SDPR-STK38 axis controls the proliferation-differentiation balance in alveolar type II cells

Area of Science:

• Pulmonary medicine
• Cell biology
• Regenerative medicine

Background:

• Alveolar type II (AT2) cells are crucial progenitors for lung homeostasis and repair.
• Dysregulation of AT2 cell proliferation and differentiation contributes to pulmonary fibrosis and acute respiratory distress syndrome.
• The role of Serum Deprivation Response Protein (SDPR) in modulating AT2 cell fate remains unclear.

Purpose of the Study:

• To investigate the regulatory role of the SDPR-STK38 axis in AT2 cell proliferation and differentiation.
• To assess the impact of this axis on lung homeostasis and regeneration following injury.

Main Methods:

• Utilized SDPR knockout mice and wild-type littermates for comparative analysis.
• Employed histology, immunostaining, lung function tests, mass spectrometry, and co-immunoprecipitation.
• Conducted gain- and loss-of-function assays to elucidate signaling pathways (GSK-3β/cyclin D1, Notch-Hes1).

Main Results:

• SDPR deficiency led to disrupted alveolar architecture, impaired lung function, excessive AT2 expansion, and reduced AT1 cell differentiation.
• STK38 was identified as a novel SDPR-binding protein; SDPR loss increased STK38, enhanced GSK-3β/cyclin D1 signaling, and promoted AT2 proliferation.
• SDPR deficiency attenuated AT2 differentiation by reducing Hes1 expression and impairing vacuole formation, exacerbating LPS-induced lung injury.

Conclusions:

• The SDPR-STK38 axis is a key regulator of AT2 cell proliferation-differentiation balance through GSK-3β/cyclin D1 and Notch-Hes1 signaling.
• SDPR deficiency causes aberrant AT2 cell expansion, hinders AT1 cell differentiation, and worsens acute lung injury.
• This pathway represents a potential therapeutic target for enhancing alveolar regeneration and treating lung injury.