1

PRESENTED BY:SYED KASHIFDEPARTMENT OF PHARMACOLOGYAACP

EXTRACELLULAR MATRIX

2

CONTENTS DEFINITION ROLE AND IMPORTANCE MOLECULAR COMPONENTS 1.PROTEOGLYCANS 2.NONPROTEOGLYCANS 3.FIBRES 4.OTHER COMPONENTS FUNCTIONS

3

4

DEFINITION ECM is a collection of extracellular

components secreted by cells that provides structural & biochemical support to the surrounding cells

It mainly includes interstitial matrix & the basement membrane

The interstitial matrix contains gels of polysaccharides & fibrous proteins

Basement membranes are sheet-like depositions of ECM on which various epithelial cells rest.

5

ROLE & IMPORTANCE ECM can serve many functions, such as providing

support, segregating tissues from one another, and regulating intercellular communication

In addition, it sequesters a wide range of cellular growth factors and acts as a local store for them. Changes in physiological conditions can trigger protease activities that cause local release of such store

6

MOLECULAR COMPONENTS Components of the ECM are produced

intracellularly by resident cells and secreted into the ECM via exocytosis. Once secreted, they then aggregate with the existing matrix. The ECM is composed of an interlocking mesh of fibrous proteins and glycosaminoglycans (GAGs).

7

PROTEOGLYCANS Glycosamines are carbohydrate polymers

 usually attached to extracellular matrix proteins to form proteoglycans(hyaluronic acid is a notable exception)

Proteoglycans have a net negative charge that attracts positively charged sodium ions (Na+), which attracts water molecules via osmosis, keeping the ECM and resident cells hydrated. Proteoglycans may also help to trap and store growth factors within the ECM.

8

9

TYPES OF PROTEOGLYCANS Heparin sulfate:Heparan sulfate (HS) is a

linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (PG) in which two or three HS chains are attached in close proximity to cell surface or ECM proteins.[ It is in this form that HS binds to a variety of protein ligands and regulates a wide variety of biological activities, including developmental processes,angiogenesis, blood coagulation, and tumour metastasis.

10

11

Chondrotoin sulfates: Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars (N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan

chondrotoin sulfates contribute to the tensile strength of cartilage, tendons, ligaments, and walls of the aorta. They have also been known to affect neuroplasticity.

12

13

Keratan sulfate: Keratan sulfate (KS), also called keratosulfate, is any of several sulfated glycosaminoglycans (structural carbohydrates) that have been found especially in the cornea, cartilage, and bone

Keratan sulfates have a variable sulfate content and, unlike many other GAGs, do not contain uronic acid. They are present in the cornea, cartilage, bones, and the horns of animals.

14

15

NON-PROTEOGLYCAN POLYSACCHARIDE

Hyaluronic acid Hyaluronic acid (or "hyaluronan") is a polysaccharide

 consisting of alternating residues of D-glucuronic acid and N-acetylglucosamine, and unlike other GAGs, is not found as a proteoglycan. Hyaluronic acid in the extracellular space confers upon tissues the ability to resist compression by providing a counteracting turgor (swelling) force by absorbing significant amounts 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.[16]

Hyaluronic acid acts as an environmental cue that regulates cell behavior during embryonic development, healing processes, inflammation, and tumor development. It interacts with a specific transmembrane receptor

16

17

FIBRES Collagen Collagens are the most abundant protein in the

ECM. In fact, collagen is the most abundant protein in the human body[18][19]and accounts for 90% of bone matrix protein content.[20] Collagens are present in the ECM as fibrillar proteins and give structural support to resident cells. Collagen is exocytosed in precursor form (procollagen), which is then cleaved by procollagen proteases to allow extracellular assembly. Disorders such as Ehlers Danlos Syndrome, osteogenesis imperfecta, and epidermolysis bullosa are linked with genetic defects in collagen-encoding genes.

18

The collagen can be divided into several families according to the types of structure they form:

Fibrillar (Type I, II, III, V, XI) Facit (Type IX, XII, XIV) Short chain (Type VIII, X) Basement membrane (Type IV) Other (Type VI, VII, XIII)

19

20

Elastin:Elastins, in contrast to collagens, give elasticity to tissues, allowing them to stretch when needed and then return to their original state. This is useful in blood vessels, the lungs, in skin, and the ligamentum nuchae, and these tissues contain high amounts of elastins. Elastins are synthesized by fibroblasts and smooth muscle cells. Elastins are highly insoluble, andtropoelastins are secreted inside a chaperone molecule, which releases the precursor molecule upon contact with a fiber of mature elastin. Tropoelastins are then deaminated to become incorporated into the elastin strand. Disorders such as cutis laxa and Williams syndrome are associated with deficient or absent elastin fibers in the ECM

21

22

Fibronectin Fibronectins are glycoproteins that connect cells

with collagen fibers in the ECM, allowing cells to move through the ECM. Fibronectins bind collagen and cell-surface integrins, causing a reorganization of the cell's cytoskeleton and facilitating cell movement. Fibronectins are secreted by cells in an unfolded, inactive form. Binding to integrins unfolds fibronectin molecules, allowing them to form dimers so that they can function properly. Fibronectins also help at the site of tissue injury by binding to platelets during blood clotting and facilitating cell movement to the affected area during wound healing.

23

24

Laminin Laminins are proteins found in the 

basal laminae of virtually all animals. Rather than forming collagen-like fibers, laminins form networks of web-like structures that resist tensile forces in the basal lamina. They also assist in cell adhesion. Laminins bind other ECM components such as collagens, nidogens, and entactins

25

26

FUNCTIONS Ecm is responsible for growth & healing of tissues It is currently being used regularly to treat ulcers

by closing the hole in the tissue that lines the stomach

Extracellular matrix proteins are commonly used in cell culture systems to maintain stem and precursor cells in an undifferentiated state during cell culture and function to induce differentiation of epithelial, endothelial and smooth muscle cells in vitro. Extracellular matrix proteins can also be used to support 3D cell culture in vitro for modelling tumor development.

27

. In terms of injury repair and tissue engineering, the extracellular matrix serves two main purposes. First, it prevents the immune system from triggering from the injury and responding with inflammation and scar tissue. Next, it facilitates the surrounding cells to repair the tissue instead of forming scar tissue

Extracellular matrix coming from pig small intestine submucosa are being used to repair "atrial septal defects" (ASD),

28

SUMMARY

29

CELL SIGNALLING:COMMUNICATION BETWEEN CELLS & THEIR ENVIRONMENT

30

CONTENTS1) DEFINITION 2) CLASSIFICATION3) Signalling molecules

31

WHAT IS CELL SIGNALING Cell signaling is a process of a cell

responding to a stimulus from its environment by relaying its information into internal compartment from its surface

The ability of cells to perceive and correctly respond to their microenvironment is the basis of cell signaling

32

CLASSIFICATION A)Extra cellular signaling or chemical signalingI. Intracrine II. Autocrine III. JuxtacrineIV. PancrineV. endocrine

B)Cell”s direct signaling or intracellular signallingVI. ReceptorsVII. Cell surface protiensVIII. Gap junctions

33

Intracrine signals are produced by the target cell that stay within the target cell.

Autocrine signals are produced by the target cell, are secreted, and affect the target cell itself via receptors. Sometimes autocrine cells can target cells close by if they are the same type of cell as the emitting cell. An example of this are immune cells.

CLASSIFICATION

34

Juxtacrine signals target adjacent (touching) cells. These signals are transmitted along cell membranes via protein or lipid components integral to the membrane and are capable of affecting either the emitting cell or cells immediately adjacent.

Paracrine signals target cells in the vicinity of the emitting cell. Neurotransmittersrepresent an example.

35

Endocrine signals target distant cells. Endocrine cells produce hormones that travel through the blood to reach all parts of the body.

36

37

SIGNAL TYPE SIGNAL PRODUCED AT

SIGNAL TARGETED AT

INTRACRINE CELLS SAME CELLS

AUTOCRINE CELLS SAME CELLS BUT VIA RECEPTORS

JUXTACRINE CELLS ADJACENT CELLS

PARACRINE CELLS CELLS IN VICINITY

ENDOCRINE CELLS DISTANT CELLS

SUMMARY

38

DIRECT CONTACT SIGNALLING1. RECEPTORS2. G-PROTEIN COUPLED RECEPTORS3. GAP JUNCTIONS

39

RECEPTORS RECEPTORS are proteinaceous structures

present either on cell surface or inside the cell

In case of membrane bound receptors signals(ligands) bind to these receptors activates them & produce a cascade of intracellular signals that alter the cell

In case of intracellular receptors the ligand enters inside the cell & brings about activation of the receptors

40

DIRECT CONTACT SIGNALING GAP JUNCTIONS These are specialised cell-cell junctions that

are formed between closely opposed plasma membranes & directly connect the cytoplasms of the joined cells via narrow water filled channels

These channels allow the exchange of small intracellular signalling molecules such as Ca & cAMP

41

CELL SURFACE RECEPTORS Al l water soluble signal molecules act by

binding to specific receptor proteins present on the target cells . Hence cell surface proteins are oftenly termed as signal transducers

There are mainly 3 types of cell surface receptors

1. Ion-channel linked receptors2. G-protein coupled receptors3. Enzyme-linked receptors

42

ION-CHANNEL LINKED RECEPTORS Also known as TRANSMITTER-GATED ION

CHANNELS or IONOTROPIC RECEPTORS They are involved in rapid synaptic signaling

between electrically excitable cells This type of signaling is mediated by

neurotransmiters that transiently open or close the ion channels formed by the proteins to which they bind thus changing the ion permeability of the plasma membrane & excitability of post synaptic cell

43

G-PROTEIN COUPLED RECEPTORS These receptors act indirectly to regulate the

activity of membrane bound protein(ion channel or enzyme)

The interaction between the receptor & the signaling is mediated by a third protein called as GTP BINDING PROTEIN(G protein)

The activation of the target protein can change the concentration of the mediators (in case of enzymes) or change the membrane permeability(in case of ion channels)

44

ENZYME LINKED RECEPTORS These when activated either function directly

as enzymes or are associated with the enzymes they activate

These are formed by single pass transmembrane proteins that have their ligand binding site outside the membrane & enzyme binding site inside the membrane

The majority of these kind of receptors are either protein kinases or associated with them & bring about phosphorylation

45

SIGNALING MOLECULES Signaling molecules interact with target cell

as a ligand to cell surface receptors & elicit cell signalling

This generally results in the activation of second messengers, leading to various physiological effects

46

There are 3 important classes of signalling molecules

: Hormones are the major signaling molecules

of the endocrine system, though they often regulate each other's secretion via local signaling (e.g. islet of Langerhans cells), and most are also expressed in tissues for local purposes (e.g. angiotensin) or failing that,structurally related molecules are 

47

48

Neurotransmitters are signaling molecules of the nervous system, also includingneuropeptides and neuromodulators. Neurotransmitters like the catecholamines are also secreted by the endocrine system into the systemic circulation.

Ex: Ach

49

Cytokines are signaling molecules of the immune system, with a primary paracrine or juxtacrine role, though they can during significant immune responses have a strong presence in the circulation, with systemic effect (altering iron metabolism or body temperature). Growth factors can be considered as cytokines or a different class

50

THANK YOU