Biomedical Engineering Reference
In-Depth Information
exhibit multipotent capabilities. The hematopoietic stem cells of the bone marrow have
been widely studied and are known to create the cellular components of blood. The bone
marrow also contains a rare population of so-called mesenchymal stem cells. These are
isolated based on their ability to adhere to culture substrates, which distinguishes them
from other cell types in the marrow, including hematopoietic stem cells. The source and fate
of these cells is an active topic of discussion, and these cells are sometimes referred to as
bone marrow stromal cells. A number of other adult tissue have also yielded multipotent
progenitor and stem cells, including blood (endothelial progenitor cells), fat (adipose stem
cells), brain (neural stem cells), and heart (cardiac stem cells). Putative stem cells also have
been identified in the stroma of the umbilical cord, as well as in amniotic fluid. Not all
researchers agree that each of these cell types is a true stem cell, but the potential for
pluripotent and multipotent stem cells to impact tissue engineering is great.
6.2.5 Stem Cell Aging
Telomerases, DNA Stability, and Natural Cell Senescence
When linear DNA is replicated, the lagging strand is synthesized discontinuously
through the formation of the so-called Okazaki fragments. The last fragment cannot be
initiated, and therefore the lagging strand will be shorter than the leading strand. Linear
chromosomes have noncoding repeating sequences on their ends that are called telo-
meres. These telomeres can be rebuilt using an enzyme called telomerase. Telomerase is
a ribonucleoprotein DNA polymerase that elongates telomeres. When expressed, telome-
rase maintains the telomere length in growing cells. The telomere hypothesis implicates
short telomere length and telomerase activation as critical players in cellular immortaliza-
tion.Thisenzymeisactiveinmicroorganisms, in stem cells, and in transformed deriva-
tives of stem cells (i.e., tumor cells). Commitment of stem cells toward their unipotent
descendants results in the loss of telomerase activity. Thus, normal somatic cells lack
this activity, and the telomeres are shortened by about 50 to 200 bp per replication.
This shortening gives rise to the so-called mitotic clock. The length of the telomeres
is about 9 to 11 kbp, and when it reaches about 5 to 7 kbp, the chromosomes become
unstable and replication ceases (Figure 6.11). This mechanism is believed to underlie the
Hayflick limit.
Telomerase activity is found in somatic hematopoietic cells but at a low activity level.
There is evidence that telomeres in immature hematopoietic cells do shorten with ontogeny
and with increased cell doublings in vitro. The rate of telomere shortening in stem cells is
finite, but it may be slower than in other somatic cells. Numerical evaluation of the conse-
quences of stem cell aging strongly suggests that there has to be some form of self-renewal
of stem cells in adults (see Exercise 1).
6.2.6 Tissue Dynamics
Tissues are comprised of many different cell types of various developmental origins
(Figure 6.12). The dynamic behavior of cells and their interactions determine overall tissue
formation, state, and function. The activities of individual cells are often substantial.
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