Alpha-Klotho Enrichment in Induced Pluripotent Stem Cell Secretome Contributes to Antioxidative Protection in Acute Lung Injury.

Gazdhar, Amiq; Ravikumar, Priya; Pastor, Johanne; Heller, Manfred; Ye, Jianfeng; Zhang, Jianning; Moe, Orson W; Geiser, Thomas; Hsia, Connie C W (2018). Alpha-Klotho Enrichment in Induced Pluripotent Stem Cell Secretome Contributes to Antioxidative Protection in Acute Lung Injury. Stem cells, 36(4), pp. 616-625. AlphaMed Press 10.1002/stem.2752

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Induced pluripotent stem cells (iPSCs) have been reported to alleviate organ injury, although the mechanisms of action remain unclear and administration of intact cells faces many limitations. 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 αKlotho at a concentration up to more than 10-fold of that in normal serum. αKlotho is an essential antioxidative cell maintenance and protective factor and an activator of the Nrf2 network. Immunodepletion of αKlotho reduced iPSC CM-mediated cytoprotection by ∼50%. Thus, the abundant αKlotho content significantly contributes to iPSC-mediated antioxidation and cytoprotection. Results uncover a major mechanism of iPSC action, suggest a fundamental role of αKlotho 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. Stem Cells 2017.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Pneumologie (Erwachsene)
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Pneumology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Massenspektrometrie- und Proteomics-Labor
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Protein- und Zellbiologie

UniBE Contributor:

Gazdhar, Amiq; Heller, Manfred and Geiser, Thomas

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1066-5099

Publisher:

AlphaMed Press

Language:

English

Submitter:

Rahel Holderegger

Date Deposited:

30 Jan 2018 10:34

Last Modified:

31 Mar 2018 01:31

Publisher DOI:

10.1002/stem.2752

PubMed ID:

29226550

Uncontrolled Keywords:

Acute lung injury Hyperoxia Induced pluripotent stem cells Oxidative stress damage Secretome Stem cells

BORIS DOI:

10.7892/boris.108531

URI:

https://boris.unibe.ch/id/eprint/108531

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