Connectivetissue(FMTC)

CONNECTIVE TISSUES (Foundation module; Dr T.Cowen; © University College London)

Connective tissues are for the most part made up of extracellular material secreted by different cells. This material comprises 1] proteinaceous filaments and 2] a soup of more or less soluble macromolecules that surrounds all the other tissues of the body providing protective padding, supporting scaffold, connections of many kinds and a nutritive bath in which the other cells of the body can live happily.

ECM can be seen as a development of multicellular organisms, designed to mediate cellular interactions including cell differentiation and maintenance; and to be a principal actor in the 'milieu interieur';

Also has an important role in defence, hence the presence of macrophages, white cells etc. extracellular space as a battleground in infection/inflammation

So, connective tissues contain 3 components: cells, protein filaments and e/c matrix.

Extracellular material can of course only be synthesised inside cells. Most cell types synthesise extracellular matrix, including muscle and epithelia - providing ways of cells relating to eachother in multicellular organisms (maybe not neurones, but this is controversial). However, the main group of cells responsible for producing ECM originate from the mesenchymal cell:

- The mesenchymal cells are pluripotential which means that they can give rise to several of the different cells responsible for forming connective tissues. These stem cells provide a supply of c/t-forming cells of different types throughout life which give rise to the two main groups of connective tissues: loose, dense and hard

*DIAGRAM OF C/T CELL ORIGINS

The exception is blood which is also a connective tissue but which originates from different cell types and which is dealt with in a separate class.

The best known of these c/t-forming cells is the fibroblast which is the principal cell of soft connective tissues.

SOFT (LOOSE AND DENSE) CONNECTIVE TISSUES:

These are produced principally by fibroblasts, but also by SMC, glia, epithelia:

- Whilst there are differences in arrangement and composition between hard and soft cts, many of the features that I shall describe for the soft cts also apply to the hard ones:

*EM YOUNG FIBROBLAST

What makes these cells so unusual is their ability to produce large quantities of proteins which inside the cell are relatively soluble but which pass to the extracellular environment by exocytosis (REM vesicles) where they polymerise to form the characteristic fibrous structures of soft and hard connective tissues. Major difference from other tissues eg. epithelia, muscle and nerve where there is little e/c material (but NB epithelia, muscle and glia all produce e.c.m. in the form of basal lamina; vital for cell to cell interactions).

* Note the prominent r.e.r and Golgi indicating the protein-synthetic role of the cell, plus the sparse, immature collagen fibres.

* The hallmark of these cells is flexibility: active - as micrograph, eg in development, less active in maturity (no prominent rer or golgi). Examples: skeleton in space; wound healing.

So, what do these cells produce?

I. THE EXTRACELLULAR MATRIX:

Forms a sort of universal biological glue composed of an intricate meshwork of extracellular protein and polysaccharide macromolecules which almost all cells of the body are in contact with. This 'glue' can be soft or hard.

* It is not an inert structural scaffold as used to be thought but has the ability to influence the type and activity of the cells within it. Some of the molecular organisation is still not understood.

* main non-fibrous component, produced by fibroblasts (also chondro- and osteo-blasts): Glycosaminoglycans (the latter in the form of proteoglycans - conjugated to proteins) forming a hydrated ground substance.

II. PROTEIN FIBRES

* TABLE OF PROTEIN FIBRES

* Fibrous components: collagens, elastin and the glycoproteins laminin, fibronectin, decorin etc.

* Collagens are the basic building block of all skeletal elements; Type I is the most abundant protein in mammals (25% of total). It is the main fibrous protein found in all connective tissues, both hard and soft. Many forms: random (loose c/t) and highly oriented (tendon, bone). Collagen fibres are highly deformable but cannot be stretched. Let us look at how it is formed:

* DIAG OF COLLAGEN FORMATION.

4] adjacent molecules are cross-linked covalently at the hydroxylated lysine component.

WHAT DOES COLLAGEN LOOK LIKE?:

3 levels of organisation: bundles and fibres ranging from 1 to many microns dia.; but principally as fibrils (EM only, 10-300nm dia.). Pale-staining in LM with acid dyes.

*HP TEM Banding on collagen fibrils

Collagens are a family of proteins with 5 principal members: collagen types I-V (different combinations of a-chains) (in fact, more are now known - up to 10):

Type I: 90% of the total collagen content; major constituent of all adult connective tissues, including bones and teeth; produced by fibroblasts, osteoblasts and odontoblasts; 64nm banding; normally about 100nm dia., but variable.

* Cartilage

Type II: in the ground substance of cartilage, i/v disc, notocord and vitreous humour of eye. EM appearance as Type I, but may be thinner.

*LM RETICULAR FIBRES

Type III: in embryos, and in adults as reticular fibres of skin, blood vessels, spleen, GI tract; produced by fibroblasts and smc's. EM appearance as I & II but fibres are finer and have a higher carbohydrate content:

*EM BASAL LAMINA

Type IV: Basal lamina of epithelial cells, also smc, Schwann. Grey 'fuzz' in EM - no fibrils or cross-banding.

But this TEM does not give the whole picture: detailed molecular organisation subject of intense study:

*DIAG. BASAL LAMINA

* laminin and proteoglycans at surfaces, collagen in the middle. Important in cell guidance (axon outgrowth, navigation and regeneration (including at neuromuscular junction); cancer).

* binding to hemidesmosomes at cell surface and to fibrillar components of ECM at 'free' surface.

Type V: identified biochemically but not structurally; widespread, particularly associated with foetal membranes.

III. ELASTIN:

Elastin is also produced by fibroblasts. It has similar constituents to collagen.

*DIAG ELASTIN

* forms sheets and filaments of strongly cross-linked fibres, with a coiled polypeptide backbone ---> elasticity.

* Also contains glycoprotein which can be seen in immature elastin as fine fibrils (~12nm dia.) on the outside surface of the fibres, otherwise amorphous. NB no cross-banding.

- laminin, fibronectin, chondronectin; all bind cells to ecm

How are these elements arranged in soft connective tissue?:

Slides showing loose, medium (adventitia) and dense (tendon, cornea) connective tissue:

* Slides of loose ct, adventitia, ligament and cornea.

(in addition to fibroblasts)

1. Adipose tissue:

* white adipose tissue

*brown fat

- white and brown fat cells; different structure and function

- brown: innervated and involved in thermogenesis

Defence:

* 3 slides of cells in connective tissue

2. Cells of the immune system: lymphocytes, plasma cells (forming antibodies) and macrophages (monocytes)

3. Mast cells: also part of immune system: binding antibodies from lymphocytes, recognising antigens and producing an inflammatory response by degranulation, liberating histamine, heparin etc.. Also involved in anaphylactic shock (systemic degranulation).

- NB oedema can also involve inflammation, due to increased leakage of plasma into tissues