72
U N I T 1
Cell and Tissue Function
terms of structure and function.
1,2
Stem cells are undif-
ferentiated cells that have the capacity to generate mul-
tiple cell types (to be discussed). In normal tissue the
size of the cell population is determined by a balance of
cell proliferation, death by apoptosis (see Chapter 2),
and emergence of newly differentiated cells from stem
cells
2
(Fig. 4-1). Several cell types proliferate during tis-
sue repair including remnants of injured parenchymal
tissue cells, vascular endothelial cells, and fibroblasts.
The proliferation of these cell types is driven by proteins
called
growth factors
. The production of growth fac-
tors and the ability of these cells to respond and expand
in sufficient numbers are important determinants of the
repair process.
All of the different cell types in the body originate
from a single cell—the fertilized ovum. As the embry-
onic cells increase in number, they differentiate, facili-
tating the development of all the different cells and
organs of the body. The process of differentiation is
regulated by a combination of internal processes involv-
ing the expression of specific genes and external stimuli
provided by neighboring cells, the ECM, and a variety
of growth factors. The process occurs in orderly steps,
with each progressive step being exchanged for a loss
of ability to develop different cell characteristics. As a
cell becomes more highly specialized, the stimuli that are
able to induce mitosis become more limited. Neurons,
which are highly specialized cells, lose their ability to
proliferate once development of the nervous system is
complete. In other, less-specialized tissues, such as the
skin and mucosal lining of the gastrointestinal tract, a
high degree of cell renewal continues throughout life.
Even in these continuously renewing cell populations,
the more specialized cells are unable to divide. Many
of these cell populations rely on
progenitor
or
parent
cells
of the same lineage. Progenitor cells are sufficiently
differentiated so that their daughter cells are limited to
the same cell line, but they have not reached the point
of differentiation that precludes the potential for active
proliferation. Some cell populations have self-renewing
multipotent stem cells, such as the epithelial stem
cells, that can differentiate into the different cell types
throughout life.
The Cell Cycle
In order to understand cell proliferation, whether physi-
ologic (as in tissue regeneration and repair) or patho-
logic (as in cancer), it is important to learn about the
cell cycle, an orderly sequence of events in which a cell
duplicates its genetic contents and divides. During the
cell cycle, the duplicated chromosomes are appropri-
ately aligned for distribution between two genetically
identical daughter cells.
The cell cycle is divided into four distinct phases
referred to as
G
1
, S, G
2
, and
M.
Gap 1 (G
1
) is the post-
mitotic phase during which deoxyribonucleic acid
(DNA) synthesis ceases while ribonucleic acid (RNA)
and protein synthesis and cell growth take place (see
Understanding the Cell Cycle).
1–4
During the
S phase,
DNA synthesis occurs, giving rise to two separate sets
of chromosomes, one for each daughter cell.
G
2
is the
premitotic phase and is similar to G
1
in that DNA syn-
thesis ceases while RNA and protein synthesis continue.
Collectively, G
1
, S, and G
2
are referred to as
interphase
.
The
M phase
is the phase of nuclear division and cyto-
kinesis. Continually dividing cells, such as the stratified
squamous epithelium of the skin, continue to cycle from
one mitotic division to the next. When environmental
conditions are adverse, such as nutrient or growth fac-
tor unavailability, or cells become terminally differenti-
ated (i.e., highly specialized), cells may exit the cell cycle,
becoming mitotically quiescent and reside in a special
resting state known as
G
0
. Cells in
G
0
may reenter the
cell cycle in response to extracellular nutrients, growth
factors, hormones, and other signals such as blood loss
or tissue injury that trigger cell renewal. Highly special-
ized and terminally differentiated cells, such as neurons,
may permanently stay in
G
0
.
Within the cell cycle are checkpoints where pauses or
arrests can be made if the specific events in the phases
of the cell cycle have not been completed. There are also
opportunities for ensuring the accuracy of DNA repli-
cation. These DNA damage checkpoints allow for any
defects to be edited and repaired, thereby ensuring that
each daughter cell receives a full complement of genetic
information, identical to that of the parent cell.
1–3
The
cyclins
are a family of proteins that control the
entry and progression of cells through the cell cycle.
1–4
Cyclins bind to (thereby activating) proteins called
cyclin-dependent kinases
(CDKs). Kinases are enzymes
that phosphorylate proteins. The CDKs phosphorylate
specific target proteins and are expressed continuously
during the cell cycle but in an inactive form, whereas the
cyclins are synthesized during specific phases of the cell
cycle and then degraded once their task is completed.
Different arrangements of cyclins and CDKs are associ-
ated with each stage of the cell cycle. For example, cyclin
B and CDK1 control the transition from G
2
to M. As
the cell moves into G
2
, cyclin B is synthesized and binds
to CDK1. The cyclin B–CDK1 complex then directs the
Tissue
stem cell
Differentiation
Apoptosis
Cell population
Cell proliferation
FIGURE 4-1.
In normal tissues, the size of the cell population
is determined by a balance of cell proliferation, death by
apoptosis, and emergence of newly differentiated cells from
stem cells.
