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Cell Death and Cell Renewal

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Title: Cell Death and Cell Renewal


1
Cell Death and Cell Renewal
17
2
17 Cell Death and Cell Renewal
  • Chapter Outline
  • Programmed Cell Death
  • Stem Cells and the Maintenance of Adult Tissues
  • Embryonic Stem Cells and Therapeutic Cloning

3
Introduction
  • Cell death and cell proliferation are balanced
    throughout the life of multicellular organisms.
  • Animal development involves not only cell
    proliferation and differentiation but also cell
    death.
  • Most cell death occurs by a normal physiological
    process of programmed cell death.

4
Introduction
  • In adult organisms, cell death must be balanced
    by cell renewal.
  • Most tissues contain stem cells that can replace
    cells that have been lost.

5
Programmed Cell Death
  • Programmed cell death is carefully regulated.
  • In adults, it balances cell proliferation and
    maintains constant cell numbers.
  • It also eliminates damaged and potentially
    dangerous cells.

6
Programmed Cell Death
  • During development, programmed cell death plays a
    key role by eliminating unwanted cells from a
    variety of tissues.

7
Programmed Cell Death
  • Necrosis Accidental cell death from acute
    injury.
  • Apoptosis Programmed cell death an active
    process.
  • Characterized by
  • DNA fragmentation
  • Chromatin condensation
  • Fragmentation of the nucleus and cell

8
Figure 17.1 Apoptosis
9
Programmed Cell Death
  • Apoptotic cells and cell fragments are recognized
    and phagocytosed by macrophages and neighboring
    cells, and are rapidly removed from tissues.
  • Necrotic cells swell and lyse the contents are
    released into the extracellular space and cause
    inflammation.

10
Programmed Cell Death
  • Apoptotic cells express eat me signals, such as
    phosphatidylserine.
  • In normal cells, phosphatidylserine is restricted
    to the inner leaflet of the plasma membrane.

11
Figure 17.2 Phagocytosis of apoptotic cells
12
Programmed Cell Death
  • Studies of C. elegans by the Robert Horvitz lab
    identified three genes with key roles in
    apoptosis.
  • C. elegans development includes the death of 131
    specific cells.
  • Their experiments used mutant strains in which
    the cell death did not occur.

13
Key Experiment 17.1 Identification of Genes
Required for Programmed Cell Death
14
Programmed Cell Death
  • The genes ced-3 and ced-4 were required for
    developmental cell death.
  • A third gene, ced-9, functioned as a negative
    regulator of apoptosis.
  • These genes are the central regulators and
    effectors of apoptosis that are highly conserved
    in evolution.

15
Figure 17.3 Programmed cell death in C. elegans
16
Programmed Cell Death
  • Ced-3 is the prototype of a family of proteases
    known as caspases.
  • Caspases have cysteine (C) residues at their
    active sites and cleave after aspartic acid (Asp)
    residues in their substrate proteins.

17
Programmed Cell Death
  • Caspases are the ultimate executioners of
    programmed cell death.
  • They bring about the events of apoptosis by
    cleaving 100 different cell target proteins.
  • The activation of an initiator caspase starts a
    chain reaction of caspase activation leading to
    death of the cell.

18
Figure 17.4 Caspase targets
19
Programmed Cell Death
  • Ced-4 and its mammalian homolog (Apaf-1) bind to
    caspases and promote their activation.
  • In mammalian cells, caspase-9 is activated by
    binding to Apaf-1 in a protein complex called the
    apoptosome.
  • Cytochrome c is also required, which is released
    from mitochondria.

20
Figure 17.5 Caspase activation
21
Programmed Cell Death
  • ced-9 in C. elegans is closely related to a
    mammalian gene called bcl-2, which was first
    identified as an oncogene.
  • Bcl-2 inhibits apoptosis. Cancer cells are unable
    to undergo apoptosis.

22
Programmed Cell Death
  • Mammalian cells encode about 20 proteins related
    to Bcl-2, in three functional groups.
  • Some inhibit apoptosis, while others induce
    caspase activation.
  • The fate of the cell is determined by the balance
    of activity of proapoptotic and antiapoptotic
    Bcl-2 family members.

23
Figure 17.6 The Bcl-2 family
24
Figure 17.7 Regulatory interactions between
Bcl-2 family members
25
Programmed Cell Death
  • In mammalian cells, members of the Bcl-2 family
    act at the mitochondria, which play a central
    role in controlling programmed cell death.
  • Cytochrome c is released from mitochondria, which
    triggers caspase activation in the apoptosome.

26
Figure 17.8 The mitochondrial pathway of
apoptosis
27
Programmed Cell Death
  • Caspases are also regulated by a family of
    proteins called the IAP (inhibitor of apoptosis).
  • They either inhibit caspase activity or target
    caspases for ubiquitination and degradation in
    the proteasome.

28
Figure 17.9 Regulation of caspases by IAPs in
Drosophila
29
Programmed Cell Death
  • Regulation of programmed cell death is mediated
    by signaling pathways, some acting to induce cell
    death and others acting to promote cell survival.
  • Many forms of cell stress, such as DNA damage,
    can trigger programmed cell death.

30
Programmed Cell Death
  • A major pathway leading to cell cycle arrest in
    response to DNA damage is mediated by the
    transcription factor p53.
  • Activation of p53 due to DNA damage can also lead
    to apoptosis.

31
Figure 17.10 Role of p53 in DNA damage-induced
apoptosis
32
Programmed Cell Death
  • A major intracellular signaling pathway that
    promotes cell survival is initiated by the enzyme
    PI 3-kinase, which activates Akt.
  • Akt then phosphorylates a number of proteins that
    regulate apoptosis.

33
Figure 17.11 The PI 3-kinase pathway and cell
survival
34
Programmed Cell Death
  • Polypeptides in the tumor necrosis factor (TNF)
    family signal cell death by activating cell
    surface receptors.
  • These receptors directly activate a distinct
    initiator caspase, caspase-8.

35
Figure 17.12 Cell death receptors (Part 1)
36
Figure 17.12 Cell death receptors (Part 2)
37
Programmed Cell Death
  • Programmed cell death can also occur by
    non-apoptotic mechanisms such as autophagy.
  • In normal cells, autophagy provides a mechanism
    for gradual turnover of the cells components by
    uptake of proteins or organelles into vesicles
    that fuse with lysosomes.

38
Programmed Cell Death
  • Autophagy can also be an alternative to apoptosis
    as a pathway of cell death.
  • Autophagic cell death does not require caspases.
  • It can be activated by cellular stress and
    provide an alternative to apoptosis when
    apoptosis is blocked.

39
Programmed Cell Death
  • Some forms of necrosis can be a programmed
    cellular response to stimuli such as infection or
    DNA damage.
  • Regulated necrosis may provide an alternative
    pathway of cell death if apoptosis does not occur.

40
Stem Cells and the Maintenance of Adult Tissues
  • In early development, cells proliferate rapidly,
    then differentiate to form the specialized cells
    of adult tissues and organs.
  • To maintain a constant number of cells in adult
    tissues, cell death must be balanced by cell
    proliferation.

41
Stem Cells and the Maintenance of Adult Tissues
  • Most differentiated cells in adult animals are no
    longer capable of proliferation.
  • If these cells are lost they are replaced by
    proliferation of cells derived from self-renewing
    stem cells.

42
Stem Cells and the Maintenance of Adult Tissues
  • Some types of differentiated cells retain the
    ability to proliferate as needed, to repair
    damaged tissue throughout the life of the
    organism.
  • Fibroblasts in connective tissue can proliferate
    quickly in response to platelet-derived growth
    factor (PDGF) released at the site of a wound.

43
Figure 17.13 Skin fibroblasts
44
Stem Cells and the Maintenance of Adult Tissues
  • Endothelial cells that line blood vessels can
    proliferate to form new blood vessels for repair
    and regrowth of damaged tissue.

45
Figure 17.14 Endothelial cells
46
Stem Cells and the Maintenance of Adult Tissues
  • Endothelial cell proliferation is triggered by
    vascular endothelial growth factor (VEGF), which
    is produced by cells that lack oxygen.

47
Figure 17.15 Proliferation of endothelial cells
48
Stem Cells and the Maintenance of Adult Tissues
  • The epithelial cells of some internal organs are
    also able to proliferate to replace damaged
    tissue.
  • Liver cells, normally arrested in the G0 phase of
    the cell cycle, are stimulated to proliferate if
    large numbers of liver cells are lost (e.g., by
    surgical removal).

49
Figure 17.16 Liver regeneration
50
Stem Cells and the Maintenance of Adult Tissues
  • Stem cells are less differentiated, self-renewing
    cells present in most adult tissues.
  • They retain the capacity to proliferate and
    replace differentiated cells throughout the
    lifetime of an animal.

51
Stem Cells and the Maintenance of Adult Tissues
  • The key property of stem cells
  • They divide to produce one daughter cell that
    remains a stem cell and one that divides and
    differentiates.

52
Figure 17.17 Stem cell proliferation
53
Stem Cells and the Maintenance of Adult Tissues
  • Many types of cells have short life spans and
    must be continually replaced by proliferation of
    stem cells
  • These include blood cells, sperm, and
    epithelial cells of the skin and lining the
    digestive tract.

54
Stem Cells and the Maintenance of Adult Tissues
  • Hematopoietic (blood-forming) stem cells were the
    first to be identified.
  • There are several distinct types of blood cells
    with specialized functions erythrocytes,
    granulocytes, macrophages, platelets, and
    lymphocytes all derived from the same population
    of stem cells.

55
Figure 17.18 Formation of blood cells
56
Stem Cells and the Maintenance of Adult Tissues
  • Epithelial cells that line the intestines live
    only a few days before they die by apoptosis.
  • New cells are derived from the continuous but
    slow division of stem cells at the bottom of
    intestinal crypts.

57
Figure 17.19 Renewal of the intestinal
epithelium (Part 1)
58
Figure 17.19 Renewal of the intestinal
epithelium (Part 2)
59
Figure 17.19 Renewal of the intestinal
epithelium (Part 3)
60
Stem Cells and the Maintenance of Adult Tissues
  • Skin and hair are also renewed by stem cells.
  • The epidermis, hair follicles, and sebaceous
    glands are all maintained by their own stem cells.

61
Figure 17.20 Stem cells of the skin
62
Stem Cells and the Maintenance of Adult Tissues
  • Stem cells also play a role in the repair of
    damaged tissue.
  • Skeletal muscle normally has little cell
    turnover, but it can regenerate rapidly in
    response to injury or exercise.
  • Regeneration is mediated by proliferation of
    satellite cellsthe stem cells of adult muscle.

63
Figure 17.21 Muscle satellite cells
64
Stem Cells and the Maintenance of Adult Tissues
  • Most adult tissues have stem cells, which reside
    in distinct microenvironments or niches.
  • Niches provide the environmental signals that
    maintain stem cells throughout life and control
    the balance between self-renewal and
    differentiation.

65
Stem Cells and the Maintenance of Adult Tissues
  • Adult stem cells have potential utility in
    clinical medicine.
  • Hematopoietic stem cell transplantation (or bone
    marrow transplantation) plays an important role
    in the treatment of a variety of cancers.

66
Figure 17.22 Hematopoietic stem cell
transplantation
67
Stem Cells and the Maintenance of Adult Tissues
  • Epithelial stem cells are also used in the form
    of skin grafts to treat burns, wounds, and ulcers.

68
Embryonic Stem Cells and Therapeutic Cloning
  • Embryonic stem cells can be grown indefinitely as
    pure stem cell populations that have
    pluripotencythe capacity to develop into all of
    the different types of cells in adult tissues.
  • Thus there is enormous interest in embryonic stem
    cells for both basic science and clinical
    applications.

69
Embryonic Stem Cells and Therapeutic Cloning
  • Embryonic stem cells were first cultured from
    mouse embryos in 1981.
  • Mouse embryonic stem cells are an important
    experimental tool
  • They can be used to introduce altered genes into
    mice.
  • They provide an outstanding model system for
    studying the molecular and cellular events
    associated with cell differentiation.

70
Figure 17.23 Culture of mammalian embryonic stem
cells
71
Key Experiment 17.2 Culture of Embryonic Stem
Cells
72
Embryonic Stem Cells and Therapeutic Cloning
  • Human embryonic stem cell lines were first
    established in 1998.
  • Clinical transplantation therapies based on
    embryonic stem cells may provide the best hope
    for treatment of diseases such as Parkinsons and
    Alzheimers disease, diabetes, and spinal cord
    injuries.

73
Embryonic Stem Cells and Therapeutic Cloning
  • Mouse embryonic stem cells are grown in the
    presence of growth factor LIF, which is required
    to maintain the cells in their undifferentiated
    state.
  • If LIF is removed, the cells aggregate and
    differentiate.
  • Stem cells can be directed to differentiate along
    specific pathways by the addition of appropriate
    growth factors.

74
Figure 17.24 Differentiation of embryonic stem
cells
75
Embryonic Stem Cells and Therapeutic Cloning
  • In 1997 Ian Wilmut and colleagues cloned Dolly
    the sheep.
  • Dolly arose by a process called somatic cell
    nuclear transfer.
  • This type of cloning in mammals is a difficult
    and inefficient process.

76
Figure 17.25 Cloning by somatic cell nuclear
transfer
77
Embryonic Stem Cells and Therapeutic Cloning
  • In therapeutic cloning, a nucleus from an adult
    human cell would be transferred to an enucleated
    egg.
  • The resulting embryo could produce differentiated
    cells for transplantation therapy.
  • This would bypass the problem of tissue rejection.

78
Figure 17.26 Therapeutic cloning
79
Embryonic Stem Cells and Therapeutic Cloning
  • Problems to be overcome
  • The low efficiency of generating embryos by
    somatic cell nuclear transfer.
  • Ethical concerns with respect to the possibility
    of cloning human beings (reproductive cloning),
    and with respect to the destruction of embryos.

80
Embryonic Stem Cells and Therapeutic Cloning
  • These technical and ethical difficulties may be
    overcome by using induced pluripotent stem
    cellsreprogramming somatic cells to resemble
    embryonic stem cells.
  • The action of only four key transcription factors
    is sufficient to reprogram adult mouse somatic
    cells.

81
Figure 17.27 Induced pluripotent stem cells
82
Embryonic Stem Cells and Therapeutic Cloning
  • Adult human fibroblasts can be reprogrammed to
    pluripotency by a similar procedure.
  • Although problems remain, induced pluripotent
    stem cells may someday be used for
    patient-specific transplantation therapy.
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