The glandular epithelial cell-specific proteome
Glandular epithelial cells are multifunctional cells with the main functions of secretion and absorption. Glandular epithelia are found at the surface of inner cavities of the respiratory system, gastrointestinal tract, and uterus, and glandular organs such as pancreas, prostate and breast.
Transcriptome analysis shows that 79% (n=15932) of all human proteins (n=20090) are detected in glandular epithelial cells and 3629 of these genes show an elevated expression in any glandular epithelial cells compared to other cell type groups. In-depth analysis of the elevated genes in glandular epithelial cells using scRNA-seq and antibody-based protein profiling allowed us to visualize the expression patterns of these proteins in the cell types of the following tissues: respiratory system, gastrointestinal tract, pancreas, male tissue and female tissues.
The glandular epithelial cell transcriptome
The scRNA-seq-based glandular epithelial cell transcriptome can be analyzed with regard to specificity, illustrating the number of genes with elevated expression in each specific glandular epithelial cell type compared to other cell types (Table 1). Genes with an elevated expression are divided into three subcategories:
Table 1. Number of genes in the subdivided specificity categories of elevated expression in the analyzed glandular epithelial cell types.
Basal respiratory cells
As shown in Table 1, 289 genes are elevated in basal respiratory cells compared to other cell types. Basal cells are small stem cells located in the basal part of the respiratory epithelium. They differentiate into the other cell types when the epithelium is injured, thereby restoring the epithelium. An example of a protein with elevated expression in basal respiratory cells and ciliated cells is tumor protein p73 (TP73), which is activated in response to cellular stress and development. Another example is cadherin 3 (CDH3), which is a member of the cadherin family of proteins involved in calcium-dependent cell adhesion.
As shown in Table 1, 298 genes are elevated in club cells compared to other cell types. Club cells (also called Clara cells) are found in the respiratory bronchiole epithelium in the lung. They are proposed to have several roles, including secretion of the extracellular substance lining the respiratory bronchioles. A protein with elevated expression in club cells is secretoglobin family 1A member 1 (SCGB1A1), a small secreted molecule that is suggested to have numerous functions, e.g. anti-inflammation, and defects in the SCGB1A1 gene are related to susceptibility to asthma. Another example is BPIFB1, which has a function in binding baterial lipopolysacharide and stimulate the immune response to it.
As shown in Table 1, 148 genes are elevated in basal respiratory cells compared to other cell types. Ionocytes correspond to one percent of all cells in the respiratory epithelium. They maintain an optimal ion concentration in the apical surface fluid essential for cilia motility. An example of a protein with elevated expression in ionocytes is Barttin CLCNK type accessory subunit beta (BSND), which is a subunit of CLC chloride channels that transport various ions across the cell membrane. Another example is prolifilin 2 (PFN2), which regulates actin cytoskeletal structure by binding actin in response to extracellular stimuli.
Respiratory ciliated cells
As shown in Table 1, 717 genes are elevated in respiratory ciliated cells compared to other cell types. Ciliated cells with motile cilia are found in many parts of the body, including the respiratory epithelium lining the bronchi and bronchioles, where they help free the airways from inhaled contaminants. A protein expressed in ciliated cells, specifically in ciliary rootlets, is cilia and flagella associated protein 157 (CFAP157), which is mainly known for its importance for flagella function. In ciliated cells, it is expressed in both ciliary rootlets and tips of cilia. Another example is forkhead box J1 (FOXJ1), which is transcription factor required for the production of motile cilia.
Gastric mucus-secreting cells
As shown in Table 1, 350 genes are elevated in gastric mucus-secreting cells compared to other cell types. Gastric mucus-secreting cells, also known as foveolar cells, cover the inside of the stomach. They produce mucus that protects the epithelial lining of the stomach from corrosive gastric acid. Examples of a protein with elevated expression in gastric mucus-secreting cells are mucin 1, cell surface associated (MUC1) and trefoil factor 1 (TFF1). Both are present in the mucus gel covering the epithelium and protect the mucosa from damage.
As shown in Table 1, 818 genes are elevated in proximal enterocytes compared to other cell types. Proximal enterocytes are simple columnar epithelial cells in the small intestine. They have the same function as distal enterocytes, namely the uptake of nutrients from the intestinal tract. An example of a protein with elevated expression in proximal enterocytes is intestinal alkaline phosphatase (ALPI) that has an important role in maintaining a healthy gut microbiome. Another example is fatty acid binding protein 2 (FABP2), which is involved in the uptake and metabolism, of long-chain fatty acids.
As shown in Table 1, 453 genes are elevated in paneth cells compared to other cell types. Paneth cells are epithelial cells located in the intestinal crypts that secrete antimicrobial peptides and immunomodulating proteins to regulate the intestinal microbiome. For example the protein encoded by C10orf99, which is suggested to function as a chemokine ligand for G-protein coupled receptor 15 (GPR15). Another example of a paneth cell elevated protein is solute carrier family 22 member 18 antisense (SLC22A18AS), which is a potential transporter protein associated with Beckwith-Wiedemann Syndrome.
As shown in Table 1, 656 genes are elevated in distal enterocytes compared to other cell types. Distal enterocytes are enterocytes located in the colon and rectum. These cells facilitate the uptake of nutrients from the intestinal lumen. An example of a protein with elevated expression in distal enterocytes is glycoprotein A33 (GPA33), which is involved in cell-cell signaling and observed in 95% of colon cancers. Another example is desmoglein 2 (DSG2), which is a component of desmosomes essential for cell-to-cell adhesion.
Intestinal goblet cells
As shown in Table 1, 303 genes are elevated in intestinal goblet cells compared to other cell types. Intestinal goblet cells lay interspersed between the enterocytes in the small intestine and in larger quantities in the large intestine. These cells secrete glycoprotein-rich mucin to create a protective mucus layer over the intestinal epithelia. Examples of glycoproteins that have elevated expression in intestinal goblet cells include Ca2+-independent lectin regenerating islet-derived protein 4 (REG4) and Ca2+-dependent lectin intelectin-1 (ITLN1). Both of these proteins are involved in inflammatory responses by binding to microbial carbohydrate chains.
Exocrine glandular cells
As shown in Table 1, 316 genes are elevated in exocrine glandular cells compared to other cell types. Exocrine glandular cells are the major cell type in the pancreas. These cells secrete digestive enzymes and NaHCO3 into ducts leading to the duodenum. Examples of exocrine glandular cell specific genes are phospholipase A2 precursor (PLA2G1B), a Ca2+ dependent phospholipase and carboxypeptidase A1 precursor (CPA1), which is a protease that cleaves C-terminally branched-chain and aromatic amino acids.
Basal prostatic cells
As shown in Table 1, 236 genes are elevated in basal prostatic cells compared to other cell types. Basal prostatic cells play an important part in the structural and luminal integrity of the prostate glands. Disruptions in these cells are associated with cancer-related issues. Keratin 15 (KRT15) is involved in keeping the structural integrity of the basal cells intact. The KRT15 family of genes is in some cases associated with disease development in prostate cancer. Another gene that is expressed in the basal prostatic cells is the nerve growth factor receptor (NGFR), which is associated with several different functions throughout the body. The receptor is known to interact with BDNF in controlling nerve cell growth and apoptosis, however, its exact function in basal prostatic cells is yet to be investigated.
Prostatic glandular cells
As shown in Table 1, 202 genes are elevated in Prostatic glandular cells compared to other cell types. The prostate is composed of prostatic glands and a non-glandular stroma. Within the glandular structures, there are secretory cells, which are separated from the basement membrane and stroma by a layer of basal cells. One example of proteins with elevated expression in prostatic glandular cells is kallikrein related peptidase 3 (KLK3), generally referred to as prostate-specific antigen (PSA), a serine protease that is synthesized by glandular cells of the prostate. Under normal conditions, PSA is secreted into the extracellular fluid in small quantities and its function is believed to be important for the liquefaction of seminal fluid in the seminal coagulum and to allow sperm to swim freely. Transglutaminase 4 (TGM4) is an enzyme assoicated with the reproductive process with the ability to cross-link proteins and conjugate polyamines to specific proteins in the s.
Breast glandular cells
As shown in Table 1, 245 genes are elevated in breast glandular cells compared to other cell types. Breast glandular cells comprise the mammary gland, which can either be lactating or non-lactating. During pregnancy, non-lactating mammary glands undergo morphological alterations and begin to produce milk due to the influence of hormonal changes. An example of a protein with elevated expression in breast glandular cells is lactalbumin alpha (LALBA), a key enzyme in milk production. Another example is prolactin induced protein (PIP), a secreted protein with unknown function that shows protein expression in breast and salivary gland.
Breast myoepithelial cells
As shown in Table 1, 232 genes are elevated in breast myoepithelial cells compared to other cell types. Breast myoepithelial cells are usually found in close proximity to breast glandular cells and are related to smooth muscle cells. The contraction of the myoepithelial cells facilitates the expulsion of the glandular cell secretion. Examples of proteins with elevated expression in breast myoepithelial cells are calponin 1 (CNN1) and myosin light chain kinase (MYLK), both of which are involved in smooth muscle contraction
Endometrial ciliated cells
As shown in Table 1, 626 genes are elevated in endometrial ciliated cells compared to other cell types. Endometrial ciliated cells line the inside of the uterus. Their cilia help move the mucus from the glandular tissue. An example of a protein with elevated expression in endometrial ciliated cells is dynein axonemal intermediate chain 2 (DNAI2), which is a component of dynein found in cilia and flagella. Another example is tektin 4 (TEKT4), which may be involved in cilium biogenesis or degradation.
Glandular and luminal cells
As shown in Table 1, 436 genes are elevated in glandular and luminal cells compared to other cell types. Endometrial glandular and luminal cells line the inside glandular mucosa (endometrium) of the uterus. During the proliferative phase of the menstrual cycle, endometrial glands, stroma and vascular endothelium all proliferate leading to an increased volume of the endometrium. The glands are lined by mucus-producing glandular cells with interspersed ciliated cells, and luminal cells line the epithelium outside of the glands. An example of a protein with elevated expression in glandular and luminal cells is progestagen associated endometrial protein (PAEP), which is a glycoprotein expressed in glandular cells with an essential role in regulating uterine environment suitable for pregnancy. Another example is cadherin 1 (CDH1), which regulates cell-to-cell adhesions, mobility and proliferation of epithelial cells.
Other glandular epithelial cells
There are additional glandular epithelial cells in the body that currently lack scRNA-seq data at Human Protein Atlas. Glandular epithelial cells also play important roles in the digestion of nutrients and protection of female tissues. Glandular cells of the salivary gland secrete proteins such as mucin 7 (MUC7), which is found in the protective and lubricating mucus produced by salivary glands, and gastric parietal cells produce hydrochloric acid with the help of ion transport proteins, such as ATPase H+/K+ transporting beta subunit (ATP4B), which is key for digestion of proteins. Glandular cells of the uterine endocervix excrete proteins such as secretory leukocyte peptidase inhibitor (SLPI), a protease inhibitor that protects epithelial surfaces from endogenous proteolytic enzymes with antimicrobial function.
Glandular epithelial cell function
Epithelial cells form sheets of cells, epithelia, that line the outer and inner surfaces of the body and constitute the building blocks for glandular tissues. Hence, epithelial cells are found in many parts of the body, including skin, airways, the digestive tract, glandular tissues and organs, as well as the urinary and reproductive systems. The wide range of functions of epithelial cells can be broadly divided into two main categories, being in charge of the transfer of compounds in or out of the body, as well as being a protective barrier against invading pathogens and physical, chemical, or biological abrasion.
Transfer of compounds is a key process for glandular epithelial cells involved in absorption and secretion. The epithelial cells in the digestive system form vast surfaces to enable efficient absorption of the ingested food particles. The same food particles must be predigested into smaller constituents before they can be taken up by the absorptive epithelial cells, a process that is made possible by the secretion of compounds such as enzymes and acid. Mucus secretion is also another important secretory function of glandular epithelial cells that protect the epithelia and enable efficient transport of microorganisms, gametes, particles, and smaller compounds in different areas of the body, such as the airways, the digestive system, and the reproductive system.
The histology of organs that contain glandular epithelial cells, including interactive images, is described in the Protein Atlas Histology Dictionary.
Here, the protein-coding genes expressed in glandular epithelial 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 glandular epithelial cell types.
The transcript profiling was based on publicly available genome-wide expression data from scRNA-seq experiments covering 25 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 444 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 25 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)