Lineage determinants in early endocrine development

Abstract

Pancreatic endocrine cells are produced from a dynamic epithelium in a process that, as in any developing organ, is driven by interacting programs of spatiotemporally regulated intercellular signals and autonomous gene regulatory networks. These algorithms work to push progenitors and their transitional intermediates through a series of railroad-station-like switching decisions to regulate flux along specific differentiation tracks. Extensive research on pancreas organogenesis over the last 20 years, greatly spurred by the potential to restore functional β-cell mass in diabetic patients by transplantation therapy, is advancing our knowledge of how endocrine lineage bias is established and allocation is promoted. The field is working towards the goal of generating a detailed blueprint of how heterogeneous cell populations interact and respond to each other, and other influences such as the extracellular matrix, to move into progressively refined and mature cell states. Here, we highlight how signaling codes and transcriptional networks might determine endocrine lineage within a complex and dynamic architecture, based largely on studies in the mouse. The process begins with the designation of multipotent progenitor cells (MPC) to pancreatic buds that subsequently move through a newly proposed period involving epithelial plexus formation-remodeling, and ends with formation of clustered endocrine islets connected to the vascular and peripheral nervous systems. Developing this knowledge base, and increasing the emphasis on direct comparisons between mouse and human, will yield a more complete and focused picture of pancreas development, and thereby inform β-cell-directed differentiation from human embryonic stem or induced pluripotent stem cells (hESC, iPSC). Additionally, a deeper understanding may provide surprising therapeutic angles by defining conditions that allow the controllable reprogramming of endodermal or pancreatic cell populations.

Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo

“…The expression of NKX6.1 distinguishes these populations and is thought to mark the progenitor cells that arise during the second transition of pancreas development, as opposed to the polyhormonal cells that arise during the first transition [19]. Results from several recent studies suggest that polyhormonal cells may develop into pancreatic a-cells following transplantation [6,16,20].…”

The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis

“…Pancreatic organogenesis proceeds through several crucial regulatory stages (Cleaver and MacDonald, 2010;Rieck et al, 2012): (1) specification and emergence of the pancreatic epithelial buds from the distal foregut endoderm; (2) expansion of an early pancreatic progenitor cell population and developmental commitment; (3) formation of a more restricted multipotent progenitor cell (MPC) population for endocrine, ductal and acinar tissues; (4) separation of committed pre-acinar cells at the tips of epithelial branches and a bipotent cell-population for islets and ducts in more central trunk domains; (5) separation of the endocrine and ductal programs, morphogenetic resolution of a precursor ductal plexus and completion of cell type-specific differentiation. This process creates three interrelated tissues: the islets of Langerhans (endocrine cells that produce polypeptide hormones, including insulin and glucagon), acini (exocrine cells that produce and secrete hydrolytic digestive enzymes) and ducts (exocrine cells that produce a bicarbonate flush and channel the acinar secretions to the intestine).…”

Feedback control of growth, differentiation, and morphogenesis of pancreatic endocrine progenitors in an epithelial plexus niche

“…While these outcomes are interpreted largely on the basis of upstream transcriptional effects on Ngn3, they are consistent with the idea that misregulated epithelial morphology precludes efficient engagement of the endocrine differentiation program. We previously proposed that the interdependency between progenitor maintenance, cell differentiation, and trunk morphogenesis reflects a programmed niche framework that coordinates the birth of endocrine cells during organogenesis (Rieck et al 2012).…”