Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia/reperfusion-induced lung injury

Abstract

BackgroundHypoxia preconditioning has been proven to be an effective method to enhance the therapeutic action of mesenchymal stem cells (MSCs). However, the beneficial effects of hypoxic MSCs in ischemia/reperfusion (I/R) lung injury have yet to be investigated. In this study, we hypothesized that the administration of hypoxic MSCs would have a positive therapeutic impact on I/R lung injury at molecular, cellular, and functional levels.MethodsI/R lung injury was induced in isolated and perfused rat lungs. Hypoxic MSCs were administered in perfusate at a low (2.5×105 cells) and high (1×106 cells) dose. Rats ventilated with a low tidal volume of 6 ml/kg served as controls. Hemodynamics, lung injury indices, inflammatory responses and activation of apoptotic pathways were determined.ResultsI/R induced permeability pulmonary edema with capillary leakage and increased levels of reactive oxygen species (ROS), pro-inflammatory cytokines, adhesion molecules, cytosolic cytochrome C, and activated MAPK, NF-κB, and apoptotic pathways. The administration of a low dose of hypoxic MSCs effectively attenuated I/R pathologic lung injury score by inhibiting inflammatory responses associated with the generation of ROS and anti-apoptosis effect, however this effect was not observed with a high dose of hypoxic MSCs. Mechanistically, a low dose of hypoxic MSCs down-regulated P38 MAPK and NF-κB signaling but upregulated glutathione, prostaglandin E2, IL-10, mitochondrial cytochrome C and Bcl-2. MSCs infused at a low dose migrated into interstitial and alveolar spaces and bronchial trees, while MSCs infused at a high dose aggregated in the microcirculation and induced pulmonary embolism.ConclusionsHypoxic MSCs can quickly migrate into extravascular lung tissue and adhere to other inflammatory or structure cells and attenuate I/R lung injury through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms. However, the dose of MSCs needs to be optimized to prevent pulmonary embolism and thrombosis.

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

“…We have demonstrated the direct immunomodulatory capacities of BMSC-CM and ADSC-CM in modulating the inflammatory response of primary AECs subjected to hypoxia-ischemia. Previous studies on rodent lung IRI have shown that MSC treatment down-regulates MIP-2, IL-1β and TNF-α expression levels while enhancing the up-regulation of anti-inflammatory IL-10 and prostaglandin E2 in bronchoalveolar lavage fluid [ 25 ]. Therefore, we have confirmed and expanded upon these finding in our own in vitro models.…”

Regulation of the mitochondrial reactive oxygen species: Strategies to control mesenchymal stem cell fates ex vivo and in vivo

“…Intriguingly, long‐term hypoxic conditions upregulated the expression of HIF‐1α, and the hypoxia MSCs showed greater cell viability, decreased ROS levels and increased resistance to oxidative stress for alleviating both early radiation‐induced pneumonia and late pulmonary fibrosis when compared to normoxia MSCs . In addition, a low dose of hypoxic MSCs but not a high dose of hypoxic MSCs can effectively attenuate ischemia/reperfusion (I/R) induced permeability pulmonary oedema by decreasing ROS related inflammatory responses and anti‐apoptosis effect . On the other hand, Karlsen et al showed that hyperoxia of room air was not adverse for the proliferation, differentiation, or phenotype of bone marrow derived MSCs in vitro.…”

Aggregation of Human Mesenchymal Stromal Cells Eliminates Their Ability to Suppress Human T Cells

“…Currently, about half of all clinical trials utilizing MSCs have locally injected MSCs (11). Local delivery of MSCs places MSCs near the site of injury or inflammation while eliminating the risk of embolization that comes with systemic infusions (12,13). However, when MSCs are injected into a spatially confined site they are known to aggregate to form spheroids.…”