Starfish Exhibit- ASSET Connections: Organizing Theme
One over-riding theme can be discerned when attempting to connect the basic life science
concepts presented in the ASSET modules with the CSC Tissue Engineering exhibit. In
many ways, tissue engineering appears to be an attempt at understanding and applying
developmental processes to human health. In essence, answers to one of the most
profound questions in life science are sought, in hopes of manipulating the biology of
patients to restore function of compromised tissues. The defining question appears to be:
“How does a single egg cell eventually develop into a multicellular organism (in this
case, human)?” This question can be broken down into a number of more specific and
detailed questions. The following diagram should help clarify these crucial questions and
developmental phenomena.
Three basic cellular phenomena provided the basis for the development of a multicellular
organism. The first, and most obvious, is proliferation. The egg cell undergoes mitosis,
producing a two-celled embryo. Further mitotic divisions ultimately generate the vast
majority of cell populations of the adult human.
However, students often interpret mitosis as a form of cellular cloning, assuming
that resulting daughter cells represent identical copies (clones) of the original parent cell.
If this were always the case, one is left with a puzzle. Why would not the late embryo,
indeed even the adult, simply be a non-descript ball of “identical” cells? Clearly, the
embryo and adult possess markedly different cells. In fact, entire areas of the embryo or
adult appear to be quite different in both structure and function. These tissues, organs,
and organ systems must have arisen from the original egg, but how? Proliferation must
be accompanied by another process, one that changes cell structure and function. This
critical and highly researched process is known as differentiation. One interesting
subset of differentiation processes includes apoptosis, the technical term for programmed
cell death. Although cell death is a necessary phenomenon within the adult, a more
apparent role can be seen in embryological development. Holes, including the mouth and
eye socket, are partly created by finely synchronized apoptosis of particular cell
populations. Webbed fingers or toes are striking, and relatively harmless, examples of
improper apoptotic events. Fascinatingly enough, apoptosis appears to be a powerful
defense against aberrant cell populations within the adult. Damaged cells, especially
those with significant chromosomal or gene alterations, activate an apoptosis mechanism,
effectively preventing further mutation which might threaten the body with cancer. It
stands to reason that metastatic cancer has somehow evaded activating this apoptosis
defense mechanism (one of the defining features of cancer), providing researchers with
more clues and potential therapeutic targets.
A more subtle, yet vital, process is also at work through the course of
development. Populations of cells, whether proliferating or differentiating, often must
organize spatially to assemble a proper functioning unit. This often involves cell
movements (migrations), which promote the 3-dimensional assemblage of tissues and
organs and their appropriate anatomical position. Clearly this process, when disturbed,
can result in serious medical consequences. Examples include a host of congenital
defects, and even the dreaded metastatic (colonizing) ability of cancers.
The above three basic cellular behaviors share at least two common molecular
mechanisms. Basically, the processing of cellular information controls each of these cell
phenomena.
1. Cells have an inherent set of instructions that largely determines their fate.
This vast set of internal information is in the form of DNA, the nucleic acid portion of
chromosomes. The information encoded within DNA can be subdivided into two types,
structural and controlling elements.
The structural elements, known as genes, encode information leading to the
formation of essential molecules called proteins. Proteins vary dramatically in function,
serving as structural components of cells and cell environments (extracellular matrix, or
ECM), immune modulators, transport or trafficking components, signaling (information)
molecules, and biological catalysts (enzymes). Simply stated, all organisms can be
defined by their proteins and the processes that result through the action of proteins.
Controlling elements of DNA serve to determine or influence gene expression.
That is, they allow particular genes to be ‘read’ and their function to be expressed
through the production of specific gene products known as proteins. Because DNA is
recognized as the ‘code of life,’ understanding the expression of that code is considered
one of the most important challenges in biology or any field of science.
2. Cells are also exposed to external, or environmental, forms of instructions. The
immediate environment of a cell often contains molecules that can alter gene expression.
Certainly, many of these molecules arrived from a more distant source, most likely other
cells. These signaling (communicating) molecules are of paramount importance in both
development and in the maintenance of the adult body. Clearly, the many cell
populations in the adult body must somehow cooperate to achieve homeostasis, or proper
physiological balance. Signaling molecules known as hormones, cytokines,
neurotransmitters, and growth factors are responsible for much of the physiological
balance so characteristic of the adult body. Similarly, developmental processes must also
be synchronized, ordered, and balanced to achieve success. Researchers continue to
investigate the role and mode of action of these signaling molecules in altering gene
expression and subsequent cell behavior.
Having established the basic process and controls of development, the connection
to tissue engineering becomes apparent. Consider just an attempt at engineering, or
fabricating, a single organ such as a bone for therapeutic intervention. Certainly, one
could imagine trying to combine the appropriate materials without considering
embryological development. However, it is tempting to recall that all of us successfully
built (developed) that bone. In addition, our bodies have a limited ability to regenerate
bone upon injury or disease. Regeneration can be thought of as a more limited aspect of
the developmental program. Considering this, a more complete understanding of
developmental and regenerative processes should serve to improve any tissue engineering
venture.
How was a particular bone created in the normal developmental process? What
questions about that process might provide valuable clues? One approach to generating
an appropriate group of questions relates to the tissue engineering triangle: cells,
scaffolds, and signals.
What cells originally developed into bone during normal embryonic processes?
What cells serve to regenerate bone in the adult? The answer to the first question can be
simplified by considering that all tissues ultimately derived from a collection of early
embryonic cells. By definition, these cells, known as embryonic stem cells, must be
pluripotent. However, it is also recognized that collections of pluripotent cells exist in
an adult, for some populations of cells must continually be replenished. These adult
stem cells and their progeny represent a microcosm or vestige of earlier embryonic
pathways. Pluripotent adult cells capable of developing into bone have been found in
bone marrow, muscle compartments, and other areas.
Scaffolds can be thought of as a mimic of the physiologic environment that serve
to promote proper cell proliferation, differentiation, and especially organization. Cell
migrations, cell-cell interactions, and cell-ECM interactions often are greatly influenced
by the local environment. Researchers continue to investigate the ECM’s found in
normal embryonic processes, as well as those present in healthy or compromised adult
tissues. A clearer understanding of these cellular environments should greatly facilitate
the fabrication of successful TE scaffolds.
The third component of the TE triangle highlights perhaps the most important
question of all. How do cells, having arisen through repeated mitotic events, eventually
change in structure and function? In normal development and in tissue regeneration,
mitotic processes provide a mechanism for expanding the cell population size. Mitosis
results in the dissemination of equivalent genomes to daughter cells. In simpler terms,
each cell has the same basic information kit (DNA). How then can different cells be
generated in these developmental pathways? Clearly, different genes must be activated
(expressed) or deactivated. But how is this controlled? Could the cell divisions
themselves partition internal signals differently? This certainly occurs at some points in
normal embryological processes. However, external (physiological environment) signals
are thought to play the dominant role in most development and adult regeneration
pathways. Signaling molecules can have profound influences on cell behaviors,
including proliferation rate, migration, and differentiation. Various growth factors have
been implicated in tissue development, regeneration, and maintenance. Scientists
continue to explore their role in development and regeneration, attempting to elucidate
the mechanism by which they alter gene expression. Tissue engineers continue to reap
the rewards of this research, identifying specific growth factors that can influence
migration, proliferation, and differentiation. They also continue to examine the
appropriate timing and localization of growth factors within tissue engineered constructs,
in hopes of more effectively controlling cell populations.
In summary, embryonic cells have the ability to proliferate, migrate, organize, and
differentiate, leading to the development of a multicellular, balanced organism.
Researchers recognize that cells display these abilities due to an innate program of
instructions (DNA) which is influenced primarily by cellular environment information
(signaling molecules). Similar developmental processes on a smaller scale permit
continual replenishment and/or regeneration of cell populations in the adult. Tissue
engineers attempt to apply their understanding of developmental processes in
regenerative medicine projects. They hope to provide appropriate pluripotent stem cells
with a biomimetic scaffold and growth factors, in a sense recreating the physiological
environment found in embryos or regenerating adult tissue. It is hoped that these cells
will then restore both the natural cell population and ECM characteristic of the intended
targeted tissue.