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

doi:10.1016/j.omtm.2021.05.018

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

Mol Ther Methods Clin Dev. 2021 Sep 20:23:184-197. doi: 10.1016/j.omtm.2021.05.018. eCollection 2021 Dec 10.

Authors

Antti I Nykänen¹, Andrea Mariscal¹, Allen Duong¹, Catalina Estrada², Aadil Ali¹, Olivia Hough¹, Andrew Sage¹, Bonnie T Chao¹, Manyin Chen¹, Hemant Gokhale¹, Hongchao Shan¹, Xiaohui Bai¹, Guan Zehong¹, Jonathan Yeung¹, Tom Waddell¹, Tereza Martinu¹, Stephen Juvet¹, Marcelo Cypel¹, Mingyao Liu¹, John E Davies³, Shaf Keshavjee^{1

3}

Affiliations

¹ 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.
² Tissue Regeneration Therapeutics, 790 Bay Street, Toronto, ON M5G 1N8, Canada.
³ Institute of Biomedical Engineering, University of Toronto, 164 College St, Toronto, ON M5S 3G9, Canada.

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.

Keywords: adenovirus; cell therapy; ex vivo lung perfusion; gene therapy; lung transplantation; mesenchymal stromal cell.