Mehdi Shafa1, Lavinia Iuliana Ionescu2, Arul Vadivel3, Jennifer J P Collins4, Liqun Xu5, Shumei Zhong5, Martin Kang5, Geneviève de Caen5, Manijeh Daneshmand6, Jenny Shi2, Katherine Z Fu2, Andrew Qi2, Ying Wang5, James Ellis7, William L Stanford8, Bernard Thébaud9. 1. 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. 2. Department of Physiology, University of Alberta, Edmonton, Canada. 3. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada. 4. 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. 5. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada. 6. Department of Pathology and Laboratory Medicine, University of Ottawa, Canada. 7. Program in Developmental & Stem Cell Biology, Hospital for Sick Children, Toronto, Canada. 8. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada. 9. 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.
Abstract
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.
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/SCIDmice. 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.
Authors: Sajit Augustine; Wei Cheng; Marc T Avey; Monica L Chan; Srinivasa Murthy Chitra Lingappa; Brian Hutton; Bernard Thébaud Journal: Stem Cells Transl Med Date: 2019-11-20 Impact factor: 6.940