Human Mesenchymal Stem Cell Secretome from Bone Marrow or Adipose-Derived Tissue Sources for Treatment of Hypoxia-Induced Pulmonary Epithelial Injury

Nala Shologu,Daniel O’Toole,John G. Laffey,Michael Scully

doi:10.3390/ijms19102996

Abstract

Alveolar epithelial dysfunction induced by hypoxic stress plays a significant role in the pathological process of lung ischemia-reperfusion injury (IRI). Mesenchymal stem cell (MSC) therapies have demonstrated efficacy in exerting protective immunomodulatory effects, thereby reducing airway inflammation in several pulmonary diseases. Aim: This study assesses the protective effects of MSC secretome from different cell sources, human bone marrow (BMSC) and adipose tissue (ADSC), in attenuating hypoxia-induced cellular stress and inflammation in pulmonary epithelial cells. Methods: Pulmonary epithelial cells, primary rat alveolar epithelial cells (AEC) and A549 cell line were pre-treated with BMSC, or ADSC conditioned medium (CM) and subjected to hypoxia for 24 h. Results: Both MSC-CM improved cell viability, reduced secretion of pro-inflammatory mediators and enhanced IL-10 anti-inflammatory cytokine production in hypoxic injured primary rat AECs. ADSC-CM reduced hypoxic cellular injury by mechanisms which include: inhibition of p38 MAPK phosphorylation and nuclear translocation of subunits in primary AECs. Both MSC-CM enhanced translocation of Bcl-2 to the nucleus, expression of cytoprotective glucose-regulated proteins (GRP) and restored matrix metalloproteinases (MMP) function, thereby promoting repair and cellular homeostasis, whereas inhibition of GRP chaperones was detrimental to cell survival. Conclusions: Elucidation of the protective mechanisms exerted by the MSC secretome is an essential step for maximizing the therapeutic effects, in addition to developing therapeutic targets-specific strategies for various pulmonary syndromes.

Highlights

Mesenchymal stem cells (MSC), are increasingly being used in pulmonary research for preclinical and clinical applications [1]
A further increase (p < 0.001) of early apoptotic cells was observed with MSC-conditioned medium (CM) pre-treatment (Figure 1C), which may be attributed to the MSC-CM delaying the cells entering late apoptosis
We show here that MSC secretome is protective in hypoxic injured pulmonary epithelial cells, by delaying cells entering apoptosis and preserving cell viability and membrane integrity

Summary

Introduction

Mesenchymal stem cells (MSC), are increasingly being used in pulmonary research for preclinical and clinical applications [1]. Though the current understanding on MSC mechanisms of action and biology has paved the way to preclinical and clinical trials, further studies are needed to explain and improve the efficacy of the current MSC therapies, for pulmonary diseases. Studies have shown that preconditioning MSCs with HSPs protects against hypoxia-induced apoptosis [6]. Stress-inducible intracellular chaperones, glucose-regulated proteins (GRP), GRP75, GRP78 and GRP94, belong to the HSP family. In addition to their traditional chaperone roles of protein folding and assembly, these GRPs assume novel functions that control signalling, proliferation, invasion, apoptosis, inflammation and immunity [7]. MSC therapy may be a feasible approach to elevate GRP expression safely and efficiently as a strategy to protect against acute lung injury (ALI)

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