Intercellular space

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Editor-In-Chief: Henry A. Hoff

Cells are the fundamental units of all known living organisms. Humans have an estimated 100 trillion or 1014 cells; a typical cell size is 10 µm; a typical cell mass is 1 ng.

Cells in culture, stained for keratin (red) and DNA (green), with a small breadth between each cell.

A space located or occurring between cells is often referred to as an intercellular space. When the space is passing a cell, or cell membrane or situated beside or between cells the term paracellular space is usually used. Epithelial cells are packed tightly together, with almost no intercellular spaces and only a small amount of intercellular substance.

Types of epithelium

An intercellular space probably can be reduced to that remaining as one membrane physically touches that of its neighboring cell. But, often cells express transmembrane proteins.

Illustration of a cell membrane with transmembrane proteins extending into paracellular space.

In order for such transmembrane proteins to function some separation distance between cell membranes must be maintained.

Intercellular fluid

Intercellular fluid is composed of water and small soluable molecules. Glucose, oxygen and amino acids diffuse into the spaces around the cells from the capillaries. Plasma leaves the capillaries and flows into the intercellular spaces between the cells of the tissues to be part of the fluid that surrounds those cells.

The space between any two cells generally is roughly a thin two dimensional sheet or layer of thickness or breadth typical for the cells involved. Fenestrated capillaries have pores in the endothelial cells (60-80 nm in diameter) that are spanned by a diaphragm of radially oriented fibrils and allow small molecules[1] and limited amounts of protein to diffuse. The paracellular breadth between cell membranes juxtaposed by tight junctions appears to be <5 nm. In a gap junction the intercellular space is reduced from 25 nm to a ~2-4 nm wide paracellular space. The width of the intercellular space between cells with desmosomes between them is very wide (about 30 nm). A 10 nm diameter corresponds to an upper mass limit of 70 kDa.[2]

Using the water (data page) and the atomic radii of the elements (data page), a water molecule is approximately 120 x 187 pm in maximum diameters (average 154 pm). This suggests the minimum number of water layers in say 3 nm is ~20. For the two most likely phosphates in solution, H2PO41- and HPO42-, the average diameters are about 413 pm and 406 pm, respectively. This suggests about 7 Pi layers in 3 nm.


Capillaries measure 5-10 μm in diameter and enable the interchange of water, oxygen, carbon dioxide, and many other nutrient and waste chemical substances between blood and surrounding tissues.[3] True capillaries branch mainly from metarterioles and provide exchange between cells and the circulation. The internal diameter of 8 μm forces the red blood cells to partially fold into bullet-like shapes and to go into single file in order for them to pass through. Continuous capillaries have a sealed endothelium and only allow small molecules, like water and ions to diffuse. There are those with numerous transport vesicles and tight junctions and those with few vesicles and tight junctions. Fenestrated capillaries have pores in the endothelial cells (60-80 nm in diameter) that are spanned by a diaphragm of radially oriented fibrils and allow small molecules[1] and limited amounts of protein to diffuse. Sinusoidal or discontinuous capillaries are special fenestrated capillaries that have larger openings (30-40 μm in diameter) in the endothelium to allow [[red blood cell]s and serum proteins to enter.

Interstitial fluid (ISF)

Hydrostatic pressure brings appropriate chemicals into the interstitial fluid.

Interstitial fluid (or tissue fluid) is a solution which bathes and surrounds the cells of multicellular animals. It is the main component of the extracellular fluid, which also includes plasma and transcellular fluid. Interstitial fluid is found in the interstitial spaces, also known as the tissue spaces. Interstitial fluid consists of a water solvent containing amino acids, sugars, fatty acids, coenzymes, hormones, neurotransmitters, salts, as well as waste products from the cells. Plasma, the major component in blood, communicates freely with interstitial fluid through pores and intercellular clefts in capillary endothelium. Interstitial mixes with and becomes intercellular fluid when it flows between cells.

Tight junctions

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Diagram of Tight junction.

Tight junctions (TJs) are the closely associated areas of two cells whose membranes are juxtaposed forming a virtual impermeable barrier to fluid. These continuous seals around cells serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space.[4] TJs create an ion-selective boundary between the apical and basolateral extracellular compartments.[5] The efficiency of the junction in preventing ion passage increases exponentially with the number of strands. TJs are the most apical intercellular junctions and function as selective barriers to macromolecules and prevent diffusion of lipids and proteins between apical and basolateral membrane domains.[6]

TEM of negatively stained proximal convoluted tubule of Rat kidney tissue at a magnification of ~55,000x and 80KV with Tight junction. Note that the three dark lines of density correspond to the density of the protein complex, and the light lines in between correspond to the paracellular space.

The paracellular space in the TEM image appears to be <5 nm.

Gap junctions

gap junction

In a gap junction the intercellular space is reduced from 25 nm to a ~2-4 nm wide paracellular space.


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Simplified diagram of the main cell junctions, showing changes in intercellular space.
Cell adhesion in desmosomes

The intercellular space is very wide (about 30 nm).

Extracellular space

This space is usually taken to be outside the plasma membrane, and occupied by fluid. The spaces occupied by extracellular fluid vary greatly in size and complexity. The stomach, which for humans may have the largest breadth between cellular layers, has a diameter in moderate distention of 24-26 cm at its maximum.[7] At the extreme a stomach diameter of over 88 cm in women and over 100 cm in men can pose a significant health risk.

The extracellular matrix (ECM) includes the interstitial matrix and the basement membrane.[8] Interstitial matrix is present between various cells (i.e., in the intercellular spaces). Gels of polysaccharides and fibrous proteins fill the interstitial space and act as a compression buffer against the stress placed on the ECM.[9]

Illustration depicting extracellular matrix (basement membrane and interstitial matrix) in relation to epithelium, endothelium and connective tissue

Hyaluronic acid in the extracellular space confers upon tissues the ability to resist compression by providing a counteracting turgor (swelling) force after absorbing a lot of water. Hyaluronic acid is thus found in abundance in the ECM of load-bearing joints. It is also a chief component of the interstitial gel. Hyaluronic acid is found on the inner surface of the cell membrane and is translocated out of the cell during biosynthesis.[10]

The epidermal basement membrane zone (BMZ) comprises a narrow and sometimes folded interface between the basal keratinocytes and the dermis. The epidermal BMZ has small (<500 nm), regularly spaced electron dense structures which are the hemidesmosomes. Anchoring filaments traverse the lamina lucida space and appear to insert into the basal lamina. Beneath the basal lamina, loop-structured, cross-banded anchoring fibrils extend more than 300 nm beneath the basement membrane within the papillary above the reticular lamina.

The anterior segment is the front third of the eye that includes the structures in front of the vitreous humour: the cornea, iris, ciliary body, and lens.[11] Within the anterior segment are two fluid-filled spaces divided by the iris plane:

Aqueous humour fills these spaces within the anterior segment to provide nutrients to the lens and corneal endothelium, and its pressure maintains the convex shape of the cornea.[12][13]

In the Diamond-Bossert model for the production of aqueous humour, active transport occurs in the nonpigmented cilary epithelial cells inducing small osmotic pressure gradients in between the cells. A higher concentration of solutes in the proximal part of the intercellular space generates a flow of water. The concentration diminishes from the proximal part to the distal part, releasing the liquid into the posterior chamber. The primary route for aqueous humour flow is first through the posterior chamber, then the narrow space between the posterior iris and the anterior lens (contributes to small resistance), through the pupil to enter the anterior chamber. From there, the aqueous humour exits the eye through the trabecular meshwork.

Pus is produced from the dead and living white blood cells which travel into the intercellular spaces around the affected cells.

Significant sizes

The diameter for atoms ranges from 62 pm (He) to 520 pm (Cs). The smallest molecule is the diatomic hydrogen (H2), with an overall length of roughly twice the 74 pm (0.74 Å) bond length. Molecules commonly used as building blocks for organic synthesis have a dimension of a few Å to several dozen Å. Single molecules cannot usually be observed by light (as noted above), but small molecules and even the outlines of individual atoms may be traced in some circumstances by use of an atomic force microscope. Some of the largest molecules are macromolecules or supermolecules.

Illustration of a polypeptide macromolecule.

As has been learned by studying the nuclear pore complex, a 10 nm diameter corresponds to an upper mass limit of 70 kDa.[2] The majority of the non-protein molecules have a molecular mass of less than 300 Da.[14]


The content on this page was first contributed by: Henry A. Hoff.

Initial content for this page in some instances came from Wikipedia.


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  11. 11.0 11.1 "Departments. Anterior segment." Cantabrian Institute of Ophthalmology.
  12. Miguel Coca-Prados, Ph.D.
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