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17
Cell Death and Cell Renewal
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
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.
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.
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.
Programmed Cell Death
During development, programmed cell
death plays a key role by eliminating
unwanted cells from a variety of
tissues.
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
Figure 17.1 Apoptosis
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.
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.
Figure 17.2 Phagocytosis of apoptotic cells
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.
Key Experiment 17.1: Identification of Genes Required for Programmed Cell Death
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.
Figure 17.3 Programmed cell death in C. elegans
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.
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.
Figure 17.4 Caspase targets
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.
Figure 17.5 Caspase activation
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.
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.
Figure 17.6 The Bcl-2 family
Figure 17.7 Regulatory interactions between Bcl-2 family members
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.
Figure 17.8 The mitochondrial pathway of apoptosis
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.
Figure 17.9 Regulation of caspases by IAPs in Drosophila
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.
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.
Figure 17.10 Role of p53 in DNA damage-induced apoptosis
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.
Figure 17.11 The PI 3-kinase pathway and cell survival
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.
Figure 17.12 Cell death receptors (Part 1)
Figure 17.12 Cell death receptors (Part 2)
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
cell’s components by uptake of
proteins or organelles into vesicles that
fuse with lysosomes.
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.
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.
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.
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.
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.
Figure 17.13 Skin fibroblasts
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.
Figure 17.14 Endothelial cells
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.
Figure 17.15 Proliferation of endothelial cells
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).
Figure 17.16 Liver regeneration
Stem Cells and the Maintenance of Adult Tissues
Stem cells are less differentiated, selfrenewing cells present in most adult
tissues.
They retain the capacity to proliferate
and replace differentiated cells
throughout the lifetime of an animal.
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.
Figure 17.17 Stem cell proliferation
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.
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.
Figure 17.18 Formation of blood cells
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.
Figure 17.19 Renewal of the intestinal epithelium (Part 1)
Figure 17.19 Renewal of the intestinal epithelium (Part 2)
Figure 17.19 Renewal of the intestinal epithelium (Part 3)
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.
Figure 17.20 Stem cells of the skin
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 cells—the stem
cells of adult muscle.
Figure 17.21 Muscle satellite cells
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.
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.
Figure 17.22 Hematopoietic stem cell transplantation
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.
Embryonic Stem Cells and Therapeutic Cloning
Embryonic stem cells can be grown
indefinitely as pure stem cell
populations that have pluripotency—
the 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.
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.
Figure 17.23 Culture of mammalian embryonic stem cells
Key Experiment 17.2: Culture of Embryonic Stem Cells
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 Parkinson’s and Alzheimer’s
disease, diabetes, and spinal cord
injuries.
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.
Figure 17.24 Differentiation of embryonic stem cells
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.
Figure 17.25 Cloning by somatic cell nuclear transfer
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.
Figure 17.26 Therapeutic cloning
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.
Embryonic Stem Cells and Therapeutic Cloning
These technical and ethical difficulties
may be overcome by using induced
pluripotent stem cells—
reprogramming somatic cells to
resemble embryonic stem cells.
The action of only four key transcription
factors is sufficient to reprogram adult
mouse somatic cells.
Figure 17.27 Induced pluripotent stem cells
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.