Therapeutic Potential of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Recovering From Murine Pulmonary Emphysema Under Cigarette Smoke Exposure

Abstract

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were shown to have potential for immunoregulation and tissue repair. The objective of this study was to investigate the effects of hUC-MSCs on emphysema in chronic obstructive pulmonary disease (COPD). The C57BL/6JNarl mice were exposed to cigarette smoke (CS) for 4 months followed by administration of hUC-MSCs at 3 × 106 (low dose), 1 × 107 (medium dose), and 3 × 107 cells/kg body weight (high dose). The hUC-MSCs caused significant decreases in emphysema severity by measuring the mean linear intercept (MLI) and destructive index (DI). A decrease in neutrophils (%) and an increase in lymphocytes (%) in bronchoalveolar lavage fluid (BALF) were observed in emphysematous mice after hUC-MSC treatment. Lung levels of interleukin (IL)-1β, C-X-C motif chemokine ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and matrix metalloproteinase (MMP)-12 significantly decreased after hUC-MSC administration. Significant reductions in tumor necrosis factor (TNF)-α, IL-1β, and IL-17A in serum occurred after hUC-MSC administration. Notably, the cell viability of lung fibroblasts improved with hUC-MSCs after being treated with CS extract (CSE). Furthermore, the hUC-MSCs-conditioned medium (hUC-MSCs-CM) restored the contractile force, and increased messenger RNA expressions of elastin and fibronectin by lung fibroblasts. In conclusion, hUC-MSCs reduced inflammatory responses and emphysema severity in CS-induced emphysematous mice.

Stem cell-based therapy for human diseases

“…The administration of UC-MSCs prevented the infiltration of inflammatory cells in peribronchiolar, perivascular, and alveolar septa and switched macrophage polarization to M2. 396 A significant reduction in proinflammatory cytokines, including IL-1β, TNF-α, and IL-8, was also observed following UC-MSC administration. 224 MSCs, including UC-MSCs, have been reported to trigger the production of secretory leukocyte protease inhibitors in epithelial cells through the secretion of HGF and epidermal growth factor (EGF), which is believed to have beneficial effects on COPD.…”

Reduction of Emphysema Severity by Human Umbilical Cord-Derived Mesenchymal Stem Cells in Mice

“…Similarly, decreases in TNF-α and KC levels were also reported in the lungs of emphysema mouse models upon the administration of hUC-MSCs [ 14 , 22 ]. MSCs decrease proinflammatory chemokines in the lungs, including TNF-α, KC, IL-1β, and matrix metalloproteinases (MMP)-12, which is attributed to increased secretion of transforming growth factor (TGF)-β [ 14 , 41 , 42 ]. This MSC-induced TGF-β secretion also reduces MMP-9 and MMP-12 expressions, which are responsible for alveolar destruction.…”

“…The recovery was reflected by significant decreases in emphysema severity and exercise oxygen desaturation. Our previous study using hUC-MSCs in a CS-induced mouse model also showed an improvement of emphysema upon hUC-MSC administration [ 14 ]. Another study using bone marrow-derived (BM)-MSCs showed a decrease in emphysematous lesions in the lungs of mice induced by PPE by intranasal instillation [ 25 ].…”

“…Six generations of cells were used throughout the study. Details of the hUC-MSC preparation and characterization were described previously [ 14 , 15 ]. Sample collection with written informed consent was carried out in accordance with the study protocol approved (A-BR-104-045) by the Ethics Committee of the National Cheng Kung University Hospital Institutional Review Board.…”

“…MSCs can release a wide range of cell signaling cytokines and growth factors that target endogenous stem cell self-renewal and migration, and stimulate host stem cells to self-renew and differentiate following an injury [ 10 ]. In our previous study on mice with CS-induced emphysema, we showed that the administration of human (h)UC-MSCs decreased pulmonary inflammatory responses and the severity of CS-induced emphysema [ 14 ]. In addition, hUC-MSCs can also reduce the pulmonary inflammatory response and display antiapoptotic effects in C57BL/6 mice with pulmonary inflammation induced by acute CS exposure [ 15 ].…”