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.

  • 778 elevated genes
  • 25 enriched genes
  • 101 group enriched genes
  • Main function: Hormone production

Transcriptome analysis shows that 75% (n=15118) of all human proteins (n=20162) are detected in endocrine cells and 778 of these genes show an elevated expression in any endocrine cells compared to other cell type groups. 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 the following types of endocrine cells: enteroendocrine cells, pancreatic endocrine cells, and Leydig cells.


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:

  • Cell type enriched: At least four-fold higher mRNA level in a certain cell type compared to any other cell type.
  • Group enriched: At least four-fold higher average mRNA level in a group of 2-10 cell types compared to any other cell type.
  • Cell type enhanced: At least four-fold higher mRNA level in a cell certain cell type compared to the average level in all other cell types.


Table 1. Number of genes in the subdivided specificity categories of elevated expression in the analyzed endocrine cell types.

Cell type
Tissue origin
Cell type enriched
Group enriched
Cell type enhanced
Total elevated
Enteroendocrine cells Colon, Rectum, Small intestine 18 44 224 286
Pancreatic endocrine cells Pancreas 7 27 168 202
Leydig cells Testis 0 39 292 331
Any endocrine cells 25 101 652 778


Enteroendocrine cells

As shown in Table 1, 286 genes are elevated in enteroendocrine cells compared to other cell types. Enteroendocrine 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 the 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 enteroendocrine cells.



PYY - rectum
010,00020,00030,00040,000nTPM
PYY - Rectum

PYY - rectum



CHGA - colon
050100150200250nTPM
CHGA - Colon

CHGA - colon


Pancreatic endocrine cells

As shown in Table 1, 202 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.



INS - pancreas
010,00020,00030,00040,00050,000nTPM
INS - Pancreas

INS - pancreas



IAPP - pancreas
0100200300400500nTPM
IAPP - Pancreas

IAPP - pancreas


Leydig cells

As shown in Table 1, 331 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 delta like non-canonical Notch ligand 1 (DLK1) which is known to maintain cells in an undifferentiated state and insulin like 3 (INSL3), a hormone which plays a role in reproductive tissue development.



DLK1 - testis
02004006008001,0001,2001,400nTPM
DLK1 - Testis

DLK1 - testis



INSL3 - testis
02004006008001,0001,2001,400nTPM
INSL3 - Testis

INSL3 - testis


Other endocrine cells

There are additional endocrine cells in the body that currently lack scRNA-seq data at Human Protein Atlas. Endocrine cells are also found in the pituitary gland, adrenal gland, and thyroid gland. 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. Those hormones are later released into the bloodstream and facilitate further downstream effects in peripheral tissues. Hormones like 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.


TSHB - pituitary gland

FSHB - pituitary gland

LHB - pituitary gland

The adrenal gland is commonly associated with the fight-or-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).


DBH - adrenal gland

IYD - thyroid gland

PTH - parathyroid gland

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 enteroendocrine 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.


Background

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 29 tissues and peripheral blood mononuclear cells (PBMCs). All datasets (unfiltered read counts of cells) were clustered separately using louvain clustering, resulting in a total of 557 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 mean normalized protein-coding transcripts per million (nTPM) 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 29 tissues and PBMC 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)
PubMed: 25613900 DOI: 10.1126/science.1260419

Fagerberg L et al., Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. (2014)
PubMed: 24309898 DOI: 10.1074/mcp.M113.035600

Guo J et al., The adult human testis transcriptional cell atlas. Cell Res. (2018)
PubMed: 30315278 DOI: 10.1038/s41422-018-0099-2

Parikh K et al., Colonic epithelial cell diversity in health and inflammatory bowel disease. Nature. (2019)
PubMed: 30814735 DOI: 10.1038/s41586-019-0992-y

Qadir MMF et al., Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche. Proc Natl Acad Sci U S A. (2020)
PubMed: 32354994 DOI: 10.1073/pnas.1918314117

Wang Y et al., Single-cell transcriptome analysis reveals differential nutrient absorption functions in human intestine. J Exp Med. (2020)
PubMed: 31753849 DOI: 10.1084/jem.20191130