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

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

doi:10.1152/ajplung.00218.2020

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.

Highlights

Advances in cell-based therapies for lung diseases provide a platform for the development of new therapeutic approaches for acute lung diseases and possibly other chronic pulmonary conditions
We have demonstrated that human bone marrow-derived Mesenchymal stromal cell (MSC) exposed to bronchoalveolar lavage fluid (BALF) samples from patients with either acute respiratory distress syndrome (ARDS) or non-ARDS lung diseases displayed both common and diseasespecific hMSC phenotypes, data that further support the hypothesis that different lung inflammatory environments have the potential to alter MSC behaviors [1]
HMSCs exposed to BALF samples from some, but not all, patients with cystic fibrosis (CF) resulted in increased cell death, as assessed by visual appearance (Fig. 1A) and by lactate dehydrogenase (LDH) release (Fig. 1, B and C). hMSCs exposed to CF BALF samples for 1 h resulted in increased cytotoxicity (LDH release) compared with hMSCs exposed to HC BALF samples (P = 0.056) (Fig. 1B)

Summary

Introduction

Advances in cell-based therapies for lung diseases provide a platform for the development of new therapeutic approaches for acute lung diseases and possibly other chronic pulmonary conditions. Growing literature demonstrates that bronchoalveolar lavage fluid (BALF) or serum obtained from preclinical lung disease models or from patients with acute respiratory distress syndrome (ARDS) elicits distinct changes in MSC functions [1, 2, 5, 21, 32, 42]. Other recent data demonstrated that ARDS BALF altered MSC protein expression with correlative effects on potential protective actions in acute lung injury [21]. We have demonstrated that human bone marrow-derived MSCs (hMSCs) exposed to BALF samples from patients with either ARDS or non-ARDS lung diseases displayed both common and diseasespecific hMSC phenotypes, data that further support the hypothesis that different lung inflammatory environments have the potential to alter MSC behaviors [1]

Methods

Results

Conclusion