio","year":"2009","unstructured":"D\u2019Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, et al.: CD4\u2009+\u2009CD25\u2009+\u2009Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury.\n                           J Clin Invest 2009, 119:2898\u2013913. 10.1172\/JCI36498","journal-title":"J Clin Invest"},{"key":"424_CR33","doi-asserted-by":"publisher","first-page":"1980","DOI":"10.1002\/stem.1432","volume":"31","author":"SM Melief","year":"2013","unstructured":"Melief SM, Schrama E, Brugman MH, Tiemessen MM, Hoogduijn MJ, Fibbe WE, et al.: Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages.\n                           Stem Cells 2013, 31:1980\u201391. 10.1002\/stem.1432","journal-title":"Stem Cells"},{"key":"424_CR34","doi-asserted-by":"publisher","first-page":"179ps7","DOI":"10.1126\/scitranslmed.3005568","volume":"5","author":"MA Fischbach","year":"2013","unstructured":"Fischbach MA, Bluestone JA, Lim WA: Cell-based therapeutics: the next pillar of medicine.\n                           Sci Transl Med 2013, 5:179ps7.","journal-title":"Sci Transl Med"}],"container-title":["Stem Cell Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/scrt542.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/scrt542\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/scrt542.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T12:25:20Z","timestamp":1728908720000},"score":1,"resource":{"primary":{"URL":"https:\/\/stemcellres.biomedcentral.com\/articles\/10.1186\/scrt542"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,29]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12]]}},"alternative-id":["424"],"URL":"https:\/\/doi.org\/10.1186\/scrt542","relation":{},"ISSN":["1757-6512"],"issn-type":[{"value":"1757-6512","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,1,29]]},"assertion":[{"value":"22 October 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 December 2014","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 January 2015","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 January 2015","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"8"}}