Immunomodulation by mesenchymal stem cells in treating human autoimmune disease-associated lung fibrosis.
BACKGROUND
Interstitial pneumonia in connective tissue diseases (CTD-IP) featuring inflammation and fibrosis is a leading cause of death in CTD-IP patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells (MSCs) may represent a promising therapeutic agent in CTD-IP. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders.


METHODS
Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-IP patients, and human primary lung fibroblasts (HLFs) from patients pathologically diagnosed with usual interstitial pneumonia (UIP) and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-IP were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals (HBMSCs) on cytotoxic T cells and CTD-UIP HLFs were investigated in vitro.


RESULTS
Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-IP patients, accompanied with a reduced regulatory T cell (Treg) level. CTD-UIP HLFs secreted proinflammatory cytokines in combination with upregulation of α-smooth muscle actin (α-SMA). The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis (IPF). HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked α-SMA activation in CTD-UIP HLFs through a TGF-β1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to IP-10 expression. MSCs secreting a higher level of TGF-β1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice.


CONCLUSIONS
Impairment of TGF-β signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-IP and to myofibroblast differentiation in CTD-UIP HLFs. HBMSCs can sensitize TGF-β1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic IP-10 production. This may in turn block progression of lung fibrosis in autoimmunity.
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, P. R. China.
Ming
M
Liu
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, P. R. China.|Department of Respiratory Medicine, Xiangyang Central Hospital, Xiangyang, Hubei province, P. R. China.
Xiansheng
X
Zeng
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, P. R. China.
Junli
J
Wang
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, P. R. China.
Zhiping
Z
Fu
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, P. R. China.|Shenzhen Beike Cell Engineering Research Institute, Shenzhen, P. R. China.
Jinsong
J
Wang
Shenzhen Beike Cell Engineering Research Institute, Shenzhen, P. R. China.
Muyun
M
Liu
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, P. R. China.
Dunqiang
D
Ren
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, P. R. China.
Baodan
B
Yu
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, P. R. China.
Lixia
L
Zheng
Shenzhen Beike Cell Engineering Research Institute, Shenzhen, P. R. China.
Xiang
X
Hu
Developmental Biology and Regenerative Medicine Program, Department of Surgery, The Saban Research Institute of Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
Wei
W
Shi
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, P. R. China. xufeili@vip.163.com.
Jun
J
Xu
D000199:Actins / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016022:Case-Control Studies; D002454:Cell Differentiation; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D056747:Immunomodulation; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D061251:Primary Cell Culture; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology*
C541116:ACTA2 protein, human; D000199:Actins; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053773:Transforming Growth Factor beta1
IL-6; IP-10; Lung fibrosis in autoimmunity; Mesenchymal stem cells; Natural killer T cells; Regulatory T cells; TGF-β1