Engineered mesenchymal stromal cell therapy during human lung ex vivo lung perfusion is compromised by acidic lung microenvironment

• Published in: Molecular therapy. Methods & clinical development 2021-12, Vol.23, p.184-197
• Main Authors: Nykänen, Antti I., Mariscal, Andrea, Duong, Allen, Estrada, Catalina, Ali, Aadil, Hough, Olivia, Sage, Andrew, Chao, Bonnie T., Chen, Manyin, Gokhale, Hemant, Shan, Hongchao, Bai, Xiaohui, Zehong, Guan, Yeung, Jonathan, Waddell, Tom, Martinu, Tereza, Juvet, Stephen, Cypel, Marcelo, Liu, Mingyao, Davies, John E., Keshavjee, Shaf
• Format: Article
• Language: English
• Subjects: adenovirus; cell therapy; ex vivo lung perfusion; gene therapy; lung transplantation; mesenchymal stromal cell; Original
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2021.05.018

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. [Display omitted] Mesenchymal stromal cells with augmented anti-inflammatory IL-10 production were administered to human lungs during ex vivo lung perfusion, a platform that enables application of novel therapeutics to donor lungs before transplantation. IL-10 production was rapid but compromised by lung injury and acidosis, indicating that the local target-tissue microenvironment affects cell-based therapies.