Cellular Communities: Tissues,

Stem Cells, and Cancer

(2nd half)

Animal connective tissues consist

largely of extracellular matrix
4 major types of tissues in animalsconnective,
epithelial, nervous, & muscular.
connective tissuesextracellular matrix is plentiful
carries the mechanical load. In other tissues
extracellular matrix is scanty & cells are directly joined
& carry the mechanical load themselves.
Animal connective tissuescan be tough & flexible e.g
tendons, dermis of the skinhard & dense e.g. bone
resilient & shock-absorbing e.g. cartilageor soft &
transparent like the jelly that fills the interior of the
eye. In all of these tissues, the tensile strength
provided by a fibrous protein collagenconnective
tissues owe their specific characters to the type of
collagen.

Fig: Extracellular matrix is plentiful in

connective tissue such as bone.

Collagen provides tensile strength in

animal connective tissues
Collagenin mammals 20 different collagen
genesare chief proteinsconstitute 25% of
the total protein masslong, stiff, triplestranded helical structure, in which three
collagen polypeptide chains are wound
assemble into ordered polymers called
collagen fibrils (thin cables 10300 nm in
diameter)can pack together into still thicker
collagen fibersOther collagen molecules
decorate the surface, link the fibrils to one
another and to other components in the
extracellular matrix.

Fig: Collagen fibrils are organized into

bundles

 The connective-tissue cellsvarious namesin

skin, tendon, & many other connective tissues
they are called fibroblasts in bone they are
called osteoblasts these molecules are
synthesized intracellular & then secreted by
exocytose cells secrete collagen molecules in a
precursor form, called precollege, with
additional peptides at each end that obstruct
assembly into collagen fibrilsExtracellular
enzymescalled precollege pretensescut off
these terminal domains to allow assembly. Some
people have a genetic defect in one of these
pretenses, or in precollege itselfhave a lower
tensile strength & are extraordinarily stretchable.
Cells in tissuesable to degrade & make matrix
for tissue growth, repair, and renewal.

Fig: Fibroblasts produce the extracellular

matrix of connective tissue.

Fig: Incorrect collagen assembly can

cause
hyperextensible skin

Cells organize the collagen that they

secrete
The connective-tissue cellscontrol this
orientation by depositing the collagen in an
oriented fashion & then by rearranging it. During
development of the tissuefibroblasts work on
the collagen, helping to compact it into sheets &
draw it out into cablese.g., in cell culture, the
intervening collagen becomes organized,
fibroblasts migrate out from the two explants
along the aligned collagen fibers, thus fibroblasts
influence the alignment of the collagen fiber
which in turn affect their distribution. Fibroblast
migration is also important for healing wounds.

Fig: Fibroblasts influence

the alignment of collagen fibers

Integrins couple the matrix outside a

cell to the cytoskeleton inside it
Cells do not attach well to bare collagenAnother
extracellular matrix protein, fibronectinprovides
a linkageA cell attaches to fibronectin by means
of a receptor protein, called an integrin
extracellular domain of the integrin binds to
fibronectin & the intracellular domain binds to actin
filaments inside the cellwhen there is tension
between the cell and the matrix, the integrin
molecule transmits that stress to the sturdier
cytoskeletonintegrins also react (by
conformational Changes) to stress & to chemical
signals that direct them to maintain their
attachment to other molecules or to let go.

Fig: Fibronectin and integrin molecules

attach a cell to the extracellular matrix

 Binding to a molecule on one side of the membrane

integrin molecule stretch out into an extended,
activated statelatch onto another molecule on the
opposite sideused to transmit chemical as well as
mechanical signals.
Humans make at least 24 different kinds of integrins
having distinct functions depending on which type
of cell they reside in e.g., the integrins on white
blood cells help those cells to crawl out of blood
vessels at sites of infection so as to deal with the
marauding microbeslacking this type of integrin
develop a disease called leucocyte adhesion
deficiencysuffer from repeated bacterial
infectionssimilarly a different form of integrin in
blood plateletslacking causes bleed excessively
because their platelets cannot bind to the necessary
clotting factor in the extracellular matrix.

 Figure 2015 An integrin molecule

switches to an active conformation
when
it binds to molecules at either of its
ends

Gels of polysaccharide and protein

Fill spaces and resist compression
Another different group of macromolecules in the
extracellular matrix of animal tissuesresisting
compression & serving as space-fillers
proteoglycansextracellular proteins linked to a
special class of complex negatively charged
polysaccharides, the glycosaminoglycans
(GAGs)many GAG chains are attached to a
single core proteinwhich may in turn be linked at
one end to another GAG, creating macromolecule
resembling a bottlebrush. In dense, compact
connective tissues e.g. tendon & boneproportion
of GAGs is small & the matrix consists almost
entirely of collagen.

Fig: Proteoglycans and GAGs can

form large aggregates

 GAGs are strongly hydrophilic & tend to adopt

highly extended conformationstheir multiple
negative charges attracting a cloud of cations,
such as Na+, that are osmotically active, causing
large amounts of water to be sucked into the
matrixcreates a swelling pressure that is
balanced by tension in the collagen fibers
interwoven with the proteoglycansSuch a matrix
is tough, resilient,& resistant to compressione.g.
cartilage matrix lining the knee joint.
Proteoglycansin addition to providing hydrated
spacecan also form gels of varying pore size &
charge density that act as filters to regulate the
passage of molecules through the extracellular
mediumcan bind secreted growth factors &
other proteins that serve as signals for cells.

Epithelial sheets and cell

junctions
Different cell types
are organized into epithelia
in which the cells are joined together, side to
side, to form multicellular sheetsit may be
many cells thick, or stratified, as in the
epidermal covering of the skin or only one cell
thick, as in the lining of the gutEpithelial cells
can take many formsSome act mainly just as
a protective barrier others have complex
biochemical functions, Some secrete specialized
products, others absorb nutrients, some detect
signalsEpithelia cover the external surface of
the bodymust have been an early feature in
the evolution of multicellular animals.

Fig: Cells can be packed together in

different ways to form an epithelial
sheet

Epithelial sheets are polarized and

rest on a Basal lamina
An epithelial sheet has two facesthe apical
surface is free & exposed to the air or to a
watery fluidthe basal surface rests on
some other tissueusually a connective
tissueto which it is attachedSupporting
the basal surface of the epithelium is a thin
tough sheet of extracellular matrix, called the
basal lamina, composed of a specialized
type of collagen (Type IV collagen) & various
other macromoleculesincluding a protein
called lamininwhich provides adhesive
sites for integrin of the epithelial cells.

Fig: A sheet of epithelial cells has

an apical and a basal surface

Fig: The basal lamina supports a sheet

of epithelial cells.

 The apical & basal faceschemically

differentreflecting a polarized internal
organizationcrucial for epithelial
functione.g. the simple columnar
epithelium that lines the small intestine
consists of two intermingled cell types:
absorptive cells & goblet cells
(secreting the mucus)Both are polarized
absorptive cells import food molecules
from the gut lumen through their apical
surface and export these molecules from
their basal surface into the underlying
tissuesgoblet cells synthesize mucus
and then discharge it from their apical

Tight junctions make an epithelium leak-proof

and separate its apical and Basal surfaces
Epithelial cell junctionsclassified according to their function
Some provide a tight seal to prevent the leakagesome
provide strong mechanical attachmentssome provide for a
special type of intimate chemical communicationThe
sealing function is served by tight junctionsseal
neighboring cells togetherjunction is formed from proteins
called claudins & occludinsalso play a key part in
maintaining the polarity of the individual epithelial cells in
two waysFirst, the tight junction around the apical rim of
each cell prevents diffusion of membrane proteins within the
plasma membrane and so keeps the apical domain of the
plasma membrane different from the basal domain. Second
junctions are sites of assembly for the complexes of
intracellular proteins that govern apico-basal polarity in the
interior of the cell.

Fig: Several types of cellcell

junctions are found in epithelia in
animals

Cytoskeleton-linked junctions Bind epithelial cells

robustly to one another and to the Basal lamina
The junctions that hold an epithelium together are of
three main typesAdherens junctions and
desmosomes bind one epithelial cell to another, while
hemidesmosomes bind epithelial cells to the basal
laminathe molecule that forms the external adhesion
spans the membrane and is linked inside the cell to
strong cytoskeletal filaments. Adherens junctions and
desmosomeboth built around transmembrane proteins
that belong to the cadherin familya cadherin molecule
of one cell binds directly to an identical cadherin
molecule in the plasma membrane of its neighborSuch
binding of like to like is called homophilic binding
binding also requires that Ca2+ be present in the
extracellular mediumhence its name

Fig: Cadherin molecules mediate

mechanical attachment of one cell to
another

 At an adherens junctioneach cadherin molecule is

tethered inside its cell, via several linker proteins,
to actin filamentsform a continuous adhesion belt
around each of the interacting epithelial cellsthis
belt is located near the apical end of the cell, just
below the tight junctionsActin bundles are thus
connected from cell to cell across the epithelium
This actin network gives the epithelial sheet the
capacity to develop tension and to change its shape
By shrinking its apical surface along one axis, the
sheet can roll itself up into a tubeor can develop a
cup-shaped concavity & eventually create a vesicle
that may pinch off from the rest of the epithelium
important in embryonic development, where they
create structures such as the neural tube, which
gives rise to the central nervous system

 At a desmosomea different set of cadherin

moleculesThese connect to intermediate
filamentsspecifically, to keratinsthese
criss-cross the cytoplasm and are spotwelded via desmosome junctions to the
bundles of keratin filaments in adjacent cells
Externally, integrins bind to the
extracellular matrix protein laminin in the
basal lamina; inside the cell, they are linked
to keratin filaments, creating a structure
that looks superficially like half a
desmosome. These attachments of
epithelial cells to the extracellular matrix
beneath them are therefore called
hemidesmosomes.

Fig: Adherens junctions form

adhesion belts around epithelial cells in the
small intestine.

Figure 2026 Epithelial sheets can

bend to form a tube or a vesicle

Fig: Desmosomes link the keratin

filaments of one cell to those of
another

Gap junctions allow ions and small

molecules to pass from cell to cell
Final type of epithelial cell junctiongap junctiongap
is not empty but is spanned by the protruding ends of
many identical protein complexes that lie in the plasma
membranes of the two apposed cellsThese
complexes, called connexons, form channels across
the two plasma membranesallow inorganic ions &
small water-soluble molecules to move directlycreates
an electrical and a metabolic coupling between the cells
Gap junctions can be opened or closed as needed.
Plant tissuescytoplasms of adjacent plant cells are
connected via minute communicating channels called
plasmodesmata, which span the intervening cell walls
Ions, small molecules, and even macromolecules such
as some proteins and microRNAs can pass

Fig: Gap junctions provide neighboring cells

with a direct channel of communication.

Fig: Plant cells are connected

via plasmodesmata

Tissue maintenance and

renewal
In the process of developmentthe
egg cell divides repeatedly to give a
clone of cellsall containing the same
genome but specialized in different
waysCells grow, divide, and die
form mechanical attachments and
generate forces for movement
produce molecular signals & they
respond to signalsremember the
effects of previous signals.

Tissues are organized mixtures of

many cell types
Tissues need mechanical strength, which is often
supplied by a supporting bed or framework of
connective tissueIn this connective tissue, blood
vessels lined with endothelial cells satisfy the need for
oxygen, nutrients, & waste disposal. Most tissues are
innervated by nerve-cell axonswhich are ensheathed
by Schwann cells that provide electrical insulation.
Macrophagesdispose of dying cells and other
unwanted debris & lymphocytescombat infection
these cell types originate outside the tissue & invade it
either early in the course of its development or
continually during life. Almost every tissue is therefore
an intricate mixture of many cell types

 In almost all adult tissuescells are continually dying &

being replacedbut the organization of the tissue must
be preserved & 3 main factors contribute to this:
1. Cell communicationthe very survival of most cells
depends on such social signals. This ensures that new
cells are produced & survive only when & where they are
required.
2. Selective cellcell adhesiondifferent cell types
have different cadherins & other adhesion molecules
tend to stick selectively, by homophilic bindingmay also
form selective attachments to certain other cell types
selectivity prevents the different cell types in a tissue
from becoming chaotically mixed.
3. Cell memoryspecialized patterns of gene
expressionevoked by signals that acted during
embryonic development, are afterward stably maintained
so that cells autonomously preserve their distinctive
character and pass it on to their progeny.

Different tissues are renewed at

different rates
Nerve cellslast a lifetime without replacementthe
cells that line the intestine, are replaced every few
daysdifferent rates & styles of cell replacement
e.g. Bone, has a turnover time of about ten years
old bone matrix is slowly eaten away by a set of cells
called osteoclastsnew matrix is deposited by
another set of cells, osteoblasts. Similarly, new red
blood cells are generated in the bone marrow &
released into the circulation after 120 days. A large
dose of ionizing radiationblocks cell division and
thus halts renewal. So there have to be control
mechanisms to keep cell production and cell loss in
balance in the normal body.