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We hypothesized that cell-free conditioned media (CM) containing the secretome of iPSCs possess antioxidative constituents that can alleviate pulmonary oxidant stress damage. We derived iPSCs from human dermal fibroblasts and harvested the CM. Addition of iPSC CM to cultured human alveolar type-1 epithelial cells mitigated hyperoxia-induced depletion of endogenous total antioxidant capacity while tracheal instillation of iPSC CM into adult rat lungs enhanced hyperoxia-induced increase in TAC. In both the in vitro and in vivo models, iPSC CM ameliorated oxidative damage to DNA, lipid, and protein, and activated the nuclear factor (erythroid 2)-related factor 2 (Nrf2) network of endogenous antioxidant proteins. Compared with control fibroblast-conditioned or cell-free media, iPSC CM is highly enriched with \u03b1Klotho at a concentration up to more than 10-fold of that in normal serum. \u03b1Klotho is an essential antioxidative cell maintenance and protective factor and an activator of the Nrf2 network. Immunodepletion of \u03b1Klotho reduced iPSC CM-mediated cytoprotection by \u223c50%. Thus, the abundant \u03b1Klotho content significantly contributes to iPSC-mediated antioxidation and cytoprotection. Results uncover a major mechanism of iPSC action, suggest a fundamental role of \u03b1Klotho in iPSC maintenance, and support the translational potential of airway delivery of cell-free iPSC secretome for protection against lung injury. The targeted cell-free secretome-based approach may also be applicable to the amelioration of injury in other organs.<\/jats:p>","DOI":"10.1002\/stem.2752","type":"journal-article","created":{"date-parts":[[2017,12,11]],"date-time":"2017-12-11T03:09:18Z","timestamp":1512961758000},"page":"616-625","source":"Crossref","is-referenced-by-count":26,"title":["Alpha-Klotho Enrichment in Induced Pluripotent Stem Cell Secretome Contributes to Antioxidative Protection in Acute Lung Injury"],"prefix":"10.1093","volume":"36","author":[{"given":"Amiq","family":"Gazdhar","sequence":"first","affiliation":[{"name":"Department of Pulmonary Medicine, University Hospital, Bern, Switzerland"},{"name":"Department of Clinical Research, University Hospital, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Ravikumar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA"},{"name":"Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanne","family":"Pastor","sequence":"additional","affiliation":[{"name":"Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Heller","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, University Hospital, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Ye","sequence":"additional","affiliation":[{"name":"Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA"},{"name":"Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orson W.","family":"Moe","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA"},{"name":"Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA"},{"name":"Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Geiser","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, University Hospital, Bern, Switzerland"},{"name":"Department of Clinical Research, University Hospital, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1995-1407","authenticated-orcid":false,"given":"Connie C. 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