Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage

Abstract

Lee Y-S. Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage. Am J Physiol Lung Cell Mol Physiol 302: L891-L908, 2012. First published February 3, 2012 doi:10.1152/ajplung.00288.2011.-Cigarette smoking causes apoptotic death, senescence, and impairment of repair functions in lung fibroblasts, which maintain the integrity of alveolar structure by producing extracellular matrix (ECM) proteins. Therefore, recovery of lung fibroblasts from cigarette smoke-induced damage may be crucial in regeneration of emphysematous lung resulting from degradation of ECM proteins and subsequent loss of alveolar cells. Recently, we reported that bone marrow-derived mesenchymal stem cell-conditioned media (MSC-CM) led to angiogenesis and regeneration of lung damaged by cigarette smoke. In this study, to further investigate reparative mechanisms for MSC-CM-mediated lung repair, we attempted to determine whether MSC-CM can recover lung fibroblasts from cigarette smoke-induced damage. In lung fibroblasts exposed to cigarette smoke extract (CSE), MSC-CM, not only inhibited apoptotic death, but also induced cell proliferation and reversed CSE-induced changes in the levels of caspase-3, p53, p21, p27, Akt, and p-Akt. MSC-CM also restored expression of ECM proteins and collagen gel contraction while suppressing CSE-induced expression of cyclooxygenase-2 and microsomal PGE 2 synthase-2. The CSE-opposing effects of MSC-CM on cell fate, expression of ECM proteins, and collagen gel contraction were partially inhibited by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. In rats, MSC-CM administration also resulted in elevation of p-Akt and restored proliferation of lung fibroblasts, which was suppressed by exposure to cigarette smoke. Taken together, these data suggest that MSC-CM may recover lung fibroblasts from cigarette smoke-induced damage, possibly through inhibition of apoptosis, induction of proliferation, and restoration of lung fibroblast repair function, which are mediated in part by the PI3K/Akt pathway. cigarette smoking; chronic obstructive pulmonary disease; emphysema CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), a leading cause of death worldwide, is most often caused by cigarette smoking. COPD is characterized by expiratory airflow limitation that is not fully reversible, accompanying inflammation, and emphysematous destruction of the lung (39). Irrespective of the high incidence and mortality rates for COPD, most current therapies for this disease are supportive, and regenerative therapies to cure emphysema are not available.As a pathophysiological mechanism, proteolytic degradation of extracellular matrix (ECM) by protease activities overwhelming antiprotease activities has long been suspected to be responsible for the emphysematous change seen in patients with COPD (45). Lung fibroblasts are considered crucial for maintenance of the integrity of alveolar structure by producing ECM proteins, including collagen, elastin, and fibronectin, which are required for attach...

Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine

“…For example, MSCs have proved to reverse apoptosis in cardiomyoblasts after ischemia, as well as damaged neurons and lung fibroblasts. 67, 68, 69 The anti-apoptotic mechanisms of MSCs are not fully understood, but several key proteins have been identified. IGF-1 and IL-6 secretion increases the expression of Akt (protein kinase B) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells).…”

“…132 MSC-conditioned media has been used to reverse cigarette smoke-induced damage in cultured lung fibroblasts; apoptotic death was inhibited, proliferation was increased and extracellular matrix synthesis was restored in response to MSC-conditioned media treatment. 69 Despite the promising basic science evidence and animal studies, human translation has yet to be optimized. In a 2012 double-blinded study of 62 COPD patients each subject received an infusion of 100 million allogeneic MSCs, resulting in significant reduction of circulating C-reactive protein.…”

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“…Aside from ALI, MSC-derived CM have also showed promising results in asthma[34] and chronic emphysema[35, 36], in terms of reducing inflammation and histological damage within the bronchoalveolar airspace and lung parenchyma. In both acute and chronic ovalbumin-induced asthma model in mice, Ionescu et al showed that MSC-derived CM attenuated inflammatory cells infiltrate into the alveolar space, restored the bronchodilator response to salbutamol, suppressed the increase in both dynamic lung resistance and elastance, and reduced airway smooth muscle layer thickening and peribronchial inflammatory infiltrate[34].…”

Esophageal epithelial cells acquire functional characteristics of activated myofibroblasts after undergoing an epithelial to mesenchymal transition

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