Digestive System Primary Cells

Composition of the Digestive System

The digestive system is a complex and coordinated system within the human body, primarily responsible for intake, breakdown, and absorption of food to provide the necessary nutrients and energy. Organs of the digestive system are shown in Figure 1. Most of the listed organs make up the gastrointestinal (GI) tract. GI tract includes the mouth, pharynx, esophagus, stomach, as well as small intestine and large intestine (colon). Food actually passes through the GI tract.

The rest of the organs of the digestive system are called accessory organs. These organs are responsible of secretion of enzymes and other substances into the GI tract, but food does not actually pass through them. Together, the GI tract and accessory organs complete the digestion and absorption of food through a series of precise physiological and biochemical processes [1-4].

The entire process is regulated by the nervous system and hormones to ensure smooth progression through each stage. The coordinated functioning of the digestive system is essential for maintaining normal physiological functions in the body and is crucial for health.

Functions of the Digestive System

There are three main functions of the digestive system relating to food: digestion of food, absorption of nutrients from food, and elimination of remaining food waste. Digestion consists of two types of processes to break down food into components which the body can absorb: mechanical digestion and chemical digestion.

Mechanical digestion physically breaks down chunks of food into smaller pieces. It mainly takes place in the mouth and the stomach. Chemical digestion chemically breaks down large, complex food molecules into simpler nutrient molecules which can be absorbed by blood or lymph. It starts in the mouth and continues in the stomach, but mainly occurs in the small intestine.

The absorption is a process in which substances pass into the blood or lymph system to circulate throughout the body. The absorption of nutrients mainly occurs in the small intestine, where nutrients such as glucose, amino acids, and fatty acids are absorbed through villi on the intestinal wall. Additionally, pancreatic and intestinal juices play a role in further absorbing food within the small intestine. Finally, any remaining solid matter from food enters the large intestine, eventually passes out of the body through the anus in the process of elimination.

Accessory Organs of the Digestive System

Accessory organs of the digestive system include the liver, the gallbladder, and the pancreas (Figure 1). They are not the sites where digestion or absorption take place. Alternatively, these organs secrete or store substances which are needed for the chemical digestion of food.

The liver is an organ with multiple functions. Its main digestive function is to produce and secret bile, which later reaches the small intestine through a duct. Bile helps to break down large globules of lipids so that they are easier to be chemically digested by enzymes. Bile also helps to reduce the acidity of food entering into the small intestine from the acidic stomach because enzymes in the small intestine need a less acidic environment to work.

The gallbladder located below the liver is a small sac that stores and concentrates the bile from the liver. It secretes the concentrated bile into the small intestine following a meal for fat digestion.

The pancreas contributes to the chemical digestion by secreting many digestive enzymes and releasing them into the small intestine to chemically digest carbohydrates, proteins, and lipids. The pancreas also secrets bicarbonate, a basic substance that neutralizes the acid, to help lessen the acidity of the small intestine environment.

Primary cells of the Digestive System

1. The widely used primary cells isolated from the GItract mainly include：

a. Oral Non-Keratinocyte Epithelial Cells: These cells are the primary constituent of the oral mucosa, forming a protective layer on the inner surface of the oral cavity. They can be further divided into melanocytes, langerhan cells, and merkel cells. They participate in sensory, absorption, and secretion functions within the oral cavity while providing protection against external stimuli. The group of oral epithelial cells are frequently replaced by cell division due to their high functional demands.

b. Oral Keratinocytes: They are squamous epithelial cells and mostly composed of cytokeratins. These cells are responsible for maintaining the barrier function and providing more effective protection of the oral mucosa [5].

c. Gingival Epithelial Cells: Gingival epithelial cells constitute the first barrier of periodontal tissue, and play an important role in resisting the invasion of periodontitis bacteria.

d. Gingival Fibroblasts: They are an important type of cell in the oral and gingival tissues, playing crucial roles in the maintenance and repair processes of periodontal tissues. They synthesize and replenish the connective fibers and the amorphous substance, and takes part in wound healing [6].

e. Esophageal Epithelial Cells: Following typical GI layering, esophageal tissue is arranged in 4 concentric layers. The inner surface of the esophagus is mucosa which is comprised of epithelium, lamina propria, and muscularis mucosae. The epithelial cells form the mucosal barrier protects the esophageal tissues from damages caused by harmful substances from the food and gastric acid [7].

f. Esophageal Smooth Muscle Cells: The third layer of esophageal tissue is muscularis propria / externa, which contains smooth muscle cells with solely this type of muscle cells at the distal end. Esophageal smooth muscle cells are responsible for propelling and transporting food into the stomach through peristaltic movements.

g. Gastric Parietal Cells: They are secretory epithelial cells located in the gastric glands of the stomach mucosal lining. Their primary function is the secretion of hydrochloric acid, which facilitates digestion of foods.

h. Gastric Chief Cells: Gastricchief cells are secretory epithelial cells located in the mucosal layer of the stomach. They secrete pepsinogen and gastric lipase enzymes, which are necessary for the digestion of proteins and lipids, respectively.

i. Gastric Enteroendocrine Cells: These cells are found within the pyloric glands of the stomach mucosa. They secrete several different GI hormones in response to both nervous stimulation or histamine release.

j. Gastric Mucous Cells: They line the surface and pits of the stomach, produce and secrete mucus protecting the stomach from corrosive gastric acids and enzymes secreted by the parietal and chief cells. This protective mucosa protects the stomach from self-digestion and damage [8].

k. Small Intestinal Enterocytes: They are the most numerous and functional cells for nutrient absorption. Many catabolic enzymes are expressed on their exterior surface  to break down molecules to sizes appropriate for uptake. The molecules taken up by enterocytes include ions, water, simple sugars, vitamins, lipids, peptides and amino acids.

l. Small Intestinal Goblet cells: These cells are responsible of secreting the mucus layer so as to protect the epithelium from the luminal contents.

m. Small Intestinal Enteroendocrine cells: These cells are in charge of secreting various GI hormones including secretin, pancreozymin, and enteroglucagon. They are the subsets of sensory intestinal epithelial cells which synapse with nerves, and are well known as neuropod

n. Colon Enterocytes: The GI tract is lined by a simple columnar epithelium of epithelial cells, called enterocytes. The epithelial layer of the colon secretes mucus to protect and lubricate the colon, as well as to regulate the absorption of water and other nutrients from the lumen.

o. Colon Enteroendocrine Cells: These cells are found scattered throughout the colonic epithelial layer, and secrete many different GI hormones in response to stimuli from the digested nutrients inside the intestinal lumen and neuronal stimulation. There are multiple types of these cells, defined upon their main hormonal product and the secretory granule ultrastructure. Although the colon contains fewer types of these cells than the small intestine, they are important for regulating intestinal motility and proliferation.

p. Enteric Glia Cells: They are located directly below the epithelial cell layer of the GI tract. These glia cells make up the majority of the enteric nervous system and share a few structural and functional aspects with astrocytes in the central nervous system. They send and receive signals from nearby enteric neurons and epithelial cells, and are believed to have an important role in maintaining the homeostasis and integrity of the GI epithelium.

2. The widely used primary cells isolated from accessory organs of the digestive system mainly include:

a. Hepatocytes: Hepatocytes are the basic component of the liver, representing 80% of the total liver volume. Theyare the main functional cells performing numerous crucial functions such as detoxification, production of some plasma proteins, carbohydrate, lipid and protein metabolism, immune cell activation to maintain homeostasis in the liver. They also play a pivotal role in liver inflammation.

b. Stellate Cells: They are responsible for vitamin A They can become activated during liver injury, infection or alcohol damage, and differentiate into myofibroblast-like cells and synthesize excessive amounts of extracellular matrix, thereby cause fibrotization of the liver [9]. These cells are also closely involved in liver regeneration.

c. Kupffer Cells: These cells are specialized stellate macrophages adhere to the sinusoidal endothelium. They are able to clear up ingested bacterial pathogens of the bloodand remove aged erythrocytes and free heme for further re-use. They also act as antigen-presenting cells in adaptive immunity and secret chemokines and cytokines that recruit and expand the population of other proinflammatory cells in the liver [10].

d. Sinusoidal Endothelial Cells: Endothelial cells form the walls of the sinusoids that carry blood throughout the liver. Endothelial cells have high endocytic capacity and are rich in lysosomal enzymes needed for degrading endocytosed material. They participate in regulating blood flow, maintaining vascular permeability, and controlling substance exchange in the blood.

e. Hepatic NK Cells: Hepatic NK cells are always in contact with sinusoidal endothelial cells and kupffer cells in the liver. They consist of two subpopulations, low-density and high-density cells. They are different from each other and from blood NK cells morphologically, immunophenotypically and functionally. Hepatic NK cells have the capacity to kill incoming malignant cells [11].

f. Cholangiocytes: These cells line the bile ducts,which transport bile produced by the hepatocytes towards the gallbladder. Functions of cholangiocytes include transporting bile to the gallbladder for storage and release [12]. Several epithelial genes typical of glandular like epithelia are specifically expressed in cholangiocytes, such as the intermediate filament keratin 19 (KRT19) and the transcription factor SRY-box transcription factor 9 (SOX9).

g. Alpha Cells: These cells are within the islets of langerhans,and responsible of detecting low glucose levels in the blood, and responding by secreting glucagon into the blood plasma, causing release of glucose from glycogen storage located in the liver and other tissues. They also produce other plasma proteins, including transthyretin (TTR) and retinol (vitamin A).

h. Beta Cells: These cells are also within the islets of langerhans, and act in opposition to alpha cells. Upon detecting elevated blood glucose levels, beta cells respond by secreting several hormones including insulin (INS), leading to the increase of the uptake of glucose by cells around the body, especially in the liver and muscle tissue, and stimulation of its conversion to glycogen or lipids for storage. Another gene with specifically expressed in alpha cells is synuclein beta (SNCB).

i. Exocrine Glandular Cells: These cells of the pancreas produce digestive enzymes include Amylase alpha 2A (AMY2A), which are secreted into the duodenum of the small intestine.

j. Ductal Cells: These cells are epithelial cells lining the pancreatic ducts, which transport the digestive enzymes secreted by the glandular cells to the duodenum. They secrete bicarbonate into the pancreatic juices, helping neutralize stomach acid and regulate the pH of the GI tract.

Future Perspective

Research on primary cells of the digestive system has been a forefront in life sciences, witnessing significant advancements in recent years. Efforts have focused on identifying and characterizing various types of primary cells across the GI tract, including those in the oral cavity, esophagus, stomach, small intestine and colon, as well as the accessory organs such as liver and pancreas, shedding light on their morphology, functions, and physiological characteristics. Studies have delved into signaling pathways within most of these cells, unraveling cellular signaling, interactions with the extracellular matrix, and regulatory mechanisms during digestion. Investigation into cell-cell interactions, such as the interactions of epithelial cell with gut microbiota and immune cells with intestinal mucosa, has provided insights into the overall functionality of the digestive system. Additionally, research has explored the roles of primary cells in digestive system diseases, offering insights into pathogenesis and identifying new therapeutic targets for conditions like GI tumors, inflammatory bowel disease, and gastric ulcers [13-15]. Advancements in stem cell technology and tissue engineering have enabled the study of regeneration and repair mechanisms of primary cells, paving the way for innovative strategies in treating digestive system disorders. These research endeavors collectively deepen our understanding of the physiology and pathology of the digestive system, offering new avenues for prevention, diagnosis, and treatment of digestive diseases.

References

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[10] P. Wu, X. Luo, M. Sun, B. Sun, M. Sun, Synergetic regulation of kupffer cells, extracellular matrix and hepatic stellate cells with versatile CXCR4-inhibiting nanocomplex for magnified therapy in liver fibrosis, Biomaterials 284 (2022) 121492.

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[12] Z. Wang, J. Faria, L.J.W. van der Laan, L.C. Penning, R. Masereeuw, B. Spee, Human Cholangiocytes Form a Polarized and Functional Bile Duct on Hollow Fiber Membranes, Front Bioeng Biotechnol 10 (2022) 868857.

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