The Strength Of Mechanical Forces Determines The Differentiation Of Alveolar Epithelial Cells

Alveoli is the gas exchange units,which contain two types of epithelial cells.Alveolar type ?(AT2)cell is the stem cell of alveoli which can proliferate and differentiate after alveolar injury.AT2 cells also secerate surfactant protein to help the alveolar expand duiring gas exchange.Alveolar type ?(AT1)cell is the very flat and cover 95%surface of alveoli.ATI cells directly contact with blood vessels and finish the gas exchange function.The differentiation of AT1 and AT2 cells is essential for the lung gas exchange function.Disruption of this process results in neonatal death or in severe lung diseases that last into adulthood.Despite the vital importance of the proper differentiation of alveolar epithelial cells,very little is known about the mechanism that controls alveolar epithelial cell fate specification.At late embryonic stages,the distal airway tubules begin to dilate to form thin-walled distal sacs and progenitor cells differentiation into AT1 and AT2 cells.But we know little about how alveolar progenitor cells differentiate to AT1 and AT2 cells,and which mechanism determines the alveolar progenitor cell fate specification.Considering both the rapidity of distal sac formation and the complex biophysical and biochemical environment of the developing lung,an ability to monitor cellular processes in real time could provide important insights about the mechanisms that control this highly dynamic developmental process.We established both in vivo and ex vivo embryonic lung live imaging systems,and used them to continuously monitor the cellular processes of alveolar progenitor cells during alveolar epithelial cell differentiation.We found that a large subset of alveolar progenitor cells is able to protrude from the airway epithelium toward the mesenchyme in an FGF10/FGFR2 signaling-dependent manner.During late embryonic development,the fetal breath movements become stronger and inhaled amniotic fluids reach to the distal airways.Mechanical forces generated by the inhalation of amniotic fluids promote the non-protruded cells become flattened and differentiate to AT1 cells.While the cell protrusion process results in reduced apical surface area and accumulation of apical myosin in protruded cells,and prevents them from being flattened by mechanical force,thereby ensuring their AT2 cell fate.This study demonstrated a sophisticated developmental process in which cell differentiation is coordinated by both mechanical forces and local growth factor.Both increased or decreased mechanical forces leads to alveolar development default,and these results explane why the baby who suffer from Potter's Sydrone have the lung development default and die after birth.These results may be useful for avoiding embryo alveolar development default which caused by amnitic fluid leakage and administrating proper pressure to premature infants who need ventilators to help breath.