Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage.
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.
Division of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon.
Sun-Yong
SY
Kim
Ji-Hyun
JH
Lee
Hyo Jeong
HJ
Kim
Mi Kyeong
MK
Park
Jin Won
JW
Huh
Jai Youl
JY
Ro
Yeon-Mok
YM
Oh
Sang-Do
SD
Lee
Yun-Song
YS
Lee
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D048429:Cell Size; D002470:Cell Survival; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry; D008168:Lung / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana
D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012906:Smoke; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt