An intercellular cleft is a channel between two cells through which molecules may travel and

gap junction Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regulate ...

s and

tight junction Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...

s may be present. Most notably, intercellular clefts are often found between

epithelial cell Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

s and the

endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

of blood vessels and

lymphatic vessel The lymphatic vessels (or lymph vessels or lymphatics) are thin-walled vessels (tubes), structured like blood vessels, that carry lymph. As part of the lymphatic system, lymph vessels are complementary to the cardiovascular system. Lymph vess ...

s, also helping to form the blood-nerve barrier surrounding nerves. Intercellular clefts are important for allowing the transportation of fluids and small solute matter through the endothelium.

Dimensions of intercellular cleft

The dimensions of intercellular clefts vary throughout the body, however cleft lengths have been determined for a series of capillaries. The average cleft length for capillaries is about 20m/cm². The depths of the intercellular clefts, measured from the luminal to the abluminal openings, vary among different types of capillaries, but the average is about 0.7 μm. The width of the intercellular clefts is about 20 nm outside the junctional region (i.e. in the larger part of the clefts). In intercellular clefts of capillaries, it has been calculated that the fractional area of the capillary wall occupied by the intercellular cleft is 20m/cm² x 20 nm (length x width)= 0.004 (0.4%). This is the fractional area of the capillary wall exposed for free diffusion of small

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are no ...

solutes and fluids⁵.

Communication via cleft

The intercellular cleft is imperative for cell-cell communication. The cleft contains

desmosome A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for ''adhering spot''), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like adh ...

s, and adheren proteins, all of which help to propagate and/or regulate cell communication through signal transduction, surface receptors, or a chemogradient. In order for a molecule to be taken into the cell either by

endocytosis 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. E ...

phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...

, or

receptor-mediated endocytosis Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). Thi ...

, often that molecule must first enter through the cleft. The intercellular cleft itself is a channel, but what flows through the channel, like ions, fluid, and small molecules and what proteins or junctions give order to the channel is critical for the life of the cells that border the intercellular cleft.

Research utilizing cleft communication

Research at the cell level can deliver proteins, ions, or specific small molecules into the intercellular cleft as a means of injecting a cell. This method is especially useful in cell-to-cell propagation of infectious cytosolic protein aggregates. In one study, protein aggregates from yeast

prion Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It ...

s were released into a mammalian intercellular cleft and were taken up by the adjacent cell, as opposed to direct cell transfer. This process would be similar to the secretion and transmission of infectious particles through the

synaptic cleft Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

between cells of the immune system, as seen in

retrovirus A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...

es. Understanding the routes of intercellular protein aggregate transfer, particularly routes involving clefts is imperative in understanding the progressive spreading of this infection⁸.

Transport in intercellular cleft

Endothelial tight junctions are most commonly found in the intercellular cleft and provide for regulation of diffusion through the membranes. These links are most commonly found in the most apical aspect of the intercellular cleft. They prevent

macromolecule A macromolecule is a very large molecule important to biophysical processes, such as a protein or nucleic acid. It is composed of thousands of covalently bonded atoms. Many macromolecules are polymers of smaller molecules called monomers. The ...

s from navigating the intercellular cleft and limit the lateral diffusion of intrinsic membrane proteins and lipids between the apical and basolateral cell surface domains. In the intercellular clefts of

capillaries A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...

, tight junctions are the first structural barriers a

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

encounters as it penetrates the interendothelial cleft, or the gap linking the blood vessel lumen with the subendothelial space². In capillary endothelium, plasma communicates with the

interstitial fluid In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 60% (range 45 to 75%) of total body weight; women and the obese typically have a lower ...

through the intercellular cleft.

Blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intra ...

without the

plasma proteins Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood p ...

red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

s, and

platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...

s pass through the intercellular cleft and into the capillary⁷.

Capillary intercellular clefts

Most notably, intercellular clefts are described in

capillary A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...

blood vessels. The three types of capillary blood vessels are continuous, fenestrated, and discontinuous, with continuous being the least porous of the three and discontinuous capillaries being extremely high in permeability. Continuous blood capillaries have the smallest intercellular clefts, with discontinuous blood capillaries having the largest intercellular clefts, commonly accompanied with gaps in the basement membrane⁶.Often, fluid is forced out of the capillaries through the intercellular clefts. Fluid is push out through the intercellular cleft at the arterial end of the capillary because that's where the pressure is the highest. However, most of this fluid returns into the capillary at the venous end, creating capillary fluid dynamics. Two opposing forces achieve this balance;

hydrostatic pressure Fluid statics or hydrostatics is the branch of fluid mechanics that studies the condition of the equilibrium of a floating body and submerged body "fluids at hydrostatic equilibrium and the pressure in a fluid, or exerted by a fluid, on an imme ...

and

colloid osmotic pressure Oncotic pressure, or colloid osmotic-pressure, is a form of osmotic pressure induced by the proteins, notably albumin, in a blood vessel's plasma (blood/liquid) that causes a pull on fluid back into the capillary. Participating colloids displace ...

, using the intercellular clefts are fluid entrances and fluid exits⁴. In addition, the size of the intercellular clefts and pores in the capillary will influence this fluid exchange. The larger the intercellular cleft, the lesser the pressure and the more fluid will flow out the cleft. This enlargement of the cleft is caused by contraction of capillary endothelial cells, often by substances such as

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...

and

bradykinin Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and ...

. However, smaller intercellular clefts do not help this fluid exchange³. Along with fluid, electrolytes are also carried through this transport in the capillary blood vessels⁴. This mechanism of fluid, electrolyte, and also small solute exchange is especially important in renal

glomerular ''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn". ''Glomerulus'' may refer to: * the filte ...

capillaries³.

Intercellular cleft and BHB

Intercellular clefts also play a role in the formation of the ''blood-heart barrier'' (BHB). The intercellular cleft between

endocardial The endocardium is the innermost layer of tissue that lines the chambers of the heart. Its cells are embryologically and biologically similar to the endothelial cells that line blood vessels. The endocardium also provides protection to the va ...

endotheliocytes is 3 to 5 times deeper than the clefts between

myocardial Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...

capillary endotheliocytes. Also, these clefts are often more twisting and have one or two tight junctions and zona adherens interacting with a circumferential actin filament band and several connecting proteins⁷. These tight junctions localize to the luminal side of the intercellular clefts, where the

glycocalyx The glycocalyx, also known as the pericellular matrix, is a glycoprotein and glycolipid covering that surrounds the cell membranes of bacteria, epithelial cells, and other cells. In 1970, Martinez-Palomo discovered the cell coating in animal cells ...

, which is important in

cell–cell recognition Cell–cell recognition is a cell's ability to distinguish one type of neighboring cell from another.Campbell, et al., Biology, ''Eighth Edition'', 2008 Pearson Education Inc. This phenomenon occurs when complementary molecules on opposing cell s ...

and

cell signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

, is more developed. The organization of the endocardial endothelium and the intercellular cleft help to establish the ''blood-heart barrier'' by ensuring an active transendothelial physicochemical gradient of various ions¹.

References

# Thiriet, M. (2015). Interactions between cardiac cell populations. In ''Diseases of the cardiac pump'' (1st ed., Vol. 7, pp. 59–61). Paris: Springer. # Gabrilovich, D. (2013). Mechanisms of neutrophil migration. In ''The neutrophils new outlook for old cells'' (3rd ed., pp. 138–144). London: Imperial College Press;. # Klabunde, R. (2014, April 30). Mechanisms of capillary exchange. Retrieved 2015, from http://www.cvphysiology.com/Microcirculation/M016.htm # Marieb, E.N. (2003). Essentials of Human Anatomy and Physiology (Seventh ed.). San Francisco: Benjamin Cummings. . # Chien, S. (1988). Mathematical models of intercellular clefts. In ''Vascular endothelium in health and disease'' (Vol. 242, pp. 3–5). New York City, New York: Plenum Press. # Capillaries. (n.d.). Retrieved from http://www.udel.edu/biology/Wags/histopage/vascularmodelingpage/circsystempage/capillaries/capillaries.html # Silberberg, A.(1988). Structure of the interendothelial cell cleft. Biorheology, 25(1–2),303–18. # Hofmann, J., Denner, P., Naussbaum- Krammer, C., Kuhn, P., Suhre, M., Scheibel, T., ... Vorberg, I. (2013). Cell-to-cell propagation of infectious cytosolic protein aggregates. ''Proceedings of the National Academy of Sciences of the United States of America,'' ''110''(15), 5951–5956–5951–5956. doi:10.1073/pnas.1217321110

External links

* {{cite journal , vauthors=Martìn-Padura I, Lostaglio S, Schneemann M, etal , title=Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration , journal=J. Cell Biol. , volume=142 , issue=1 , pages=117–27 , date=July 1998 , pmid=9660867 , pmc=2133024, doi=10.1083/jcb.142.1.117 Cell biology