{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:14:17Z","timestamp":1791231257142,"version":"4.1.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T00:00:00Z","timestamp":1464739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Abnormal alveolar macrophages (AM) are found in chronic obstructive pulmonary disease, asthma, cystic fibrosis, and adenosine deaminase deficiency (ADA\u2212\/\u2212). There is no specific treatment strategy to compensate for these innate immune abnormalities. Recent findings suggest AMs are of early embryonic or fetal origin. Pluripotent stem cells (PSCs) as a source of embryonic-derived AMs for therapeutic use in acute and chronic airway diseases has yet to be investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine if embryonic Myb\u2212\/\u2212 alveolar-like macrophages have therapeutic value on pulmonary transplantation in acute and chronic airway diseases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Directed differentiation of murine PSCs was used in factor-defined media to produce expandable embryonic macrophages conditioned to an alveolar-like phenotype with granulocyte\u2013macrophage colony\u2013stimulating factor. AMs were partially depleted in mice to create an acute lung injury. To model a chronic lung disease, ADA\u2212\/\u2212 mice were used. Alveolar-like macrophages were intratracheally transplanted to the injured animals and therapeutic potential was determined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>The differentiation protocol is highly efficient and adaptable to human PSCs. The PSC macrophages are phenotypically like AMs both functionally and by ligand marker characterization. They engulf bacteria and apoptotic cells and are better phagocytes than bone marrow\u2013derived macrophages. In vivo, these macrophages remain in healthy airways for at least 4 weeks, can engulf neutrophils during acute lung injury, enhance pulmonary tissue repair, and promote survival in ADA\u2212\/\u2212 mice. Animals receiving the macrophages do not develop abnormal pathology or teratomas.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>PSCs are a reliable source to produce therapeutically active alveolar-like macrophages to treat airway disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201509-1838oc","type":"journal-article","created":{"date-parts":[[2016,1,5]],"date-time":"2016-01-05T17:23:44Z","timestamp":1452014624000},"page":"1219-1229","source":"Crossref","is-referenced-by-count":47,"title":["Alveolar-like Stem Cell\u2013derived\n                    <i>Myb<\/i>\n                    <i>\u2212<\/i>\n                    Macrophages Promote Recovery and Survival in Airway Disease"],"prefix":"10.1093","volume":"193","author":[{"given":"Michael L.","family":"Litvack","sequence":"first","affiliation":[{"name":"Program of Physiology and Experimental Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore J.","family":"Wigle","sequence":"additional","affiliation":[{"name":"Program of Physiology and Experimental Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce","family":"Lee","sequence":"additional","affiliation":[{"name":"Program of Physiology and Experimental Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxia","family":"Wang","sequence":"additional","affiliation":[{"name":"Program of Physiology and Experimental Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Ackerley","sequence":"additional","affiliation":[{"name":"Program of Physiology and Experimental Medicine"},{"name":"Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyal","family":"Grunebaum","sequence":"additional","affiliation":[{"name":"Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"},{"name":"Developmental and Stem Cell Biology Program, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Post","sequence":"additional","affiliation":[{"name":"Program of Physiology and Experimental Medicine"},{"name":"Division of Immunology and Allergy, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,6,1]]},"reference":[{"key":"2026032100060125900_bib1","doi-asserted-by":"crossref","first-page":"L936","DOI":"10.1152\/ajplung.90625.2008","article-title":"Lung environment determines unique phenotype of alveolar macrophages","volume":"296","author":"Guth","year":"2009","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026032100060125900_bib2","doi-asserted-by":"crossref","first-page":"3488","DOI":"10.4049\/jimmunol.179.6.3488","article-title":"Lung macrophages serve as obligatory intermediate between blood monocytes and alveolar macrophages","volume":"179","author":"Landsman","year":"2007","journal-title":"J Immunol"},{"key":"2026032100060125900_bib3","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1084\/jem.20131199","article-title":"Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF","volume":"210","author":"Guilliams","year":"2013","journal-title":"J Exp Med"},{"key":"2026032100060125900_bib4","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.1002\/jcp.24009","article-title":"Alveolar macrophage dynamics in murine lung regeneration","volume":"227","author":"Chamoto","year":"2012","journal-title":"J Cell Physiol"},{"key":"2026032100060125900_bib5","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.immuni.2013.04.004","article-title":"Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes","volume":"38","author":"Hashimoto","year":"2013","journal-title":"Immunity"},{"key":"2026032100060125900_bib6","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nature13989","article-title":"Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors","volume":"518","author":"Gomez Perdiguero","year":"2015","journal-title":"Nature"},{"key":"2026032100060125900_bib7","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1378\/chest.08-2943","article-title":"Pulmonary alveolar proteinosis: a bench-to-bedside story of granulocyte-macrophage colony-stimulating factor dysfunction","volume":"136","author":"Greenhill","year":"2009","journal-title":"Chest"},{"key":"2026032100060125900_bib8","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1046\/j.1440-1711.2003.t01-1-01170.x","article-title":"Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells","volume":"81","author":"Hodge","year":"2003","journal-title":"Immunol Cell Biol"},{"key":"2026032100060125900_bib9","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1089\/jir.2011.0027","article-title":"Macrophages in allergic asthma: fine-tuning their pro- and anti-inflammatory actions for disease resolution","volume":"31","author":"Moreira","year":"2011","journal-title":"J Interferon Cytokine Res"},{"key":"2026032100060125900_bib10","first-page":"2740","article-title":"NF-{kappa}B signaling in fetal lung macrophages disrupts airway morphogenesis","volume-title":"J Immunol","author":"Blackwell","year":"2011"},{"key":"2026032100060125900_bib11","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1165\/rcmb.2008-0170OC","article-title":"Macrophages directly contribute to the exaggerated inflammatory response in cystic fibrosis transmembrane conductance regulator-\/- mice","volume":"40","author":"Bruscia","year":"2009","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026032100060125900_bib12","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1038\/ncb1456","article-title":"CFTR regulates phagosome acidification in macrophages and alters bactericidal activity","volume":"8","author":"Di","year":"2006","journal-title":"Nat Cell Biol"},{"key":"2026032100060125900_bib13","first-page":"1467","article-title":"Pulmonary alveolar proteinosis in adenosine deaminase-deficient mice","volume-title":"J Allergy Clin Immunol","author":"Dhanju","year":"2014"},{"key":"2026032100060125900_bib14","doi-asserted-by":"crossref","first-page":"L86","DOI":"10.1152\/ajplung.00283.2014","article-title":"Transforming growth factor-\u03b2 induces microRNA-29b to promote murine alveolar macrophage dysfunction after bone marrow transplantation","volume":"308","author":"Domingo-Gonzalez","year":"2015","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026032100060125900_bib15","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3389\/fimmu.2013.00126","article-title":"Defective pulmonary innate immune responses post-stem cell transplantation; review and results from one model system","volume":"4","author":"Domingo-Gonzalez","year":"2013","journal-title":"Front Immunol"},{"key":"2026032100060125900_bib16","doi-asserted-by":"crossref","first-page":"4416","DOI":"10.4049\/jimmunol.171.8.4416","article-title":"Defective phagocytosis and clearance of Pseudomonas aeruginosa in the lung following bone marrow transplantation","volume":"171","author":"Ojielo","year":"2003","journal-title":"J Immunol"},{"key":"2026032100060125900_bib17","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nature13807","article-title":"Pulmonary macrophage transplantation therapy","volume":"514","author":"Suzuki","year":"2014","journal-title":"Nature"},{"key":"2026032100060125900_bib18","doi-asserted-by":"crossref","first-page":"250ra113","DOI":"10.1126\/scitranslmed.3009750","article-title":"Pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for hereditary pulmonary alveolar proteinosis","volume":"6","author":"Happle","year":"2014","journal-title":"Sci Transl Med"},{"key":"2026032100060125900_bib19","doi-asserted-by":"crossref","first-page":"319","DOI":"10.2174\/1574888X09666140228144812","article-title":"Therapeutic potential and mechanisms of action of mesenchymal stromal cells for acute respiratory distress syndrome","volume":"9","author":"Curley","year":"2014","journal-title":"Curr Stem Cell Res Ther"},{"key":"2026032100060125900_bib20","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1126\/science.1219179","article-title":"A lineage of myeloid cells independent of Myb and hematopoietic stem cells","volume":"336","author":"Schulz","year":"2012","journal-title":"Science"},{"key":"2026032100060125900_bib21","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.stemcr.2015.01.004","article-title":"Acellular lung scaffolds direct differentiation of endoderm to functional airway epithelial cells: requirement of matrix-bound HS proteoglycans","volume":"4","author":"Shojaie","year":"2015","journal-title":"Stem Cell Rep"},{"key":"2026032100060125900_bib22","doi-asserted-by":"crossref","first-page":"L795","DOI":"10.1152\/ajplung.00048.2013","article-title":"Mechanical ventilation-induced apoptosis in newborn rat lung is mediated via FasL\/Fas pathway","volume":"305","author":"Kroon","year":"2013","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026032100060125900_bib23","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1038\/ni.2419","article-title":"Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages","volume":"13","author":"Gautier","year":"2012","journal-title":"Nat Immunol"},{"key":"2026032100060125900_bib24","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/gene.20095","article-title":"Mouse in red: red fluorescent protein expression in mouse ES cells, embryos, and adult animals","volume":"40","author":"Vintersten","year":"2004","journal-title":"Genesis"},{"key":"2026032100060125900_bib25","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1164\/rccm.200501-109OC","article-title":"Surfactant palmitoylmyristoylphosphatidylcholine is a marker for alveolar size during disease","volume":"172","author":"Ridsdale","year":"2005","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100060125900_bib26","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.healun.2003.10.007","article-title":"Depletion of alveolar macrophages by clodronate-liposomes aggravates ischemia-reperfusion injury of the lung","volume":"24","author":"Nakamura","year":"2005","journal-title":"J Heart Lung Transplant"},{"key":"2026032100060125900_bib27","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1159\/000160953","article-title":"Selective depletion of alveolar macrophages in polymicrobial sepsis increases lung injury, bacterial load and mortality but does not affect cytokine release","volume":"77","author":"Traeger","year":"2009","journal-title":"Respiration"},{"key":"2026032100060125900_bib28","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.4049\/jimmunol.175.3.1937","article-title":"Adenosine-dependent pulmonary fibrosis in adenosine deaminase-deficient mice","volume":"175","author":"Chunn","year":"2005","journal-title":"J Immunol"},{"key":"2026032100060125900_bib29","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1084\/jem.192.2.159","article-title":"Metabolic consequences of adenosine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation, and airway obstruction","volume":"192","author":"Blackburn","year":"2000","journal-title":"J Exp Med"},{"key":"2026032100060125900_bib30","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1136\/thoraxjnl-2015-206813","article-title":"Human mesenchymal stromal cells decrease the severity of acute lung injury induced by E. coli in the rat","volume":"70","author":"Devaney","year":"2015","journal-title":"Thorax"},{"key":"2026032100060125900_bib31","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1016\/j.jaci.2012.02.003","article-title":"Pulmonary alveolar proteinosis in patients with adenosine deaminase deficiency","volume":"129","author":"Grunebaum","year":"2012","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100060125900_bib32","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1172\/JCI36666","article-title":"Amelioration of emphysema in mice through lentiviral transduction of long-lived pulmonary alveolar macrophages","volume":"120","author":"Wilson","year":"2010","journal-title":"J Clin Invest"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/193\/11\/1219\/67267117\/ajrccm_193_11_1219.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/193\/11\/1219\/67267117\/ajrccm_193_11_1219.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T04:06:12Z","timestamp":1774065972000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/193\/11\/1219\/8508933"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,1]]},"references-count":32,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2016,6,1]]},"published-print":{"date-parts":[[2016,6,1]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201509-1838oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,6]]},"published":{"date-parts":[[2016,6,1]]}}}