Apoptosis and proliferation during human salivary gland development.

ABSTRACT

Human salivary gland (SG) branching morphogenesis is an intricate mechanism divided into stages, prebud, initial bud, pseudoglandular, canalicular, and terminal bud, to form the final lobular structure of the organ. The coordination of molecular cascades, including cell proliferation and apoptosis, are fundamental to this process. The intrinsic apoptosis pathway appears to be important in the early phases of ductal cavitation and luminisation; however, the role of the extrinsic apoptosis pathway has still to be determined. Questions remain as to whether the latter mechanism participates in the maintenance of the ductal lumen; therefore, the present study investigated the expression of proteins Prostate apoptosis response-4 (Par-4), Fas cell surface death receptor (Fas), Fas ligand (FasL), pleckstrin homology-like domain family A member 1 (PHLDA1), caspase-3, B-cell CLL/lymphoma 2 (Bcl-2), survivin, Ki-67, mucin 1 (MUC1), and secreted protein acidic and cysteine-rich (SPARC) during distinct phases of human SG development (50 specimens). This strategy aimed to draw an immunomorphological map of the proteins involved in apoptosis, cell proliferation, and tissue maturation during the SG branching morphogenesis process. Par-4 was positive at all stages except the pre-acinar phase. Fas and FasL were expressed in few cells. PHLDA1 was expressed in all phases but not in the terminal bud. Bcl-2 expression was mainly negative (expressed in few cells). Survivin showed a cytoplasmic expression pattern in the early phases of development, which changed to a predominantly nuclear expression during development into more differentiated structures. Ki-67 was expressed mainly at the pseudoglandular stage. MUC1 was positive in the pseudoglandular stage with a cytoplasmic pattern in regions of early luminal opening. Immunostaining for SPARC and caspase-3 was negative. Our results suggest that proteins associated with the regulation of extrinsic and intrinsic apoptosis contribute to apoptosis during specific phases of the early formation of SGs in humans.