Molecular Therapy: Methods & Clinical Development (Dec 2021)
Engineered mesenchymal stromal cell therapy during human lung ex vivo lung perfusion is compromised by acidic lung microenvironment
- Antti I. Nykänen,
- Andrea Mariscal,
- Allen Duong,
- Catalina Estrada,
- Aadil Ali,
- Olivia Hough,
- Andrew Sage,
- Bonnie T. Chao,
- Manyin Chen,
- Hemant Gokhale,
- Hongchao Shan,
- Xiaohui Bai,
- Guan Zehong,
- Jonathan Yeung,
- Tom Waddell,
- Tereza Martinu,
- Stephen Juvet,
- Marcelo Cypel,
- Mingyao Liu,
- John E. Davies,
- Shaf Keshavjee
Affiliations
- Antti I. Nykänen
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Andrea Mariscal
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Allen Duong
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Catalina Estrada
- Tissue Regeneration Therapeutics, 790 Bay Street, Toronto, ON M5G 1N8, Canada
- Aadil Ali
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Olivia Hough
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Andrew Sage
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Bonnie T. Chao
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Manyin Chen
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Hemant Gokhale
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Hongchao Shan
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Xiaohui Bai
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Guan Zehong
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Jonathan Yeung
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Tom Waddell
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Tereza Martinu
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Stephen Juvet
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Marcelo Cypel
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- Mingyao Liu
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada
- John E. Davies
- Institute of Biomedical Engineering, University of Toronto, 164 College St, Toronto, ON M5S 3G9, Canada
- Shaf Keshavjee
- Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada; Institute of Biomedical Engineering, University of Toronto, 164 College St, Toronto, ON M5S 3G9, Canada; Corresponding author: Shaf Keshavjee, Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
- Journal volume & issue
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Vol. 23
pp. 184 – 197
Abstract
Ex vivo lung perfusion (EVLP) is an excellent platform to apply novel therapeutics, such as gene and cell therapies, before lung transplantation. We investigated the concept of human donor lung engineering during EVLP by combining gene and cell therapies. Premodified cryopreserved mesenchymal stromal cells with augmented anti-inflammatory interleukin-10 production (MSCIL-10) were administered during EVLP to human lungs that had various degrees of underlying lung injury. Cryopreserved MSCIL-10 had excellent viability, and they immediately and efficiently elevated perfusate and lung tissue IL-10 levels during EVLP. However, MSCIL-10 function was compromised by the poor metabolic conditions present in the most damaged lungs. Similarly, exposing cultured MSCIL-10 to poor metabolic, and especially acidic, conditions decreased their IL-10 production. In conclusion, we found that “off-the-shelf” MSCIL-10 therapy of human lungs during EVLP is safe and feasible, and results in rapid IL-10 elevation, and that the acidic target-tissue microenvironment may compromise the efficacy of cell-based therapies.
