Origin and Differentiation of a New Class of Serotonin-Expressing Enteroendocrine Cells
Researcher: Andrew Leiter, MD, PhD Location: University of Massachusetts Medical School State: Massachusetts Year: 2006 Status: Finished
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To identify and characterize precursor cells that differentiate into serotonin-expressing enteroendocrine cells and to identify a distinct pathway controlling their differentiation.
To identify and characterize precursor cells that differentiate into serotonin-expressing enteroendocrine cells and to identify a pathway controlling their differentiation that is distinct from other enteroendocrine cells.
Gastrointestinal carcinoid tumors express serotonin and therefore are thought to arise from serotonin-expressing intestinal endocrine cells. At present, relatively little genetic information is available to support this theory. This proposal is based on two observations made by Dr. Leiter. First, some normal serotonin expressing cells develop differently than all other hormone-producing cells in the GI tract by a novel yet uncharacterized pathway. Second, Dr. Leiter has induced small intestinal tumors producing serotonin in genetically altered (transgenic) mice by putting a mutant gene into immature endocrine cells. The cancers in these mice arise from changes in a gene similar to mutations seen in some aggressive human carcinoids. This proposal aims to identify how serotonin cells become specialized to produce this hormone and to examine their potential to form carcinoid tumors in mice. Understanding how potentially normal cells give rise to carcinoids will be important for identifying new therapeutic targets for treating these tumors.
Research Progress and Results:
Identified a new population of serotonin producing cells.
The goals of Dr. Leiter’s project were to characterize the developmental origin of serotonin cells. Serotonin cells are believed to be related to the cell of origin for serotonin producing mid gut carcinoids. Dr. Leiter developed methods to isolate relatively pure serotonin cells from the stomach and the small intestine and analyzed all the genes expressed by RNA Sequencing. Often the pattern of genes expressed provides important clues about cell origins.
To our surprise, in addition to serotonin producing endocrine cells, Dr. Leiter’s group identified a new population of serotonin cells. Surprisingly, these did not show a gene expression signature for endocrine cells but instead appeared to be mast cells. Mast cells are a bone marrow cell involved in immune regulation. Mast cells migrate to and reside in the intestine and produce serotonin.
In addition to serotonin cells, Dr. Leiter extended the original project to study histamine producing cells in the stomach which some investigators propose is a mast cell. This population was chosen because these cells are believed to be the source for many stomach carcinoids. The gene expression pattern of these cells clearly suggested that they were endocrine cells, not bone marrow derived mast cells.
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