SMAD signaling and airway cell fate determination
Embargo Date
2022-03-30
OA Version
Citation
Abstract
BACKGROUND: Goblet cell hyperplasia is a key feature of asthma and other airway
diseases. It is likely regulated by the BMP/TGF-b/SMAD signaling pathway which is
expressed in low levels in basal and goblet cells but highly active in other differentiated
cell types. Therefore, SMAD signaling may be the main determinant of goblet vs nonmucus cell fate in the airway.
OBJECTIVE: To determine the role of SMAD in goblet cell fate determination in the airway
utilizing a knockout SMAD4 cell line.
METHODS: Human adult and mouse tracheal SMAD4 knockout basal cell lines were
generated. SMAD4 deletion was confirmed with western blot for both cell lines. Cells
were cultured using an air-liquid interface to stimulate normal physiologic differentiation.
RESULTS: Raised levels of goblet cells were noted in the human ALI. No ciliated cells
were found in culture and club cell generation was also drastically lowered.
CONCLUSIONS: In human cells, differentiation of goblet cells was increased by SMAD
deletion while differentiation of non-mucus cells was lowered. Lack of ciliated or normal
levels of club cells after an extended culture suggests SMAD signaling is required for a
non-mucus cell fate. These data support a role for SMAD signaling in both goblet cell
generation and cell differentiation.