Abstract
IntroductionPulmonary emphysema is a major component of chronic obstructive pulmonary disease (COPD). Emphysema progression attributed not only to alveolar structure loss and pulmonary regeneration impairment, but also to excessive inflammatory response, proteolytic and anti-proteolytic activity imbalance, lung epithelial cells apoptosis, and abnormal lung remodeling. To ameliorate lung damage with higher efficiency in lung tissue engineering and cell therapy, pre-differentiating graft cells into more restricted cell types before transplantation could enhance their ability to anatomically and functionally integrate into damaged lung. In this study, we aimed to evaluate the regenerative and repair ability of lung alveolar epithelium in emphysema model by using lung epithelial progenitors which pre-differentiated from amniotic fluid mesenchymal stem cells (AFMSCs).MethodsPre-differentiation of eGFP-expressing AFMSCs to lung epithelial progenitor-like cells (LEPLCs) was established under a modified small airway growth media (mSAGM) for 7-day induction. Pre-differentiated AFMSCs were intratracheally injected into porcine pancreatic elastase (PPE)-induced emphysema mice at day 14, and then inflammatory-, fibrotic-, and emphysema-related indices and pathological changes were assessed at 6 weeks after PPE administration.ResultsAn optimal LEPLCs pre-differentiation condition has been achieved, which resulted in a yield of approximately 20% lung epithelial progenitors-like cells from AFMSCs in a 7-day period. In PPE-induced emphysema mice, transplantation of LEPLCs significantly improved regeneration of lung tissues through integrating into the lung alveolar structure, relieved airway inflammation, increased expression of growth factors such as vascular endothelial growth factor (VEGF), and reduced matrix metalloproteinases and lung remodeling factors when compared with mice injected with AFMSCs. Histopathologic examination observed a significant amelioration in DNA damage in alveolar cells, detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), the mean linear intercept, and the collagen deposition in the LEPLC-transplanted groups.ConclusionTransplantation of predifferentiated AFMSCs through intratracheal injection showed better alveolar regeneration and reverse elastase-induced pulmonary emphysema in PPE-induced pulmonary emphysema mice.
Highlights
Pulmonary emphysema is a major component of chronic obstructive pulmonary disease (COPD)
In porcine pancreatic elastase (PPE)-induced emphysema mice, transplantation of lung epithelial progenitor-like cells (LEPLCs) significantly improved regeneration of lung tissues through integrating into the lung alveolar structure, relieved airway inflammation, increased expression of growth factors such as vascular endothelial growth factor (VEGF), and reduced matrix metalloproteinases and lung remodeling factors when compared with mice injected with amniotic fluid mesenchymal stem cells (AFMSCs)
Type I alveolar epithelial cells were characterized as the Downregulated expression of emphysema factors in LEPLCtransplanted PPE-induced pulmonary emphysema mice To assess the effects of LEPLCs in the PPE-induced pulmonary emphysema model, the mRNA expression levels of candidate emphysema-related genes were determined
Summary
Pulmonary emphysema is a major component of chronic obstructive pulmonary disease (COPD). Emphysema is one of the major components of COPD, which is characterized by persistent and chronic inflammation, alveolar walls destruction, and permanent enlargement of air spaces. This leads to progressive disability and death in COPD patients worldwide [2]. Years of noxious particle exposure causes the infiltration of inflammatory cells, especially neutrophils and macrophages, into the airways This results in the activation of various proteolytic enzymes and proteinases, including neutrophil elastase and matrix metalloproteinase-9, which destroy the alveolar structure [3]. Apoptosis of lung epithelial and endothelial cells is critical for the pathogenesis of emphysema caused by cigarette smoke exposure [4]. Persistent oxidative stress could deplete the balance between self-renewal and cell differentiation in stem cells and progenitors, which results in impaired alveolar regeneration in lung tissue with emphysema [6]
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