Human Adipose-Derived Mesenchymal Stem Cells Ameliorate Elastase-Induced Emphysema in Mice by Mesenchymal–Epithelial Transition

Abstract

Purpose: Chronic obstructive pulmonary disease (COPD) is a worldwide problem because of its high prevalence and mortality. However, there is no fundamental treatment to ameliorate their pathological change in COPD lung. Recently, adipose-derived mesenchymal stem cells (ADSCs) have attracted attention in the field of regenerative medicine to repair damaged organs. Moreover, their utility in treating respiratory diseases has been reported in some animal models. However, the detailed mechanism by which ADSCs improve chronic respiratory diseases, including COPD, remains to be elucidated. We examined whether human ADSCs (hADSCs) ameliorated elastase-induced emphysema and whether hADSCs differentiated into alveolar epithelial cells in a murine model of COPD. Methods: Female SCID-beige mice (6 weeks old) were divided into the following four groups according to whether they received an intratracheal injection of phosphate-buffered saline or porcine pancreatic elastase, and whether they received an intravenous injection of saline or hADSCs 3 days after intratracheal injection; Control group, hADSC group, Elastase group, and Elastase-hADSC group. We evaluated the lung function, assessed histological changes, and compared gene expression between hADSCs isolated from the lung of Elastase-hADSC group and naïve hADSCs 28 days after saline or elastase administration. Results: hADSCs improved the pathogenesis of COPD, including the mean linear intercept and forced expiratory volume, in an elastase-induced emphysema model in mice. Furthermore, hADSCs were observed in the lungs of elastase-treated mice at 25 days after administration. These cells expressed genes related to mesenchymal-epithelial transition and surface markers of alveolar epithelial cells, such as TTF-1, β-catenin, and E-cadherin. Conclusion: hADSCs have the potential to improve the pathogenesis of COPD by differentiating into alveolar epithelial cells by mesenchymal-epithelial transition.

Mesenchymal Stem Cells from COPD Patients Are Capable of Restoring Elastase-Induced Emphysema in a Murine Experimental Model

“…We then tested COPD and non-COPD AD-MSC therapeutic potential in vivo by administrating intratracheally two doses of cell suspensions and found that both cohorts were capable of reducing emphysema in our elastase mouse model, as demonstrated by reduction in more than 50% of the emphysematous areas. Other preclinical studies from Antunes et al [ 25 ] and Fujioka et al [ 26 ] support the therapeutic applicability of AD-MSC in reducing elastase-induced emphysema; however, they only tested AD-MSC from healthy human subjects. Two phase I/II clinical studies have started to evaluate the effect of autologous AD-MSC as single cells or in the form of stem vascular fraction (SVF) applied right after isolation intravenously in patients with COPD (NCT04433104 and NCT02216630 respectively).…”

Oxidative Stress and Inflammation in Acute and Chronic Lung Injuries

“…As the primary risk factor for COPD, CS is largely employed in basic research. Other experimental stimulants include porcine pancreatic elastase (PPE), the main alternative for CS [ 167 ], papain [ 168 ], air pollution [ 169 , 170 ], or biomass burn [ 171 ], either alone or combined with other provocations such as lipopolysaccharide (LPS) [ 172 ]. Some protocols consider mixing CS and other stimuli to provoke an exacerbation superimposed on tissue destruction, typical of emphysema [ 173 ].…”

The Mesenchymal-Epithelial Transition and Metaplasia

“…The Mesenchymal-Epithelial Transition and Metaplasia progenitors as opposed to terminally differentiated cell types 9,21,22 . MET does not usually replace one differentiated cell type with another differentiated cell type 1,9,21,22 , making it difficult to explicitly define the process as a form of metaplasia.…”

“…MET does not usually replace one differentiated cell type with another differentiated cell type 1,9,21,22 , making it difficult to explicitly define the process as a form of metaplasia. Rather, MET often involves the reprogramming of undifferentiated cells such as mesenchymal stem cells (MSCs) 21 , embryonic stem cells (ESCs) 1 , and cancer stem cells (CSCs) 2,22 .…”

“…It is poorly understood how epithelial cells derived from different types of mesenchymal cells differ on the molecular level. MSCs and fibroblasts (FB) represent two distinct types of mesenchymal cells that are both known to undergo MET 9,21 . An experiment that could help elucidate the differences between MSC-derived and fibroblast-derived epithelial cells could be done by culturing MSCs and FB separately on nanostructures known to promote MET 13 .…”