Biomedical Engineering Reference
In-Depth Information
gland, and kidney. Although nearly every technique of cellular and developmen-
tal biology has been applied to it (see reviews (3,11)), and a vast amount has
been learned, there is still some uncertainty as to the mechanism of branching.
When I pose the question "What makes an airplane fly?" most people an-
swer with some variation on the theme of lift, i.e., the net force generated by the
balance of flows of air around the object. Rarely does anyone answer that it is
the pilot manipulating the vast number of controls in the cockpit who makes the
airplane fly—though that is an equally correct answer.
When I pose the question "What makes a developing organ branch?" most
biologists answer with a discussion of the switches, not of the forces. Yet just as
we could not understand the airplane without understanding the physical forces
that it generates, and its physical interaction with its environment, we cannot
understand branching morphogenesis without understanding the physical forces
that its tissues generate, and the organ's physical interactions with its environ-
ment.
The next logical step in morphogenesis research is study of the biophysical
and biomechanical aspects, which are what create and modify form (53). This
chapter compares the biomechanical aspects of the currently competing theories
of branching morphogenesis, and suggests new experiments and new interpreta-
tions of old experiments.
It is assumed, though not proven, that the mechanism of morphogenesis is
the same in all the branched organ systems, but that it is differences in gene ex-
pression and protein/polysaccharide/proteoglycan production that cause the
morphological differences. Although the developmental biology of all of these
organs has been widely studied, because of the assumed unity of mechanism,
one organ, the rodent submandibular (salivary) gland, has been studied in the
greatest detail.
The general features of branching morphogenesis in vivo are as follows.
Glandular organs are constructed initially as a disorganized mass of mesenchy-
mal tissue surrounding a finger of epithelium, which has a simple unbranched
shape. Then the finger flattens slightly, and is split into two or more lobules by
the formation of one or more clefts. These new lobules grow as the extracellular
matrix (ECM) around the clefts gets denser and mesenchymal cells condense
around the clefts and the stalks of the lobules (Figure 1). When the young lob-
ules have grown sufficiently larger, there is another branching, in the same fash-
ion, followed by extension and condensation, cleft-grow-cleft-grow, until a
highly branched structure has formed.
The morphological differences between mature glands are substantial, but
differences can be seen at the stage of clefting. For example, the lung branches
only dichotomously, with rounded clefts, whereas the submandibular gland
forms multiple very sharp clefts in each branching lobule. The lung also forms
its dichotomous clefts in nearly orthogonal directions in successive branching
generations. A mature gland is highly structured (62), and can be thought of as
