 |
Developmental Biology of the Endoderm and Pancreas
Summary: Doug Melton's laboratory is interested in the genes and stem cells that give rise to the pancreas and insulin-producing beta cells, with possible therapeutic implications for diabetes.
Research in our laboratory focuses on the developmental biology of the pancreas. We wish to understand how the pancreas normally develops and use that information to grow and develop pancreatic cells (islets of Langerhans) in culture. One goal of this project is to establish how vertebrates make an organ from undifferentiated embryonic cells. A longer-term goal has practical significance: if our studies are successful, it should be possible to apply our conclusions to human cells and provide a source of insulin-producing β cells for transplantation into diabetics.
Our main challenge is to understand the precursor, or stem, cells that give rise to the pancreas and to characterize the key gene products that specify cell fates and functions during organogenesis. To this end, we use several vertebrate organisms, including frogs, chickens, and zebrafish, but the majority of our studies are done with mice and human embryonic stem cells. We use a wide variety of techniques, including functional genomics and gene arrays for gene discovery, tissue explants and grafting for analyzing inductive signals, and developmental genetics for direct assays of gene function. The aim of all our experiments is to understand the genes, cells, and tissues that direct pancreatic organogenesis.
Development of the Endoderm and Pancreas
The pancreas develops as an evagination from the embryonic endoderm. In mice and humans, two independent buds form. One of the first steps required for pancreatic development is an inductive interaction between the endoderm and adjacent mes/ectoderm. This interaction sets up a prepattern in the endoderm for various organ-forming regions, including the pancreas, but pancreatic-specific genes are not turned on at this stage. One possibility is that soluble factors secreted by the mes/ectoderm or endoderm itself set up the prepattern in the endoderm.
Subsequent inductive interactions occur between the notochord and the endodermal epithelium. These permissive inductions allow the pancreatic buds to emerge and continue development. About this time, the first pancreatic-specific genes are expressed, including Pdx1. When the epithelial sheet folds up to make a tube, the two lateral regions fuse to form the site where the ventral bud will emerge. The middle region forms the dorsal pancreatic bud. The two pancreatic buds require interactions with adjacent mesenchyme for further pancreatic growth and differentiation. As development continues, the two buds merge to form one organ while exocrine and endocrine cytodifferentiation proceeds. For each of these steps we aim to identify the genes that regulate development.
Pancreatic Stem Cells
In addition to work on genes that regulate pancreatic organogenesis, our laboratory has several projects aimed at the identification of cells capable of producing or turning into pancreatic islets. In embryos there are precursor or stem cells that give rise to the pancreatic lineage, and these cells are being intensely studied. In addition, embryonic stem cells (ES cells) can function as a general precursor for many kinds of cells, including β cells. In the adult, studies show that new pancreatic β cells are not formed by the differentiation of a precursor or stem cell, but rather by the simple process of self-duplication from pre-existing β cells.
At each step of the development from an egg or stem cell to a functional pancreas, decisions are made that affect the fate of cells. For example, an embryonic stem cell can be directed to one of the three germ layers, ectoderm, mesoderm, or endoderm; the latter is the germ layer that will give rise to the pancreas. Subsequently, the endoderm is subdivided into different organ regions, including the thymus, lung, liver, stomach, intestines, and pancreas. Once cells are set aside to form the pancreas, additional decisions are made to parse cells into the ductal, exocrine, or endocrine lineages. The islet of Langerhans is a kind of "mini" endocrine organ consisting of various cell types, including the insulin-producing β cells. If we can understand the gene products that signal cells to become islets, this information could also be used to treat patients directly by stimulating growth and differentiation of new β cells in vivo.
Work from our laboratory and others has identified genes involved in the various steps of pancreatic development. Yet we still do not know all the genes or steps needed to drive cells from an immature embryonic state to a fully formed β cell. As this information accumulates, we are focusing much of our effort on directing the differentiation of embryonic stem cells, including both mouse and human embryonic stem cells, into pancreatic islets and β cells. If we can direct the differentiation of human cells into functional β cells, we will extend our findings to clinical applications for the treatment of diabetes.
Last updated: November 4, 2008
|
|
|
|
