Synthetic Morphogens and Pro-morphogens for Aided Tissue Regeneration - Biologically Responsive Biomaterials for Tissue Engineering - page 45

A second condition to be fulfilled to generate spatial patterns during
embryogenesis is robustness. This means that the distribution of morphogens
must be reproducible and provide a reliable signalling regardless of the occur-
rence of other processes that can alter their distribution [ 10 ] . For example, the
same morphogen binding sites of the extracellular matrix (ECM) can be altered,
thus becoming a hindrance to the regular diffusion of these molecules [ 11 ] . It has
been calculated that the complex geometry of the ECM can increase the diffusion
times of morphogens as much as fivefold [ 12 ]; this tortuous space also contributes
to the generation of local variations in the morphogen gradient. In summary, mor-
phogen diffusion will depend on the three-dimensional structure of the tissue as
well as on the density and complex topology of cell-to-cell contacts. Indeed, sol-
uble morphogens can bind to cell-surface receptors and be internalised by a pro-
cess called endocytosis [ 1 ] .
The interaction between morphogens and cells is not only limited to the
biospecific recognition mediated by receptors. The need for morphogens to play a
role as positional cues requires a mechanism in the cell that enables the interpreta-
tion of a given concentration within the gradient (Fig. 3.1 ). If the position of a cell
within a tissue is determined by signals at single-cell level, it can be speculated that
morphogen concentration thresholds need to be present so that different genes can
be activated at given morphogen concentration levels. The binding of morphogens
to receptors can also play a role on morphogen distribution as the saturation of the
receptors can block the gradient effect [ 13 ] .
Wolpert et al. [ 14 ] have proposed a model of morphogen gradient response by
the cells in the embryo. In this model, there would be an initial state where all the
cells in a given region are equivalent, but they are all able to enter several pheno-
types. These phenotypes are acquired depending on the space distribution of the
morphogens. With time, the morphogen distribution becomes stable and at this
stage each cell reads the concentration and compares it with a set of threshold to
finally respond only to the signal that is present at the cell location. However, it has
to be outlined that the effect of time on the effectiveness of the morphogen gradient
has not yet been proven.
Other alternative mechanisms and structures that regulate morphogen gradi-
ents have been suggested. For example, during Drosophila development,
cytonemes which are actin-based filopodial extensions appear to be oriented pref-
erentially towards both the anteroposterior and dorsoventral organiser cells and
therefore it has been suggested that they can be involved in the DPP signalling
mechanism [ 1 ] .
Together with cell-to-cell interactions, morphogens have also been indicated as
possible regulators of cell polarity. Indeed, for a tissue to form it is important that cells
can assume polarity, i.e. the ability to acquire directional information. This property is
important for the final structure of the tissue and consequently for its functionality.
It has to be said that it appears improbable that morphogen concentration is the
only factor determining cell fate within the developing embryo. Therefore, morpho-
gens may only be part of the signalling dictating cell fate and position. Cell position
could be more accurately tuned by cell-cell interactions.