The endocrine cell-specific proteome
The human body has a slow and a fast type of systemic signaling system: the endocrine and the nervous system, respectively. The endocrine system communicates through the production and secretion of messenger biomolecules, called hormones, using the cardiovascular system. The cells in charge of the production and secretion of hormones are called endocrine cells and are distributed in many parts of the body in the form of major endocrine organs, such as the adrenal gland and thyroid gland, or organ-associated cells distributed throughout the human body, in for example the brain and the digestive system. Hormones regulate numerous functions of the body, including digestion, reproduction and fight-and-flight response. Transcriptome analysis shows that 75% (n=14743) of all human proteins (n=19670) are detected in endocrine cells and 1289 of these genes show an elevated expression in any endocrine cells compared to other cell type groups.
The endocrine cell transcriptome
The scRNA-seq-based endocrine cell transcriptome can be analyzed with regard to specificity, illustrating the number of genes with elevated expression in each specific endocrine cell type compared to other cell types (Table 1). Genes with an elevated expression are divided into three subcategories:
Protein expression of genes elevated in endocrine cells
In-depth analysis of the elevated genes in endocrine cells using scRNA-seq and antibody-based protein profiling allowed us to visualize the expression patterns of these proteins in different types of endocrine cells: pancreatic endocrine cells, intestinal endocrine cells and Leydig cells in testis.
Pancreatic endocrine cells
As shown in Table 1, 403 genes are elevated in pancreatic endocrine cells compared to other cell types. The pancreatic endocrine cells found in islets of Langerhans constitute 2% of the pancreas, and are responsible for maintaining a steady blood glucose level by secreting hormones regulating uptake and release of glucose. Examples of proteins expressed in pancreatic endocrine cells include insulin (INS), which is secreted following elevated blood glucose levels and stimulates glucose uptake upon binding insulin receptors, and islet amyloid polypeptide (IAPP), a hormone that regulates glucose metabolism and acts as a satiation signal.
Intestinal endocrine cells
As shown in Table 1, 445 genes are elevated in intestinal endocrine cells compared to other cell types. Intestinal endocrine cells are spread out in the epithelium of the intestines, including the colon and rectum. These cells secrete to the blood numerous hormones (proteins) that in other organs regulate digestive functions such as the release of digestive enzymes and blood sugar balance. An example is peptide YY (PYY), which inhibits secretion of digestive enzymes from the pancreas and peristaltic movements in the jejunum and colon. Another important protein is chromogranin A (CHGA), a precursor for several hormones necessary for maintaining balance in e.g. insulin production in the pancreas and adrenaline release in the adrenal gland. CHGA is produced by endocrine cells in several tissues, but its expression is elevated in intestinal endocrine cells.
Leydig cells - testis
As shown in Table 1, 466 genes are elevated in Leydig cells compared to other cell types. Leydig cells are hormone-producing endocrine cells that are located outside the seminiferous ducts in the testis. The interactions between Leydig cells, Sertoli cells and germinal cells are essential, both for the development of testis and the progress of spermatogenesis. Of the highly enriched genes in testis, only a few are specifically expressed in Leydig cells. Examples of proteins with elevated expression in Leydig cells include the enzyme steroidogenic acute regulatory protein (STAR), that plays a key role in the acute regulation of steroid hormone synthesis by enhancing the conversion of cholesterol into pregnenolone, and insulin-like 3 (INSL3), suggested to act as a hormone involved in the development of the urogenital tract and intra-abdominal testicular descent.
Other endocrine cells
Endocrine cells are also found in various other hormone-producing organs in the body, including the pituitary gland, adrenal gland, thyroid gland and female ovaries. The pituitary gland, at the base of the brain, is referred to as the master endocrine gland since it regulates most other endocrine organs in the body. The anterior part consists mainly of hormone-producing epithelial cells (somatotropes, corticotrophs, thyrotropes, gonadotropes and lactotropes) that store hormones in secretory granules, to later be released into the bloodstream and facilitates further downstream effects in peripheral tissues, including thyroid stimulating hormone (TSHB), produced in thyrotropes, follicle-stimulating hormone (FSHB) and luteinizing hormone (LHB), produced in gonadotropes and important regulators of the reproductive system.
The adrenal gland is commonly associated with the fight-and-flight stress response by the endocrine production and release of catecholamines noradrenaline and adrenaline in the adrenal medulla. Several proteins are linked to this process, including dopamine beta-hydroxylase (DBH), an enzyme expressed in the medulla of the adrenal gland. The endocrine cells of the thyroid gland are important for the regulation of metabolic rate. They produce the thyroid hormones thyroxine (T4), which is converted to another important hormone triiodothyronine (T3) through the action of enzyme iodotyrosine deiodinase (IYD). Four tiny parathyroid glands are positioned behind the thyroid gland, whose endocrine cells play an important role in the regulation of calcium homeostasis by producing and releasing parathyroid hormone (PTH). The ovaries produce and release mature oocytes and produce hormones needed for female reproduction. Inhibin alpha subunit (INHA) is produced in the ovaries and testis and inhibits the release of follicle stimulating hormone (FSH) from the pituitary gland, and is in this way a negative feedback signal important for hormone level regulation.
Endocrine cell function
Endocrine cells are characterized by the secretion of various hormones (signaling molecules) to the blood. These hormones are usually transported from their production site to other organs where they regulate numerous functions of the body, including digestion, reproduction, fight-and-flight response, metabolism, sleep and psychological states. Hormone production is dynamic and feedback loops strictly regulate the amount of hormones depending on numerous factors e.g. circadian clock, age, menstrual cycle and pregnancy.
Hormone production in endocrine cells is stimulated mainly by endocrine signaling or neuroendocrine signaling, depending on the characteristics of the target endocrine cell. During endocrine signaling, hormones produced by other endocrine cells bind to receptors on the surface of the target endocrine cells and set off an intracellular signaling cascade that results in the production and secretion of the appropriate hormone. An example of this is the so called hypothalamus - pituitary - gonadal axis, which involves the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which bind to gonadotropic cells in the anterior part of the pituitary gland. In response, gonadotropic cells release follicle-stimulating hormone (FSH) and luteinizing hormone (LH) which control gonadal function in reproductive organs.
Neuroendocrine signaling is restricted to neuroendocrine cells since they share characteristics of both neuronal and endocrine cells. They produce hormones in response to nervous stimuli (changes in membrane potential). Examples are intestinal endocrine cells, cells in the adrenal medulla and pancreatic endocrine cells.
The histology of organs that contain endocrine cells, including interactive images, is described in the Protein Atlas Histology Dictionary.
Here, the protein-coding genes expressed in endocrine cells are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize corresponding protein expression patterns of genes with elevated expression in different endocrine cell types.
The transcript profiling was based on publicly available genome-wide expression data from scRNA-seq experiments covering 13 different normal tissues, as well as analysis of human peripheral blood mononuclear cells (PBMCs). All datasets (unfiltered read counts of cells) were clustered separately using louvain clustering and the clusters obtained were gathered at the end, resulting in a total of 192 different cell type clusters. The clusters were then manually annotated based on a survey of known tissue and cell type-specific markers. The scRNA-seq data from each cluster of cells was aggregated to average normalized protein-coding transcripts per million (pTPM) and the normalized expression value (nTPM) across all protein-coding genes. A specificity and distribution classification was performed to determine the number of genes elevated in these single cell types, and the number of genes detected in one, several or all cell types, respectively.
It should be noted that since the analysis was limited to datasets from 13 organs only, not all human cell types are represented. Furthermore, some cell types are present only in low amounts, or identified only in mixed cell clusters, which may affect the results and bias the cell type specificity.
Relevant links and publications
Uhlén M et al., Tissue-based map of the human proteome. Science (2015)