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, uterus and fallopian tube, and glandular organs such as pancreas, prostate and breast.
Transcriptome analysis shows that 81% (n=16352) of all human proteins (n=20162) are detected in glandular epithelial cells and 3555 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 ciliated cells and glandular epithelial cell types of the respiratory system, salivary gland, gastrointestinal tract, pancreas, male tissues 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.
As shown in Table 1, 534 genes are elevated in 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, and in glandular epithelia of reproductive tissues. Ciliated cells facilitate mucociliary transport of cells and particles needed for the clearance of unwanted particles in the respiratory tract and the transport of gametes and the early embryo during reproduction. An example of an important protein with elevated expression in ciliated cells is forkhead box J1 (FOXJ1), which is a nuclear transcription factor required for the production of motile cilia. Another example is dynein axonemal intermediate chain 2 (DNAI2), which is a component of the motor protein dynein that is needed for the movement of cilia and the sperm tail flagella.
Basal respiratory cells
As shown in Table 1, 297 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 is basal cell adhesion molecule (BCAM), which is a receptor for the extracellular matrix laminin that may mediate intracellular signalling. 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, 177 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, 269 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.
Mucus glandular cells
As shown in Table 1, 152 genes are elevated in mucus glandular cells compared to other cell types. Mucus glandular cells are crucially important for creating a protective dental biofilm with mucins and lysozymes. A protein expressed in mucus glandular cells is MACC1, a transcription factor for MET. A second example is chromosome 6 open reading frame 58 (C6orf58) with no clear function.
Serous glandular cells
As shown in Table 1, 239 genes are elevated in serous glandular cells compared to other cell types. Serous glandular cells produce a watery secretion containing antimicrobial proteins as well as enzymes to initiate digestion. An example of an enzyme involved in carbohydrate digestion is amylase 1A (AMY1A) which has enriched expression in serous glandular cells. Another example of a gene with enriched expression in serous glandular cells is lactoperoxidase (LPO) which is an enzyme that activates antimicrobial agents in the saliva.
Gastric mucus-secreting cells
As shown in Table 1, 449 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, 884 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, 392 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. An example of a protein with elevated expression in paneth cells is guanylate cyclase activator 2A (GUCA2A), which activates intestinal guanylate cyclase. Another example is GPR15LG, which is suggested to function as a chemokine ligand for G-protein coupled receptor 15 (GPR15).
As shown in Table 1, 674 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 membrane spanning 4-domains A12 (MS4A12), which is a membrane receptor involved in cell proliferation and motility.
Intestinal goblet cells
As shown in Table 1, 351 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 mucins to create a protective mucus layer over the intestinal epithelia. An example of a protein with elevated expression in intestinal goblet cells is mucin 2 (MUC2), which is one type of the aforementioned mucin. Another example is chloride channel accessory 1 (CLCA1), which is speculated to be involved in regulation of mucus production and secretion.
Exocrine glandular cells
As shown in Table 1, 199 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, 205 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. An example of a protein with elevated expression in basal prostatic cells is claudin 1 (CLDN1), which as a component of tight junctions enables cell to cell adhesion.
Prostatic glandular cells
As shown in Table 1, 267 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 seminal tract.
Breast glandular cells
As shown in Table 1, 155 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 casein alpha s1 (CSN1S1), a milk protein important for the transport of calcium phosphate.
Breast myoepithelial cells
As shown in Table 1, 170 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
Glandular and luminal cells
As shown in Table 1, 342 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.
As shown in Table 1, 150 genes are elevated in secretory cells compared to other cell types. The glandular epithelium of the fallopian tube is lined by mucus-producing secretory cells and ciliated cells, working in tandem to secrete and move mucus in order to transport the gamets during sexual reproduction. An example of a protein with elevated expression in secretory cells is oviductal glycoprotein 1 (OVGP1), which is a glycoprotein expressed by the secretory cells during the late follicular phase of the ovarian cycle. Another example is cysteine rich secretory protein 3 (CRISP3), which is a secreted protein important in both female and male reproductive tissues.
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. 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 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)