Pathology, Lecture 13 (Lecture Notes)

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    Tissue repair Lec#1

    Ismaeel Matalqa

    Yousef, Deeb, Hamza, Malik

    31/10/2010

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    Pathology 13

    Sunday, 31-10-2010

    Before we start , there are some abbreviations you should know through you are

    studying this beautiful lecture!

    ECM= extra cellular matrix CT= connective tissue RB= Retinoblastoma

    NOW lets start

    We are going to discus about the tissue repair today, but before that I want you

    to know the vision and the mission of our medicine school in JUST and you can

    see in slide 5 the vision of our faculty of medicine at JUST is to lead medical

    education using creativity and innovation, to advance health with quality and

    compassion, to search and discover with imagination and innovation; and to

    achieve and maintain human health and well-being to the maximum attainable

    levels.

    So this is the vision of our school, and off course the mission is a community of

    scholars who stimulate & inspire medical students to be leaders in advancing

    medicine at different levels of health care and who participate in advancing

    medical science and research.

    So these are the vision and the missions of our school and probably you should be

    familiar with these kinds of things

    Now go back to our lecture tissue repair..

    The simple definition for repair is: restoration of tissue architecture and function

    after an injury.

    So what are the processes, which repair usually after an injury which usually we

    call it insult or inflammation to achieve such restoration of structure and function.

    So to restore the structure or the architecture and function of the injury organ or

    tissue.

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    There are two main mechanism of repair, one of them is the regeneration, which

    is the replacement of the damaged cells by similar parenchymal cells, same kind

    with the same nature, like liver regenerations, so it regenerate itself by producing

    new liver cells, off course this require intact CT scaffold; scaffold mean the

    framework ( ) , and the scaffold of the organs is the CT or the ECM, so this the

    scaffold of the tissues or the organ, and we need this framework to be intact first

    to regenerate this cell which had been damaged or destroyed, and off course in

    this process the tissue of the organ will return to the normal state.

    The other process or mechanism is the healing and fibrosis; which is usually

    remained up with scar formation and in this case the ECM is severely damaged, so

    the scaffold, the CT, the ECM is severely damaged, and this will lead to

    replacement of such lost of tissue or damaged of cell by CT which is the fibertissue, the fibroblast.

    Now in some conditions in tissue spaces like for example the lung where its

    occupied by inflammatory exudates, or in the pleura, this will lead to a process we

    call it organization, so its healing by organization, and the typically example of

    this is the organizing pneumonia.

    So there are two mechanism either regeneration or healing fibrosis (which will

    lead to scar formation).

    In slide #8

    This diagram illustrates the difference between the two mechanisms

    (regeneration and the repairing by scar).

    Here if we take as an example the liver.. this is the liver and you can see here this

    is the central vein and these aggregations are the portal tract and it has a typical

    model a hexagonal model of the liver architecture, where there is a central veinsurrounded portal tract.

    And you can see on the picture below (or figure 3-1 page 60), these are

    hepatocytes that are arranged into cores and between these cores hepatocytes

    there is a CT frame which is reticular tissue and we call it the reticular tissue

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    frame which is the ECM or scaffold or the supportive CT, and of course there is a

    portal triad which contain the hepatic artery, portal vein and the bile duct.

    Now, if there is an injury which is directed to cells which means leading to loss of

    the hepatocytes, which are the cells this will in turn will lead to proliferation of

    the residual cells within the intact matrix and there are some cells with potential

    to regenerate which are the stem cells and this will lead to regeneration and

    restoration to its normal structure and normal function as it was.

    And we call this repair by

    regeneration.

    On the other hand, if the injury has

    led to destruction of cells and matrix

    which is the CT, this will lead to

    decomposition of CT, proliferation of

    residual cells within the disrupted

    matrix and of course this will lead to

    lying down of these amounts or

    deposition of collagen and reticular

    and other fibrous tissue and this will

    lead to scarring or fibrosis.

    We call this repair by scarring or fibrosis.

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    So tissues of cells can have either: repair by regeneration or repair by scarring.

    and this depends on:

    y the severity of the injury

    y the type of injury

    y the type of the tissue

    And we will see later that there are some specific tissues or cells which are NOT

    capable of regeneration and subsequently repair by regeneration and the end

    result for these specific tissues or cells or organs ALL THE TIME is repair by

    scarring. And this is very important from clinical point of view.

    ***************

    The normal homeostatic is the balance between proliferation and apoptosis

    which means if you have cells, usually there is an equilibrium of pulse between

    the cell proliferation and cell death (apoptosis : programmed cell death).

    So if this programmed death continue to fail to act, this will lead to continuous

    proliferation of the cells and there will be increase in the mass of the cells,

    increase in the size of the cells and this will lead to what we call tumors

    proliferation (tumor formation).

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    Tumor is a mass and it is neoplastic which means that it will lead to the formation

    of malignancy, so this is in a very simple way; it is the actual mechanism of

    proliferation and formation of tumors in general whether they are benign or

    malignant.

    And you see on below (figure 3-18 page 78) a cell injury, you have regeneration

    and of course there are different types of cells.

    According to this, there are:

    - Renewing tissues which can divide and replacing the cells and this can easily

    regenerate by producing new cells.

    - Quiescent or stable tissue like the liver which is a prototype of these types of

    cells.

    In general the parenchymal cells are an example of this type of cells

    which include: liver, kidney and pancreas.

    When there is an injury they will compensate the growth of the liver or kidney or

    pancreas and there will be like this compensation and then replacement or

    hyperplasia of these cells.

    .

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    And this is actually the main principle in the liver transplantwhere in it some

    times, if it is a large donor if you take the liver from somebody who is very

    reactive so we take part of the liver and you put this liver and anastomose that

    liver in its right anatomical site where it can regeneration and attain the normal

    size of the liver by different mechanisms.

    So this is the principle of transplantation regarding liver in this case.

    The healing on the other hand when there are a wound and there are wound

    healing by scar formation or chronic inflammation which is so severe and

    destructive and will lead to fibrosis.

    The Control of Cell Proliferation

    There are three main elements:

    - The remnants of the injured tissue, these remnants usually they are attempting to

    restore normal structure, by different choices, whether it is by regeneration or

    heeling.

    - Vascular endothelial cells, by creating new blood vessels in the area, that is of

    course to supply blood and nutrition to the proliferating area. This process is

    called angiogenesis; formation of new blood vessels.- Fibroblasts, which is part of the ECM. The main function of the fibroblasts here is

    to make the fibrous tissue or the other types of CT; collagen for example.

    * Notice here that the onset action of all these cells and components in driven by

    proteins; we called them Growth Factors.

    This figure illustrates the Homeostasis of the

    cells, the balance between them:

    - The baseline cell population comes from the

    stem cells, so, the stem cells are the source of

    all the baseline cell population weather they

    (the stem cells) are from the embryonic stem

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    cells during the embryonic life, or from the adult stem cells.

    - These baseline cells may differentiate to another more specialized types of cells,

    and of course, they ( baseline cells ) may undergo cell death ( apoptosis : the

    programmed cell death ), or if you keep stimulation and the growth factors still

    working on these types of Population cells, this will lead to Proliferation, and of

    course, the massive proliferation will lead to abnormal growth .

    - So, the equilibrium between the proliferation and the cell death is the key that

    keep our tissues and organs under control regarding growth.

    - If you block the converting from stem cells to baseline cell population or inhibit

    apoptosis, cell proliferation will increase and this will lead to tumor formation.

    - If you block the concerting from baseline cell population to the proliferated cells,

    this will lead to continuous cell death or apoptosis, and then; lose of function.

    - So, it is equilibrium between cell death and proliferation which keeps all these

    tissues in order.

    We have different types of cells in our body, and these cells have different

    Proliferative Potential, and according to this, we can put the cells in three

    different groups or classes:

    Labile cells, which are the continuously dividing and continuously dying

    cells. The main examples of this class are :

    - The stem cells, which have the ability to self renewal the differentiation.

    In our body, we have:

    - Skin epidermis cells, and you know that these cells are have a natural situation

    of being labial cells, which differentiate continuously. Oral cavity, vagina, cervix.

    The ducts like salivary glands, pancreas, common bile duct etc.

    - GIT epithelium, which have the very characteristic pattern of continuous death

    the proliferation.

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    Uterus and here the best example is the endometrium, during the cycles of the

    endometrium.

    Fallopian tubes and the bladder urothelium (urinary bladder).

    - Bone marrow cells, which keep producing WBCs, RBCs and platelets.

    Stable cells ( Quiescent cells ) , these cells remain is a stable-like condition

    until it is activated , so they dont normally proliferate or regenerate until the

    insult of an activators , which bring them to action , and enter the cell cycle and

    proliferate .

    The main examples of these cells:

    - The liver, pancreas and Kidney, which we call them The solid organs . And all

    these organs can be transplanted.

    - Smooth muscle, endothelial cells and fibroblasts.

    Permanent, nondividing cells.

    There are two important examples of these cells:

    - Cardiac muscle and Neurons. And that explains why somebody how had

    myocardial infarction will have fibrous scaring, and this fibrous scaring will lead to

    eventually to impairment of the heart function and cardiac failure. In the same

    way, any injury to the brain or to the peripheral nerves, this will lead to

    permanent damage.

    However, there is some exceptions, because there is some ways so that we can

    use the stem cells of the people and inject them, so that they can begin

    proliferation.

    And this is of course a great hope because if we use the stem cells, and their roll

    in treatment and management of different diseases that are not to be treated at

    all.

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    The cell cycle

    We know that there is a multiple steps in the cell cycle where it get activated and

    the DNA replication followed by mitosis , we call it a cell cycle .

    And you know there are certain phases of this cell cycle. Here we have the G0,

    which the cell is nondividing. Cells in liver or kidney can get activated and enter

    the cycle again. So we have the G1 phase which is the pre-synthetic phase, then it

    will move to DNA duplication phase, followed by the pre-mitotic phase and then

    the mitotic phase (mitosis).

    The permanent cells like the cardiac or the neuronal cells they will reside here

    without any chance to get the cycle again unless there are some specific

    conditions, but in general they are resident cells or permanent cells.

    So, if you have cell cycle like working all around the hour this of course will lead to

    proliferation, continuous proliferation, so we need to have some sort of

    regulators that regulate the cell growth itself, where to start proliferation and

    growth and where to stop. On the other hand there are some cells which might

    get some defects in DNA and this abnormal DNA if you let it go through the cycle

    and continues its replication; this will lead to the formation of abnormal cells, so

    we need to stop these cells.

    So through this cycle there are some sorts ofcheck points like the police check

    points, so we call it in this stage restriction points. And you see here in the picture

    below (or in the figure page 61 3-3) the centrosome duplication in the G1

    restriction point. The another check point called G2 check point. So if you

    understand this you can understand thing related to tumor and cancer.

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    G1 pre-synthetic growth phase, when there is growth there is increase in the

    mass.

    The S phase is responsible for DNA synthesis.

    The G2 is the pre-mitotic phase of growth.

    The last is the M which is the mitotic phase, where the mitosis takes place.

    The G0 is stable and has the stable cells where they remain stable, whereas the

    permanent cells do not enter to the cell cycle.

    Here are the cell cycle landmarks slide#15, at the transition between G1 and S

    phase and the transition between G2 & M phase we have 2 check points, (G1/S)

    check point and the (G2/M) check point. These are points where certain factor of

    activators and inhibitors of the cell cycle act. The inhibitors had a role in stopping

    the proliferation in stopping the cell cycle at any of these check points to allow for

    replacement of any damage DNA Material or any other sort of damage to be

    replaced and if the cells are able to replace the damage, it can reenter into the

    cell cycle again if stimulated to enter the cells cycle so remember we have 2 check

    points.

    So again as u can see in the

    figure, in the cell we have G0,

    G1, S, G2, and M phases we

    mean by the Ggrowth phase.

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    Stem cells

    They are the progenitor cells for different types of tissues and they can

    proliferate and produce different types of tissues according to their subtype and

    they have these characteristics they are capable of self renewal and capable ofreplication that is called asymmetric replication and they have the capacity to

    develop into multiple tissues, multiple regions with extensive proliferate

    potentials.

    Stem cells have important characteristics. You hear a lot about it in treatment of

    myocardial infarction, in treatment of spinal cord injury, treatment some difficult

    immunological diseases and that by transplant.

    [Slide#16], Stem cells have Self renewal capacity and Asymmetric replication. and

    we mean by asymmetric replication that after each cell division, some progeny

    enter a differentiation pathway, while others remains undifferentiated , and this

    is 1 of characteristics of the stem cells .

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    The other characteristic is Capacity to develop into multiple lineages, so u can

    have 1 kind of stem cell and it can differentiate to different directions. And of

    course it has Extensive proliferative potential.

    Now we can divide them into embryonic stem cells which are Pluripotent cellsthat can give rise to all tissues of the body. And thats 1 of the important things

    now is to have the Umbilical cord blood , just directly after giving birth .

    If later we have diabetes we can use these his own umbilical stem cells , and if

    he has e.g. spinal cord injury he can use his own umbilical stem cells to regenerate

    from spinal cord cell injury or he had like cardiac infarction.

    On the other hand there is what we call adult stem cells, they have a big

    differentiation capacity, and however bone marrow and some adult tissue have a big

    and better differentiation capability than others . And those who do fat liposuction,

    You know to reduce weight, they take out the fat from the body, they take out the

    adipose tissue; and this adipose tissue contains a few stem cells but still contains stem

    cells and accumulation of these fats in the human body could cause certain diseases like

    myocardial infarction.

    So what is the impact of embryonic stem cells on medicine??

    y

    It helps in studying of a specific signaling and differentiation steps in the process,

    and in many various researches.

    y also it is used in the production of a knockout mice

    y Potentially in therapeutic cloning which is the generation of a specific cell types

    to regenerate damaged tissue in our bodies . There has been a lot of problems

    about this subject CLONING as you all know, ethical problems and other things

    but it happened to be accepted in specific trials of cloning, and I say specific ones

    scientifically, a lot of talk going on about this subject and we will not discuss morethan this

    y Another point is the differentiation plasticity, it means the ability of stem cells to

    go into different directions of differentiation and also what we call the

    transdifferentiation of stem cells which led to revolution in current medicine in

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    what we call the regenerative medicine; in which they can produce and heal

    different types of tissues and organs.

    To the next slide, slide #18 and we have here the steps of therapeutic cloning, so we

    have the patient cell here in the left top of the slide and on the right we have theenucleated cell as we took the nucleus out of this cell, after that we emerge the nucleus

    of our patient cell into the other cell and this will lead to the formation of blastocyst-

    nuclear transfer blastocyst- these usually have the nucleus of the patient and thus have

    all the chromatin, the DNA material, transcription factors .. Etc.

    When you dissolve or disassociate these blastocyests into embryonic stem cell, and

    you can use these stem cells in treatment of various life diseases, you can get them into

    more directions of differentiation either in vivo or in vitro.

    In vivo means injecting these stem cells in the patient himself.

    In vitro means in the labs in certain cultures for studying and conducting a research. so

    these stem cells can differentiate into blood cells or into neurons or even into muscle

    cells this is really a great achievement in my opinion; because as you know if a neuron

    was degenerated due to some kind of disease, we cant fix the problem by any type of

    drugs . Otherwise we fix it or try to fix through this important process of regeneration.

    Now we look at the locations of stem cells in our body, for example here (in the

    picture below) the epidermis as you can see here is the hair follicle and here is the bulb

    and in the hair follicle bulge itself you can find the stem cells, they usually regenerate

    and differentiate.

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    .. in the right picture of slide 19 >> you can see the goblet cells and the Paneth cells

    and in between you can find the Crypt cells (the stem cells) and this is very important.

    The next slide is a picture of the liver and you if you look to the right picture you will find

    stem cells in the top the corneal cells (the stem cells) right between the Cornea andthe Conjunctiva.

    So there are some examples here in the next slide of adult stem cells.

    1. The hematopoietic stem cells in the bone marrow

    2. The herring canal in the liver

    3. Skeletal muscles have stem cells though, they are few but still present and called

    Satellite cells, this one is important.

    4.

    The intestine has the Crypt cells.

    5. The skin has the hair follicle bulge in contrast.

    Now the cell cycle has to have some regulators, Cyclins are regulators of the cell

    cycle, these cyclins are proteins-family proteins- that control the entry of the cell at

    specific stages in the cell cycle, we call this cell cyclins, you got it?? cyclins from cycle.

    How do cyclins regulate the cell cycle??

    Now a specific cyclin level rises at a specific stage of the cycle and after the cell departs

    this stage, the cyclin level decreases rapidly in order to accomplish their function and to

    let the cycle continues as it is suppose to .. These cyclins have to bind to cyclin-

    dependent kinases (CDKs), so now we have complex of cyclin and CDK ok!! They have to

    be combined together to get the job done- to make their actions on the signaling

    process.

    Different combinations are associated with each phase of the cell cycle, and these

    combinations are necessary for each cycle as we will see, they exert their functions by

    phosphorylating of another proteins called the -kinase phosphorylate proteins- we havean example of this is the cyclin B-CDK1, so it is a cyclin with cyclin-dependent kinase 1,

    this cyclin activate the transition from the G2 phase to the M phase -the mitotic phase-.

    Another example here is the cyclin D-CDK4,6 a cyclin with cyclin-dependent kinase 4,6

    which activates the transition from the G1 phase to the S phase. A lot of details of this

    subject I will not go throw because you will do these details in Neoplasia.

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    So one of the most important cell cycle regulating Genes is the RB Gene one of the

    big discoveries of the century in this field . And its action, its way of control actually

    gives us an insight or as a prototype of how these profactors, suppressers, activators

    and regulators act on each other. now this diagram in slide #25 is very important for you

    to understand, it implies how the RB is in its activated form which is the

    hypophosphorylated RB and it interacts with some certain proteins and you can see how

    the Growth Factors and the Growth Inhibitors act on this process on the function of the

    RB.

    This diagram is really from the Neoplasia section not from the repair and you go back

    home and look at it, study it and I will go throw it again and give examples.

    Thank you..

    FINISHED

    Forgive us if there are any mistakes, we did our best, but this job is really very

    hard, we hope that U all appreciate our efforts

    Enjoy studying

    DONE BY: Yousef Odeh

    Deeb Zahran

    Hamza B. Younis

    Malik Al- Houranie