C h a p t e r 4
Cell Proliferation and Tissue Regeneration and Repair
73
events leading to mitosis, including DNA replication and
assembly of the mitotic spindle. Although each phase of
the cell cycle is monitored carefully, the transition from
G
2
to M is believed to be one of the most important
checkpoints in the cell cycle. In addition to the synthesis
and degradation of the cyclins, the cyclin–CDK com-
plexes are regulated by the binding of CDK inhibitors.
The CDK inhibitors are particularly important in regu-
lating cell cycle checkpoints during which mistakes in
DNA replication are repaired. The finding that the cell
cycle can be reactivated by removing CDK inhibitors in
quiescent and nonproliferating cells has potential impli-
cations for tissue repair and cell replacement therapy.
4
Proliferative Capacity ofTissues
The capacity for regeneration varies with the tissue
and cell type. Body tissues are divided into three types
depending on the ability of their cells to undergo regen-
eration: (1) continuously dividing, (2) stable, and (3)
permanent tissues.
1,2
Continuously dividing
or
labile
tissues are those in
which the cells continue to divide and replicate through-
out life, replacing cells that are continually being
destroyed. They include the surface epithelial cells of
the skin, oral cavity, vagina, and cervix; the columnar
epithelium of the gastrointestinal tract, uterus, and fal-
lopian tubes; the transitional epithelium of the urinary
tract; and bone marrow cells. These tissues can readily
regenerate after injury as long as a pool of stem cells is
preserved. Bleeding, for example, stimulates the rapid
proliferation of replacement cells by the blood-forming
progenitor cells of the bone marrow.
Stable
tissues contain cells that normally stop divid-
ing when growth ceases. Cells in these tissues remain
quiescent in the G
0
stage of the cell cycle. However,
these cells are capable of undergoing regeneration when
confronted with an appropriate stimulus; thus, they
are capable of reconstituting the tissue of origin. Stable
cells constitute the parenchyma of solid organs such as
the liver and kidney. They also include smooth muscle
cells, vascular endothelial cells, and fibroblasts, the pro-
liferation of which is particularly important to wound
healing.
The cells in
permanent
tissues do not proliferate.
The cells in these tissues are considered to be terminally
differentiated and do not undergo mitotic division in
postnatal life. The permanent cells include nerve cells,
skeletal muscle cells, and cardiac muscle cells. These
cells do not normally regenerate; once destroyed, they
are replaced with fibrous scar tissue that lacks the func-
tional characteristics of the destroyed tissue.
Stem Cells
Another type of tissue cell, called a
stem cell,
remains
incompletely differentiated throughout life.
1,2,5
In most
continuously dividing tissues, the mature cells are ter-
minally differentiated and short lived. As mature cells
die the tissue is replenished by the differentiation of cells
generated from stem cells. Stem cells are reserve cells that
remain quiescent until there is a need for cell replenish-
ment, in which case they divide, producing other stem
cells and cells that can carry out the functions of the dif-
ferentiated cell. When a stem cell divides, one daughter
cell retains the stem cell characteristics, and the other
daughter cell becomes a progenitor cell that undergoes a
process that leads to terminal differentiation (Fig. 4-2).
Stem cells are characterized by three important prop-
erties: self-renewal, asymmetric replication, and differ-
ential potential.
1,2
Self-renewal
means that the stem cells
can undergo numerous mitotic divisions while main-
taining an undifferentiated state.
Asymmetric replica-
tion
means that after each cell division, some progeny of
the stem cell enter a differentiation pathway, while oth-
ers remain undifferentiated, retaining their self-renewal
capacity. The progeny of each progenitor cell follows a
more restricted genetic program, with the differentiating
cells undergoing multiple mitotic divisions in the process
of becoming a more mature cell type, and with each gen-
eration of cells becoming more specialized. In this way, a
single stem cell can give rise to the many cells needed for
normal tissue repair or blood cell production.
The term
potency
is used to define the differentia-
tion potential of stem cells.
Totipotent stem cells
are
those produced by a fertilized ovum. The first few cells
produced after fertilization are totipotent and can dif-
ferentiate into embryonic and extraembryonic cells.
Totipotent stem cells give rise to
pluripotent stem cells
that can differentiate into the three germ layers of the
embryo.
Multipotent stem cell
s are cells such as hema-
topoietic stem cells that give rise to a family of cells,
including the red blood cells and all the various types
of leukocytes. Finally,
unipotent stem cells
produce only
one cell type but retain the property of self-renewal.
Dividing stem cell
Stem cell
Progenitor cell
Daughter cells
Differentiated cells
FIGURE 4-2.
Mechanisms of stem cell–mediated cell
replacement. Division of a stem cell with an unlimited potential
for proliferation results in one daughter cell, which retains
the characteristics of a stem cell, and a second daughter cell
that differentiates into a progenitor or parent cell, with limited
potential for differentiation and proliferation. As the daughter
cells of the progenitor cell proliferate they become more
differentiated, until they reach the stage where they are fully
differentiated.
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