TY - JOUR
T1 - Human Airway Basal Cells Undergo Reversible Squamous Differentiation and Reshape Innate Immunity
AU - Zhang, Yihan
AU - Black, Katharine Elliot
AU - Phung, Thien Khoi N.
AU - Thundivalappil, Sujatha Rajeev
AU - Lin, Tian
AU - Wang, Wei
AU - Xu, Jie
AU - Zhang, Cheng
AU - Hariri, Lida P.
AU - Lapey, Allen
AU - Li, Hu
AU - Lerou, Paul Hubert
AU - Ai, Xingbin
AU - Que, Jianwen
AU - Park, Jin Ah
AU - Hurley, Bryan P.
AU - Mou, Hongmei
PY - 2023/6/1
Y1 - 2023/6/1
N2 - Histological and lineage immunofluorescence examination revealed that healthy conducting airways of humans and animals harbor sporadic poorly differentiated epithelial patches mostly in the dorsal noncartilage regions that remarkably manifest squamous differentiation. In vitro analysis demonstrated that this squamous phenotype is not due to intrinsic functional change in underlying airway basal cells. Rather, it is a reversible physiological response to persistent Wnt signaling stimulation during de novo differentiation. Squamous epithelial cells have elevated gene signatures of glucose uptake and cellular glycolysis. Inhibition of glycolysis or a decrease in glucose availability suppresses Wnt-induced squamous epithelial differentiation. Compared with pseudostratified airway epithelial cells, a cascade of mucosal protective functions is impaired in squamous epithelial cells, featuring increased epithelial permeability, spontaneous epithelial unjamming, and enhanced inflammatory responses. Our study raises the possibility that the squamous differentiation naturally occurring in healthy airways identified herein may represent "vulnerable spots" within the airway mucosa that are sensitive to damage and inflammation when confronted by infection or injury. Squamous metaplasia and hyperplasia are hallmarks of many airway diseases, thereby expanding these areas of vulnerability with potential pathological consequences. Thus, investigation of physiological and reversible squamous differentiation from healthy airway basal cells may provide critical knowledge to understand pathogenic squamous remodeling, which is often nonreversible, progressive, and hyperinflammatory.
AB - Histological and lineage immunofluorescence examination revealed that healthy conducting airways of humans and animals harbor sporadic poorly differentiated epithelial patches mostly in the dorsal noncartilage regions that remarkably manifest squamous differentiation. In vitro analysis demonstrated that this squamous phenotype is not due to intrinsic functional change in underlying airway basal cells. Rather, it is a reversible physiological response to persistent Wnt signaling stimulation during de novo differentiation. Squamous epithelial cells have elevated gene signatures of glucose uptake and cellular glycolysis. Inhibition of glycolysis or a decrease in glucose availability suppresses Wnt-induced squamous epithelial differentiation. Compared with pseudostratified airway epithelial cells, a cascade of mucosal protective functions is impaired in squamous epithelial cells, featuring increased epithelial permeability, spontaneous epithelial unjamming, and enhanced inflammatory responses. Our study raises the possibility that the squamous differentiation naturally occurring in healthy airways identified herein may represent "vulnerable spots" within the airway mucosa that are sensitive to damage and inflammation when confronted by infection or injury. Squamous metaplasia and hyperplasia are hallmarks of many airway diseases, thereby expanding these areas of vulnerability with potential pathological consequences. Thus, investigation of physiological and reversible squamous differentiation from healthy airway basal cells may provide critical knowledge to understand pathogenic squamous remodeling, which is often nonreversible, progressive, and hyperinflammatory.
KW - WNT signaling
KW - glycolysis
KW - human airway epithelium
KW - innate immunity
KW - squamous differentiation
UR - http://www.scopus.com/inward/record.url?scp=85160966792&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85160966792&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2022-0299OC
DO - 10.1165/rcmb.2022-0299OC
M3 - Article
C2 - 36753317
AN - SCOPUS:85160966792
SN - 1044-1549
VL - 68
SP - 664
EP - 678
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 6
ER -