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 T. Sage, B.T. Chao, Manyin Chen, H. Gokhale, Hongchao Shan, Xiaohui Bai, Guan Zehong, Jonathan Yeung, Tom Waddell, Tereza Martinu, S. Juvet, Marcelo Cypel, Mingyao Liu, John E. Davies, Shaf Keshavjee
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 (MSC IL-10 ) were administered during EVLP to human lungs that had various degrees of underlying lung injury. Cryopreserved MSC IL-10 had excellent viability, and they immediately and efficiently elevated perfusate and lung tissue IL-10 levels during EVLP. However, MSC IL-10 function was compromised by the poor metabolic conditions present in the most damaged lungs. Similarly, exposing cultured MSC IL-10 to poor metabolic, and especially acidic, conditions decreased their IL-10 production. In conclusion, we found that "off-the-shelf" MSC IL-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.