Transcytosis

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Transcytosis (also known as cytopempsis) [1] is a type of transcellular transport in which various macromolecules are transported across the interior of a cell. Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ejected on the other side. Examples of macromolecules transported include IgA, [2] transferrin, [3] and insulin. [4] While transcytosis is most commonly observed in epithelial cells, the process is also present elsewhere. Blood capillaries are a well-known site for transcytosis, [5] though it occurs in other cells, including neurons, [6] osteoclasts [7] and M cells of the intestine. [8]

Contents

Regulation

The regulation of transcytosis varies greatly due to the many different tissues in which this process is observed. Various tissue-specific mechanisms of transcytosis have been identified. Brefeldin A, a commonly used inhibitor of ER-to-Golgi apparatus transport, has been shown to inhibit transcytosis in dog kidney cells, which provided the first clues as to the nature of transcytosis regulation. [9] Transcytosis in dog kidney cells has also been shown be regulated at the apical membrane by Rab17, [10] as well as Rab11a and Rab25. [11] Further work on dog kidney cells has shown that a signaling cascade involving the phosphorylation of EGFR by Yes leading to the activation of Rab11FIP5 by MAPK1 upregulates transcytosis. [12] Transcytosis has been shown to be inhibited by the combination of progesterone and estradiol followed by activation mediated by prolactin in the rabbit mammary gland during pregnancy. [13] In the thyroid, follicular cell transcytosis is regulated positively by TSH [ citation needed ]. The phosphorylation of caveolin 1 induced by hydrogen peroxide has been shown to be critical to the activation of transcytosis in pulmonary vascular tissue. [14] It can therefore be concluded that the regulation of transcytosis is a complex process that varies between tissues.

Role in pathogenesis

Due to the function of transcytosis as a process that transports macromolecules across cells, it can be a convenient mechanism by which pathogens can invade a tissue. Transcytosis has been shown to be critical to the entry of Cronobacter sakazakii across the intestinal epithelium as well as the blood–brain barrier. [15] Listeria monocytogenes has been shown to enter the intestinal lumen via transcytosis across goblet cells. [16] Shiga toxin secreted by enterohemorrhagic E. coli has been shown to be transcytosed into the intestinal lumen. [17] From these examples, it can be said that transcytosis is vital to the process of pathogenesis for a variety of infectious agents.

Clinical applications

Pharmaceutical companies, such as Lundbeck, are currently exploring the use of transcytosis as a mechanism for transporting therapeutic drugs across the human blood–brain barrier (BBB).[ citation needed ] Exploiting the body's own transport mechanism can help to overcome the high selectivity of the BBB, which typically blocks the uptake of most therapeutic antibodies into the brain and central nervous system (CNS). The pharmaceutical company Genentech, after having synthesized a therapeutic antibody that effectively inhibited BACE1 enzymatic function, experienced problems transferring adequate, efficient levels of the antibody within the brain. BACE1 is the enzyme which processes amyloid precursor proteins into amyloid-β peptides, including the species that aggregate to form amyloid plaques associated with Alzheimer's disease.[ citation needed ]

Molecules are transported across an epithelial or endothelial barrier by one of two routes: 1) a transcellular route through the intracellular compartment of the cell, or 2) a paracellular route through the extracellular space between adjacent cells. [18] The transcellular route is also called transcytosis. Transcytosis can be receptor-mediated and consists of three steps: 1) receptor-mediated endocytosis of the molecule on one side of the cell, e.g. the luminal side; 2) movement of the molecule through the intracellular compartment typically within the endosomal system; and 3) exocytosis of the molecule to the extracellular space on the other side of the cell, e.g. the abluminal side.

Transcytosis may be either unidirectional or bidirectional. Unidirectional transcytosis may occur selectively in the luminal to abluminal direction, or in the reverse direction, in the abluminal to luminal direction.

Transcytosis is prominent in brain microvascular peptide and protein transport, [19] because the brain microvascular endothelium, which forms the blood-brain barrier (BBB) in vivo, expresses unique, epithelial-like, high-resistance tight junctions. [20] The brain endothelial tight junctions virtually eliminate the paracellular pathway of solute transport across the microvascular endothelial wall in brain. In contrast, the endothelial barrier in peripheral organs does not express tight junctions, and solute movement through the paracellular pathway is prominent at the endothelial barrier in organs other than the brain or spinal cord. [21]

Receptor-mediated transcytosis, or RMT, across the BBB is a potential pathway for drug delivery to the brain, particularly for biologic drugs such as recombinant proteins. [22] The non-transportable drug, or therapeutic protein, is genetically fused to a transporter protein. The transporter protein may be an endogenous peptide, or peptidomimetic monoclonal antibody, which undergoes RMT across the BBB via transport on brain endothelial receptors such as the insulin receptor or transferrin receptor. The transporter protein acts as a molecular Trojan horse to ferry into brain the therapeutic protein that is genetically fused to the receptor-specific Trojan horse protein.

Monoclonal antibody Trojan horses that target the BBB insulin or transferrin receptor have been in drug development for over 10 years at ArmaGen, Inc., a biotechnology company in Los Angeles. ArmaGen has developed genetically engineered antibodies against both the insulin and transferrin receptors, and has fused to these antibodies different therapeutic proteins, including lysosomal enzymes, therapeutic antibodies, decoy receptors, and neurotrophins. [23] These therapeutic proteins alone do not cross the BBB, but following genetic fusion to the Trojan horse antibody, the therapeutic protein penetrates the BBB at a rate comparable to small molecules. In 2015, ArmaGen will be the first to enter human clinical trials with the BBB Trojan horse fusion proteins that delivery protein drugs to the brain via the transcytosis pathway. The human diseases initially targeted by ArmaGen are lysosomal storage diseases that adversely affect the brain. Inherited diseases create a condition where a specific lysosomal enzyme is not produced, leading to serious brain conditions including mental retardation, behavioral problems, and then dementia. Although the missing enzyme can be manufactured by drug companies, the enzyme drug alone does not treat the brain, because the enzyme alone does not cross the BBB. ArmaGen has re-engineered the missing lysosomal enzyme as a Trojan horse-enzyme fusion protein that crosses the BBB. The first clinical trials of the new Trojan horse fusion protein technology will treat the brain in lysosomal storage disorders, including one of the mucopolysaccharidosis type I diseases, (MPSIH), also called Hurler syndrome, and MPS Type II, also called Hunter syndrome.

Researchers at Genentech proposed the creation of a bispecific antibody that could bind the BBB membrane, induce receptor-mediated transcytosis, and release itself on the other side into the brain and CNS. They utilized a mouse bispecific antibody with two active sites performing different functions. One arm had a low-affinity anti-transferrin receptor binding site that induces transcytosis. A high-affinity binding site would result in the antibody not being able to release from the BBB membrane after transcytosis. This way, the amount of transported antibody is based on the concentration of antibody on either side of the barrier. The other arm had the previously developed high-affinity anti-BACE1 binding site that would inhibit BACE1 function and prevent amyloid plaque formation. Genentech was able to demonstrate in mouse models that the new bispecific antibody was able to reach therapeutic levels in the brain. [24] Genentech's method of disguising and transporting the therapeutic antibody by attaching it to a receptor-mediated transcytosis activator has been referred to as the "Trojan Horse" method.

Related Research Articles

<span class="mw-page-title-main">Endocytosis</span> Cellular process

Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. Endocytosis includes pinocytosis and phagocytosis. It is a form of active transport.

<span class="mw-page-title-main">Blood–brain barrier</span> Semipermeable capillary border that allows selective passage of blood constituents into the brain

The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from non-selectively crossing into the extracellular fluid of the central nervous system where neurons reside. The blood–brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. This system allows the passage of some small molecules by passive diffusion, as well as the selective and active transport of various nutrients, ions, organic anions, and macromolecules such as glucose and amino acids that are crucial to neural function.

<span class="mw-page-title-main">Transferrin</span> Mammalian protein found in Homo sapiens

Transferrins are glycoproteins found in vertebrates which bind to and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encoded by the TF gene and produced as a 76 kDa glycoprotein.

<span class="mw-page-title-main">Endosome</span> Vacuole to which materials ingested by endocytosis are delivered

Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can follow this pathway all the way to lysosomes for degradation or can be recycled back to the cell membrane in the endocytic cycle. Molecules are also transported to endosomes from the trans Golgi network and either continue to lysosomes or recycle back to the Golgi apparatus.

Protease-activated receptors(PAR) are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, myocytes and neurons.

Intestinal permeability is a term describing the control of material passing from inside the gastrointestinal tract through the cells lining the gut wall, into the rest of the body. The intestine normally exhibits some permeability, which allows nutrients to pass through the gut, while also maintaining a barrier function to keep potentially harmful substances from leaving the intestine and migrating to the body more widely. In a healthy human intestine, small particles can migrate through tight junction claudin pore pathways, and particles up to 10–15 Å can transit through the paracellular space uptake route. There is some evidence abnormally increased intestinal permeability may play a role in some chronic diseases and inflammatory conditions. The most well understood condition with observed increased intestinal permeability is celiac disease.

Microfold cells are found in the gut-associated lymphoid tissue (GALT) of the Peyer's patches in the small intestine, and in the mucosa-associated lymphoid tissue (MALT) of other parts of the gastrointestinal tract. These cells are known to initiate mucosal immunity responses on the apical membrane of the M cells and allow for transport of microbes and particles across the epithelial cell layer from the gut lumen to the lamina propria where interactions with immune cells can take place.

<span class="mw-page-title-main">Transferrin receptor</span>

Transferrin receptor (TfR) is a carrier protein for transferrin. It is needed for the import of iron into the cell and is regulated in response to intracellular iron concentration. It imports iron by internalizing the transferrin-iron complex through receptor-mediated endocytosis. The existence of a receptor for transferrin iron uptake had been recognized over half a century back. Earlier two transferrin receptors in humans, transferrin receptor 1 and transferrin receptor 2 had been characterized and until recently cellular iron uptake was believed to occur chiefly via these two well documented transferrin receptors. Both these receptors are transmembrane glycoproteins. TfR1 is a high affinity ubiquitously expressed receptor while expression of TfR2 is restricted to certain cell types and is unaffected by intracellular iron concentrations. TfR2 binds to transferrin with a 25-30 fold lower affinity than TfR1. Although TfR1 mediated iron uptake is the major pathway for iron acquisition by most cells and especially developing erythrocytes, several studies have indicated that the uptake mechanism varies depending upon the cell type. It is also reported that Tf uptake exists independent of these TfRs although the mechanisms are not well characterized. The multifunctional glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase has been shown to utilize post translational modifications to exhibit higher order moonlighting behavior wherein it switches its function as a holo or apo transferrin receptor leading to either iron delivery or iron export respectively.

The neonatal Fc receptor is a protein that in humans is encoded by the FCGRT gene. It is an IgG Fc receptor which is similar in structure to the MHC class I molecule and also associates with beta-2-microglobulin. In rodents, FcRn was originally identified as the receptor that transports maternal immunoglobulin G (IgG) from mother to neonatal offspring via mother's milk, leading to its name as the neonatal Fc receptor. In humans, FcRn is present in the placenta where it transports mother's IgG to the growing fetus. FcRn has also been shown to play a role in regulating IgG and serum albumin turnover. Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF-α, and down-regulated by IFN-γ.

<span class="mw-page-title-main">Secretory component</span>

The secretory component is a component of immunoglobulin A (IgA). Secretory component is a proteolytic cleavage product of the polymeric immunoglobulin receptor which remains associated with dimeric IgA in sero-mucus secretions. Polymeric IgA binds to the polymeric immunoglobulin receptor on the basolateral surface of epithelial cells and is taken up into the cell via transcytosis. The receptor-IgA complex passes through the cellular compartments before being secreted on the luminal surface of the epithelial cells, still attached to the receptor. Proteolysis of the receptor occurs and the dimeric IgA molecule, along with the secretory component, are free to diffuse throughout the lumen.

<span class="mw-page-title-main">VE-cadherin</span>

Cadherin 5, type 2 or VE-cadherin also known as CD144, is a type of cadherin. It is encoded by the human gene CDH5.

<span class="mw-page-title-main">Transferrin receptor 1</span>

Transferrin receptor protein 1 (TfR1), also known as Cluster of Differentiation 71 (CD71), is a protein that in humans is encoded by the TFRC gene. TfR1 is required for iron import from transferrin into cells by endocytosis.

<span class="mw-page-title-main">Intestinal epithelium</span> Single-cell layer lining the intestines

The intestinal epithelium is the single cell layer that form the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelial cells, it serves two main functions: absorbing useful substances into the body and restricting the entry of harmful substances. As part of its protective role, the intestinal epithelium forms an important component of the intestinal mucosal barrier. Certain diseases and conditions are caused by functional defects in the intestinal epithelium. On the other hand, various diseases and conditions can lead to its dysfunction which, in turn, can lead to further complications.

<span class="mw-page-title-main">Paclitaxel trevatide</span>

Paclitaxel trevatide is an experimental chemotherapy drug that is under development by Angiochem Inc, a Canadian biotech company. Phase II clinical trials have completed for several indications, and the company is preparing for phase III trials.

Cytosis Movement of molecules into or out of cells

Cytosis is a transport mechanism for the movement of large quantities of molecules into and out of cells.

Transcellular transport involves the transportation of solutes by a cell through a cell. Transcellular transport can occur in three different ways active transport, passive transport, and transcytosis.

<span class="mw-page-title-main">Nanoparticle–biomolecule conjugate</span> Tailored macromolecule with covalently-bonded bio-active substances targeting specific tissues

A nanoparticle–biomolecule conjugate is a nanoparticle with biomolecules attached to its surface. Nanoparticles are minuscule particles, typically measured in nanometers (nm), that are used in nanobiotechnology to explore the functions of biomolecules. Properties of the ultrafine particles are characterized by the components on their surfaces more so than larger structures, such as cells, due to large surface area-to-volume ratios. Large surface area-to-volume-ratios of nanoparticles optimize the potential for interactions with biomolecules.

Nanoparticles for drug delivery to the brain is a method for transporting drug molecules across the blood–brain barrier (BBB) using nanoparticles. These drugs cross the BBB and deliver pharmaceuticals to the brain for therapeutic treatment of neurological disorders. These disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, depression, and brain tumors. Part of the difficulty in finding cures for these central nervous system (CNS) disorders is that there is yet no truly efficient delivery method for drugs to cross the BBB. Antibiotics, antineoplastic agents, and a variety of CNS-active drugs, especially neuropeptides, are a few examples of molecules that cannot pass the BBB alone. With the aid of nanoparticle delivery systems, however, studies have shown that some drugs can now cross the BBB, and even exhibit lower toxicity and decrease adverse effects throughout the body. Toxicity is an important concept for pharmacology because high toxicity levels in the body could be detrimental to the patient by affecting other organs and disrupting their function. Further, the BBB is not the only physiological barrier for drug delivery to the brain. Other biological factors influence how drugs are transported throughout the body and how they target specific locations for action. Some of these pathophysiological factors include blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered gene expression and protein synthesis. Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.

The blood-spinal cord barrier (BSCB) is a semipermeable anatomical interface that consists of the specialized small blood vessels that surround the spinal cord. While similar to the blood-brain barrier in function and morphology, it is physiologically independent and has several distinct characteristics. The BSCB is involved in many disorders affecting the central nervous system, including neurodegenerative diseases, pain disorders, and traumatic spinal cord injury. In conjunction with the blood-brain barrier, the BSCB contributes to the difficulty in delivering drugs to the central nervous system, which makes drug targeting of the BSCB an important goal in pharmaceutical research.

<span class="mw-page-title-main">Focused ultrasound for intracranial drug delivery</span> Medical technique

Focused ultrasound for intracrainial drug delivery is a non-invasive technique that uses high-frequency sound waves to disrupt tight junctions in the blood-brain barrier (BBB), allowing for increased passage of therapeutics into the brain. The BBB normally blocks nearly 98% of drugs from accessing the central nervous system, so FUS has the potential to address a major challenge in intracranial drug delivery by providing targeted and reversible BBB disruption. Using FUS to enhance drug delivery to the brain could significantly improve patient outcomes for a variety of diseases including Alzheimer's disease, Parkinson's disease, and brain cancer.

References

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