Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells

Soraia C. Abreu, Thomas H. Hampton, Evan Hoffman, Jacob Dearborn, Alix Ashare, Karatatiwant Singh Sidhu, Dwight E. Matthews, David H. McKenna, Eyal Amiel, Jayita Barua, Anna Krasnodembskaya, Karen English, Bernard Mahon, Claudia Dos Santos, Fernanda F. Cruz, Daniel C. Chambers, Kathleen D. Liu, Michael A. Matthay, Robert A. Cramer, Bruce A. StantonPatricia R.M. Rocco, Matthew J. Wargo, Daniel J. Weiss, Sara Rolandsson Enes

Research output: Contribution to journalArticlepeer-review

Abstract

Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) samples, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function were compared with effects of BALF collected from healthy volunteers. CF BALF samples that cultured positive for Aspergillus sp. (Asp) induced rapid MSC death, usually within several hours of exposure. Further analyses suggested the fungal toxin gliotoxin as a potential mediator contributing to CF BALF-induced MSC death. RNA sequencing analyses of MSCs exposed to either Asp+ or Asp− CF BALF samples identified a number of differentially expressed transcripts, including those involved in interferon signaling, antimicrobial gene expression, and cell death. Toxicity did not correlate with bacterial lung infections. These results suggest that the potential use of MSC-based cell therapies for CF or other lung diseases may not be warranted in the presence of Aspergillus.

Original languageEnglish (US)
Pages (from-to)L908-L925
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume319
Issue number6
DOIs
StatePublished - Nov 30 2020

Bibliographical note

Funding Information:
The RNA sequencing was performed by Dr. Fred W. Kolling at the Geisel School of Medicine at Dartmouth in the Genomics Shared Resources, which was established by equipment grants from the National Institutes of Health and National Science Foundation and is supported by a Cancer Center Core Grant (P30CA023108) from the National Cancer Institute. The flow cytometry data were performed at the Harry Hood Bassett Flow Cytometry and Cell Sorting Facility (FACS) at UVM. We acknowledge assistance from the NHLBI PACT program, University of Minnesota, Molecular and Cellular Therapeutics (contract HHSN26820 1000008). The authors also acknowledge the European Union (EU) and European Respiratory Society (ERS) for financial support.

Funding Information:
The authors gratefully acknowledge Drs. Nuria Villalba and Kalev Freeman for assistance with the histone content measurements, Drs. Jennifer L. Ather and Matthew E. Poynter for assistance with the cytokine measurements, Dr. Sourabh Dhingra for preparation of the A. fumigatus culture filtrates, and Drs. Daniel F. McAuley (Queen?s University, Belfast), Cecilia O?Kane (Queen?s University, Belfast), Edith Zemanick (Children?s Hospital, Colorado), and Linh Do (Cystic Fibrosis Foundation) for preparing and providing patient BALF samples. The RNA sequencing was performed by Dr. Fred W. Kolling at the Geisel School of Medicine at Dartmouth in the Genomics Shared Resources, which was established by equipment grants from the National Institutes of Health and National Science Foundation and is supported by a Cancer Center Core Grant (P30CA023108) from the National Cancer Institute. The flow cytometry data were performed at the Harry Hood Bassett Flow Cytometry and Cell Sorting Facility (FACS) at UVM. We acknowledge assistance from the NHLBI PACT program, University of Minnesota, Molecular and Cellular Therapeutics (contract HHSN26820 1000008). The authors also acknowledge the European Union (EU) and European Respiratory Society (ERS) for financial support.

Publisher Copyright:
Copyright © 2020 The Authors.

Keywords

  • Aspergillus infection
  • Cell therapy
  • Cystic fibrosis
  • Gliotoxin
  • Mesenchymal stromal cell

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