A three-stage assembly program governing pancreatic, plasma, pituitary, and bone secretory cell differentiation: A strategy to augment protein delivery.

Defective secretory cell function underlies many diseases, and recent therapeutic strategies have focused on enhancing protein synthesis and delivery by targeting the secretory machinery of mature cells. However, mature differentiated cells appear to have intrinsic limits to their secretory capacity. In this review, we propose new strategies for engineering these cells to overcome these limits on secretion. The integrated stress response (ISR) and the related unfolded protein response (UPR) are stress adaptation systems that modulate transcriptional and translational programs of gene expression. These programs drive remodeling of cellular architecture to boost protein production and trafficking but also play critical roles in the differentiation of secretory cells. This dual function suggests that the limits of the secretory capacity of mature cells are pre-programmed during development. A potentially more effective therapeutic approach to expand protein secretion may lie in reprogramming the secretory capacity early in differentiation. Two additional transcriptional programs work in concert with the ISR and UPR to shape differentiated cell identities, their secretory outputs, and production capacity. The first involves lineage-determining transcription factors that define both cell type and secretory products. The second involves "scaling factors" that set the magnitude of the cell's protein synthesis and secretion capacity. We explore the mechanisms by which these three programs-lineage specification, scaling, and stress adaptation-interact to define and potentially enhance secretory capacity. We will illustrate this integrated model across several secretory cell types, including pancreatic, plasma, pituitary, and bone secretory cells, with a focus on applications to enhance therapeutic outcomes in osteoporosis.