Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 684

cell migration depends on a gradient of VEGFa, the followers — stalk cells —
proliferate under the control of VEGFa concentration [ 1394 ]. Selection of tip from
stalk cells results from Delta-like ligand DLL4 and its receptor Notch-1. Ligand
DLL4 is preferentially produced in tip cells that reside close to a high VEGF
concentration. Endothelial cells at tips of new tubes compete for leader positions.
They can suppress the Notch-restricted, tip-cell phenotype of their immediate
neighbors when they synthesize DLL4 and present DLL4 to adjacent migrating
cells [ 1394 ]. Many other primary messengers participate in blood vessel branching
such as guidance molecules (netrins, semaphorins, and slits).

11.3.4.2 Signaling in the Tracheobronchial Tree

In developing lungs, branching is bounded by a volume of mesenchymal tissue.
The bronchial tree indeed develops by branching of the airway epithelium into
a surrounding mesenchyme. Reciprocal feedbacks between the airway epithelium
and surrounding mesenchyme control the normal sequence and three-dimensional
pattern of branching events [ 1392 ].
The branched tree can be generated by a genetically tractable, hierarchical, and
modular program that contains 3 local modes of branching used in 3 different
orders, i.e., at different times: domain branching at the branching onset and planar
and orthogonal bifurcations [ 1392 ]. These branching modes may arise from the
combination of a few elements, i.e., a master branch generator and 3 genetically
encoded slaves that govern the pattern of branching events [ 1392 ]: (1) a domain
specifier; (2) a genetically programmed periodicity generator that determines when
side branches arise; (3) a bifurcator that defines branching loci, i.e., their occurrence
time; and (4) a rotator that directs the bifurcation angle w.r.t. the stem plane. These
branching modules are characterized by their coupling and repetitive occurrence.
A primary conduit constructs branching domains that serve as scaffolds. Branch-
ing arises at different positions directed by the periodicity generator to give rise
to 2 coplanar branches, one of which undergoes domain branching and the other
bifurcates again in a planar manner. Planar bifurcation, i.e., splitting of a branch tip
into 2 branches, generates most ternary and some quaternary branches. Orthogonal
bifurcation involves planar bifurcation with rotation of the bifurcation plane to give
rise to higher-order generations.
Several types of sequences arise according to branching modes [ 1392 ]. In
sequence 1 , a founder branch formed by domain branching uses immediately and
permanently the orthogonal branching mode. In sequence 2 , a founder branch
formed by domain branching utilizes domain branching for some daughter tubes that
then employ permanently the orthogonal branching mode. The founder forms other
daughter ducts by planar bifurcation that themselves undergo planar bifurcation at
their tips to form domain branches along their length. These domain branches switch
permanently to orthogonal bifurcation. Other sequences can be observed.