Module 6 - Lecture 1

NPTEL – Biotechnology – Tissue Engineering
How Cell-Extra cellular matrix interactions
can co-ordinate cell fates?
S. Swaminathan
Director
Centre for Nanotechnology & Advanced Biomaterials
School of Chemical & Biotechnology
SASTRA University
Thanjavur 613 401
Tamil Nadu
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NPTEL – Biotechnology – Tissue Engineering
Table of Contents
1. HOW CELL-EXTRA CELLULAR MATRIX INTERACTIONS CAN COORDINATE CELL FATES? .............................................................................3
2. MODIFYING THE ECM ................................................................................6
2.1 Malfunctions in ECM signalling ...............................................................6
2.2 Malfunctioning morphoregulatory control loop ........................................7
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NPTEL – Biotechnology – Tissue Engineering
1. How Cell-Extra cellular matrix interactions can coordinate cell fates?
As we all know cell adhesion, migration, proliferation, differentiation and even
cell death form a part of the cell fate processes. Now let us take one simple
example i.e cells adhesion. Cell adhesion is the primary factor for controlling
most of the cell fate.
For example; cell migration where speed is mainly
regulated by the cell-ECM interactions. This we have seen in the factors
regulating the cell migration speed. Similarly let us take apoptosis. This is
programmed cell death where the cells attain round or spherical morphology
due to the fragmentation of cytoskeleton proteins.
The major role of
cytoskeleton in migration and also adhesion has well understood. i.e cell
surface receptor like integrins communicate the cell with the ECM thereby
providing the link to the actin cytoskeleton. This is why the cell loses its
specific phenotype during apoptosis and become round morphology via the
fragmentation of cytoskeleton proteins. These examples make the readers
understand the role of cell-ECM interaction in coordination of cell fate
process.
The extracellular matrix comprising of different number of proteins like
collagen,
elastin
and
polysaccharides
like
glycosaminoglycans,
proteoglycans, interconnects all of the cells in a tissue and their cytoskeleton
elements.
The ECM molecules are synthesized, secreted, oriented and
modified by the cells present in the tissues. It is a multifunctional matrix. It
can provide a structural as well as mechanical support to the tissues. The
ECM can serve as a substrate for the cells to migrate and place to locate the
signals for communication. Hence, the ECM dynamic and is being modified
constantly. There are number of receptors on the cell surface facilitating the
cell-ECM interactions. This signal may be signal for migration, replication,
differentiation, and apoptosis. Hence, it is clear that the cell fate process has
been regulated by the ECM components. ECM signals are very stable and
even very specific and very strong as compared to diffusible growth factor
signal.
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NPTEL – Biotechnology – Tissue Engineering
Mainly, proteoglycans, special glycoprotein, collagen, soluble multiadhesive
proteins like fibronectin are the ECM components. The binding of cell to the
ECM is mainly through the integrins, which is class of heterodimeric proteins.
There are 18 human α and 8 β subunits.
There are three different classes of integrin-based junctions called
hemidesmosomes, focal contacts and fibrillar contacts. The integrins are the
cell adhesion receptors and they bind to the small peptide sequence within
the larger ECM molecules. Among the different integrin based junctions, focal
and fibrillar contacts are attached through the specific proteins with actin
cytoskeleton proteins in the cell. Thereby it is subjected to the contraction
force generated by the actin-myosin interactions. In case of focal contacts,
(oval structures) the cell is mainly attached to the matrix protein called
vitronectin via αvβ3 integrins. This is because the vitronectin serves as a rigid
substrate, thus αvβ3 integrins cannot move due to contractile forces. This in
turn develops the high tension leading to the association of the specific
proteins like paxillin, vinculin. However, for fibrillar contacts (elongated or dot
like structure), matrix protein fibronectin attach with the cells through α5β1
integrins. Here there is no recruitment of vinculin and paxillin. Fibrillar contact
contains tensin instead of vinculin and paxillin. Hemidesmosomes are the
intracellular protein plaques found in the epithelial tissues, which can connect
the basement membrane to cytoskeleton actin filaments via integrins.
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NPTEL – Biotechnology – Tissue Engineering
Fig1: Integrin-based adhesion junctions (A) Focal and Fibrillar contacts; (B) Hemidesmosome
Let us take an example of RGD. This peptide sequence has arginine-glycineaspartic acid.
This sequence can mimic some features of larger ECM
components like fibronectin.
Ligand binding to integrins requires the
simultaneous binding of divalent cations. How many numbers of binding sites
are required to generate a cell response?
One research group, has
immobilized the tripeptide binding sequence on a cell growth surface at
varying densities. Then as function of surface density of RGD binding sites
especially for fibroblast, cell attachment, spreading and growth were
examined.
From this experiment, they have identified that an average
receptor spacing of 440 nm was sufficient for cell attachment and spreading
and 160 nm for focal point adhesion formation.
Let us take another example of cell adhesion in the circulatory system. This is
because cell adhesion is the primary component in response of immune cells
to the specific infections. The cell has to attach to the endothelial surface first
and then migrate to the target site. The balance between the bond length,
dissociation rates and affinity strength can determine the process of adhesion.
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NPTEL – Biotechnology – Tissue Engineering
2. Modifying the ECM
Cells produce as well as degrade the ECM in their own environment. One
good example for this is chondrocytes and surrounding ECM. Cartilage is a
tissue chiefly composed of ECM, mainly collagen. It has been reported that
the production of collagen occurs on the order of days with diffusion into the
ECM about 100 µm per day.
ECM in the cartilage tissue is constantly
synthesised, degraded and also remodelled in response mechanical
deformations. The deposition of proteoglycan in the ECM surrounding the
chondrocyte was found in a direction perpendicular to that of the
compression.
Cells produce newly formed ECM molecules that may (i)
migrate to the matrix where they may continue to; (ii) diffuse away from the
cell; (iii) become immobilized within the existing matrix; (iv) proteolytic enzyme
can cause degradation of the matrix leading to the release and transport of
the degraded matrix molecules.
2.1 Malfunctions in ECM signalling
It is clear that the ECM regulates the cell behaviour and coordinates the cell
function and homeostasis.
In addition, the three-dimensional architecture,
composition and remodelling of ECM contributes the micro-environmental
signalling that direct the cell shape, migration, viability, growth and
differentiation. Hence any malfunction of cell-ECM signalling leads to various
pathological states such as degenerative, malignant, developmental, immune
and hemostatic disorders.
Especially mutations in genes encoding ECM
protein, ECM remodelling protein, ECM receptors will lead to diseases. This
mutation can alter both structural properties ECM molecules as well as
function of the protein that degrade the ECM mainly in the matrix metalloprotease (MMPs) family. MMPs are responsible for the interactions between
the cell and the surrounding ECM.
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NPTEL – Biotechnology – Tissue Engineering
2.2 Malfunctioning morphoregulatory control loop
Tumour-suppressor genes, Rb and p53 and ECM interactions form a
regulatory feedback loop.
ECM as well as integrins controls the
phosphorylation of Rb and transcription, translocation and degradation of p53.
This in turn can regulate the expression of MMPs, thereby degrading the
ECM.
P53 regulates the cell-ECM interactions through the transcription
control of ECM components such as collagen, laminin, fibronectin etc. This
type of feed-back loop promotes cell fate process such as apoptosis and
migration.
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