PU.1 alleviates the inhibitory effects of cigarette smoke on endothelial progenitor cell function and lung-homing through Wnt/β-catenin and CXCL12/CXCR4 pathways
Introduction Endothelial progenitor cells (EPCs) dysfunction is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The transcription factor PU.1 is essential for the maintenance of stem/progenitor cell homeostasis. However, the role of PU.1 in COPD and its effects on EPC f...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
European Publishing
2024-01-01
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| Series: | Tobacco Induced Diseases |
| Subjects: | |
| Online Access: | https://www.tobaccoinduceddiseases.org/PU-1-alleviates-the-inhibitory-effects-of-cigarette-smoke-non-endothelial-progenitor,174661,0,2.html |
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| Summary: | Introduction
Endothelial progenitor cells (EPCs) dysfunction is involved in the
pathogenesis of chronic obstructive pulmonary disease (COPD). The transcription
factor PU.1 is essential for the maintenance of stem/progenitor cell homeostasis.
However, the role of PU.1 in COPD and its effects on EPC function and lunghoming,
remain unclear. This study aimed to explore the protective activity of
PU.1 and the underlying mechanisms in a cigarette smoke extract (CSE)-induced
emphysema mouse model.
Methods
C57BL/6 mice were treated with CSE to establish a murine emphysema
model and injected with overexpressed PU.1 or negative control adeno-associated
virus. Morphometry of lung slides, lung function, and apoptosis of lung tissues
were evaluated. Immunofluorescence co-localization was used to analyze EPCs
homing into the lung. Flow cytometry was performed to detect EPC count in
lung tissues and bone marrow (BM). The angiogenic ability of BM-derived EPCs
cultured in vitro was examined by tube formation assay. We determined the
expression levels of PU.1, β-catenin, C-X-C motif ligand 12 (CXCL12), C-X-C
motif receptor 4 (CXCR4), stem cell antigen-1 (Sca-1), and stemness genes.
Results
CSE exposure significantly reduced the expression of PU.1 in mouse lung
tissues, BM, and BM-derived EPCs. PU.1 overexpression attenuated CSE-induced
emphysematous changes, lung function decline, and apoptosis. In emphysematous
mice, PU.1 overexpression markedly reversed the decreased proportion of EPCs
in BM and promoted the lung-homing of EPCs. The impaired angiogenic ability
of BM-derived EPCs induced by CSE could be restored by the overexpression of
PU.1. In addition, PU.1 upregulation evidently reversed the decreased expression
of β-catenin, CXCL12, CXCR4, Scal-1, and stemness genes in mouse lung tissues,
BM, and BM-derived EPCs after CSE exposure.
Conclusions
PU.1 alleviates the inhibitory effects of CSE on EPC function and lunghoming
via activating the canonical Wnt/β-catenin pathway and CXCL12/CXCR4
axis. While further research is needed, our research may indicate a potential
therapeutic target for COPD patients. |
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| ISSN: | 1617-9625 |