Mandatory role of HMGA1 in human airway epithelial normal differentiation and post-injury regeneration
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Haijun Zhang1, Jing Yang1, Matthew S. Walters1, Michelle R. Staudt1, Yael Strulovici-Barel1, Jacqueline Salit1, Jason G. Mezey1,2, Philip L. Leopold1 and Ronald G. Crystal1
1Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA
2Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, USA
Ronald G. Crystal, email: [email protected]
Keywords: HMGA1; regeneration; differentiation; wound repair; COPD
Received: October 19, 2017 Accepted: January 20, 2018 Epub: February 16, 2018 Published: March 06, 2018
Due to high levels of expression in aggressive tumors, high mobility group AT-hook 1 (HMGA1) has recently attracted attention as a potential anti-tumor target. However, HMGA1 is also expressed in normal somatic progenitor cells, raising the question: how might systemic anti-HMGA1 therapies affect the structure and function of normal tissue differentiation? In the present study, RNA sequencing data demonstrated HMGA1 is highly expressed in human airway basal stem/progenitor cells (BC), but decreases with BC differentiation in air-liquid interface cultures (ALI). BC collected from nonsmokers, healthy smokers, and smokers with chronic obstructive pulmonary disease (COPD) displayed a range of HMGA1 expression levels. Low initial expression levels of HMGA1 in BC were associated with decreased ability to maintain a differentiated ALI epithelium. HMGA1 down-regulation in BC diminished BC proliferation, suppressed gene expression related to normal proliferation and differentiation, decreased airway epithelial resistance, suppressed junctional and cell polarity gene expression, and delayed wound closure of airway epithelium following injury. Furthermore, silencing of HMGA1 in airway BC in ALI increased the expression of genes associated with airway remodeling in COPD including squamous, epithelial-mesenchymal transition (EMT), and inflammatory genes. Together, the data suggests HMGA1 plays a central role in normal airway differentiation, and thus caution should be used to monitor airway epithelial structure and function in the context of systemic HMGA1-targeted therapies.
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