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

ABSTRACT: 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 ?Klotho at a concentration up to more than 10-fold of that in normal serum. ?Klotho is an essential antioxidative cell maintenance and protective factor and an activator of the Nrf2 network. Immunodepletion of ?Klotho reduced iPSC CM-mediated cytoprotection by ?50%. Thus, the abundant ?Klotho content significantly contributes to iPSC-mediated antioxidation and cytoprotection. Results uncover a major mechanism of iPSC action, suggest a fundamental role of ?Klotho 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 2018;36:616-625.

SUBMITTER: Gazdhar A

PROVIDER: S-EPMC5876101 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Gazdhar Amiq A Ravikumar Priya P Pastor Johanne J Heller Manfred M Ye Jianfeng J Zhang Jianning J Moe Orson W OW Geiser Thomas T Hsia Connie C W CCW

Stem cells (Dayton, Ohio) 20171225 4

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 epithelia ...[more]

PMID: 29226550

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Project description:BackgroundPlatinum based agents-cisplatin and carboplatin in combination with taxanes are used for the treatment of ovarian cancer (OC) patients. However, the majority of OC patients develop recurrent, platinum resistant disease that is uniformly fatal. Platinum treatment enriches for chemoresistant aldehyde dehydrogenase (ALDH) + ovarian cancer stem cells (OCSCs), which contribute to tumor recurrence and disease relapse. Acquired platinum resistance also includes metabolic reprograming and switching to oxidative phosphorylation (OXPHOS). Chemosensitive cells rely on glycolysis while chemoresistant cells have the ability to switch between glycolysis and OXPHOS, depending on which pathway drives a selective advantage for growth and chemoresistance. High expression of genes involved in OXPHOS and high production of mitochondrial ROS are characteristics of OCSCs, suggesting that OCSCs favor OXPHOS over glycolysis. Based on connections between OCSCs, chemoresistance and OXPHOS, we hypothesize that platinum treatment induces changes in metabolism that contribute to platinum-induced enrichment of OCSCs.MethodsThe effect of cisplatin on mitochondrial activity was assessed by JC1 staining and expression of OXPHOS genes by RT-qPCR. Cisplatin-induced changes in Sirtuin 1 (SIRT1) levels and activity were assessed by western blot. Small molecule inhibitors of mitochondrial complex I and SIRT1 were used to determine if their enzymatic activity contributes to the platinum-induced enrichment of OCSCs. The percentage of ALDH + OCSCs in OC cells and tumor tissue from xenograft models across different treatment conditions was analyzed using ALDEFLUOR assay and flow cytometry.ResultsWe demonstrate that platinum treatment increases mitochondrial activity. Combined treatment of platinum agents and OXPHOS inhibitors blocks the platinum-induced enrichment of ALDH + OCSCs in vitro and in vivo. Furthermore, platinum treatment increases SIRT1 levels and subsequent deacetylase activity, which likely contributes to the increase in platinum-induced mitochondrial activity.ConclusionsThese findings on metabolic pathways altered by platinum-based chemotherapy have uncovered key targets that can be exploited therapeutically to block the platinum-induced enrichment of OCSCs, ultimately improving the survival of OC patients.

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

Publications

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

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