PMID- 29056548 OWN - NLM STAT- MEDLINE DCOM- 20190318 LR - 20190318 IS - 1477-2566 (Electronic) IS - 1465-3249 (Linking) VI - 20 IP - 1 DP - 2018 Jan TI - Human induced pluripotent stem cell-derived lung progenitor and alveolar epithelial cells attenuate hyperoxia-induced lung injury. PG - 108-125 LID - S1465-3249(17)30702-8 [pii] LID - 10.1016/j.jcyt.2017.09.003 [doi] AB - BACKGROUND AIMS: Bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by disrupted lung growth, is the most common complication in extreme premature infants. BPD leads to persistent pulmonary disease later in life. Alveolar epithelial type 2 cells (AEC2s), a subset of which represent distal lung progenitor cells (LPCs), promote normal lung growth and repair. AEC2 depletion may contribute to persistent lung injury in BPD. We hypothesized that induced pluripotent stem cell (iPSC)-derived AECs prevent lung damage in experimental oxygen-induced BPD. METHODS: Mouse AECs (mAECs), miPSCs/mouse embryonic stem sells, human umbilical cord mesenchymal stromal cells (hUCMSCs), human (h)iPSCs, hiPSC-derived LPCs and hiPSC-derived AECs were delivered intratracheally to hyperoxia-exposed newborn mice. Cells were pre-labeled with a red fluorescent dye for in vivo tracking. RESULTS: Airway delivery of primary mAECs and undifferentiated murine pluripotent cells prevented hyperoxia-induced impairment in lung function and alveolar growth in neonatal mice. Similar to hUCMSC therapy, undifferentiated hiPSCs also preserved lung function and alveolar growth in hyperoxia-exposed neonatal NOD/SCID mice. Long-term assessment of hiPSC administration revealed local teratoma formation and cellular infiltration in various organs. To develop a clinically relevant cell therapy, we used a highly efficient method to differentiate hiPSCs into a homogenous population of AEC2s. Airway delivery of hiPSC-derived AEC2s and hiPSC-derived LPCs, improved lung function and structure and resulted in long-term engraftment without evidence of tumor formation. CONCLUSIONS: hiPSC-derived AEC2 therapy appears effective and safe in this model and warrants further exploration as a therapeutic option for BPD and other lung diseases characterized by AEC injury. CI - Copyright (c) 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. FAU - Shafa, Mehdi AU - Shafa M AD - Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada. FAU - Ionescu, Lavinia Iuliana AU - Ionescu LI AD - Department of Physiology, University of Alberta, Edmonton, Canada. FAU - Vadivel, Arul AU - Vadivel A AD - Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada. FAU - Collins, Jennifer J P AU - Collins JJP AD - Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada; Department of Pediatric Surgery, Erasmus University Medical Centre, Sophia Children's Hospital, Rotterdam, The Netherlands. FAU - Xu, Liqun AU - Xu L AD - Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada. FAU - Zhong, Shumei AU - Zhong S AD - Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada. FAU - Kang, Martin AU - Kang M AD - Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada. FAU - de Caen, Genevieve AU - de Caen G AD - Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada. FAU - Daneshmand, Manijeh AU - Daneshmand M AD - Department of Pathology and Laboratory Medicine, University of Ottawa, Canada. FAU - Shi, Jenny AU - Shi J AD - Department of Physiology, University of Alberta, Edmonton, Canada. FAU - Fu, Katherine Z AU - Fu KZ AD - Department of Physiology, University of Alberta, Edmonton, Canada. FAU - Qi, Andrew AU - Qi A AD - Department of Physiology, University of Alberta, Edmonton, Canada. FAU - Wang, Ying AU - Wang Y AD - Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada. FAU - Ellis, James AU - Ellis J AD - Program in Developmental & Stem Cell Biology, Hospital for Sick Children, Toronto, Canada. FAU - Stanford, William L AU - Stanford WL AD - Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada. FAU - Thebaud, Bernard AU - Thebaud B AD - Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada; Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada. Electronic address: bthebaud@ohri.ca. LA - eng GR - FDN 143316/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171020 PL - England TA - Cytotherapy JT - Cytotherapy JID - 100895309 RN - S88TT14065 (Oxygen) SB - IM MH - Alveolar Epithelial Cells/*cytology MH - Animals MH - Animals, Newborn MH - Cell Differentiation MH - Disease Models, Animal MH - Humans MH - Hyperoxia/*complications MH - Induced Pluripotent Stem Cells/*cytology/ultrastructure MH - Lung Injury/*etiology/pathology/*therapy MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Oxygen MH - Teratoma/pathology OTO - NOTNLM OT - alveolar epithelial cells OT - bronchopulmonary dysplasia OT - induced pluripotent stem cells OT - lung injury OT - newborn OT - oxygen OT - regenerative medicine EDAT- 2017/10/24 06:00 MHDA- 2019/03/19 06:00 CRDT- 2017/10/24 06:00 PHST- 2016/12/09 00:00 [received] PHST- 2017/09/02 00:00 [revised] PHST- 2017/09/02 00:00 [accepted] PHST- 2017/10/24 06:00 [pubmed] PHST- 2019/03/19 06:00 [medline] PHST- 2017/10/24 06:00 [entrez] AID - S1465-3249(17)30702-8 [pii] AID - 10.1016/j.jcyt.2017.09.003 [doi] PST - ppublish SO - Cytotherapy. 2018 Jan;20(1):108-125. doi: 10.1016/j.jcyt.2017.09.003. Epub 2017 Oct 20.