Mechanosensory Pathways in Angiocrine Mediated Tissue Regeneration - Mechanical and Chemical Signaling in Angiogenesis - page 19

hepatocyte proliferation. Physiological liver regeneration would therefore depend
on the proper inductive and proliferative functioning of liver SECs. Thus,
uncovering the cellular mechanisms by which organisms recognize and respond to
tissue damage remains an important step towards developing therapeutic strategies
to promote organ regeneration. In this chapter, we demonstrate the mechanism by
which tissue-specific subsets of endothelial cells promote organ regeneration, and
further discuss the roles of physical forces and molecular signals in initiating and
terminating angiocrine-mediated tissue regeneration.

1 Introduction

Mammalian cells are able to sense, decode, and respond to physical stimuli in a
manner specific to their type. Physical stimuli play a role in virtually all stages of
cell differentiation, as early as embryogenesis—where stiffness and contractility
provide mechanosensory cues to dictate cell proliferation and differentiation
(reviewed in [ 1 ])—to post-natal cranial development [ 2 ]. They also play an
integral role in tissue engineering [ 3 , 4 ] and regeneration [ 5 , 6 ]. For instance, frogs
(Xenopus laevis) during development can only undergo gastrulation, convergence
and extension movements if the mesoderm and notochord maintain their stiffness
and avoid buckling [ 7 , 8 ]. Throughout this rearrangement, the marginal zone
becomes stiffer in order to avoid tissue deformation and collapse during gastru-
lation [ 9 ]. This increased stiffness further provides the mechanical strength that
initiates the following developmental events. Whether these changes also serve as
cues within the mechanosensory pathway to trigger other related cellular processes
is unknown.
Cell contractility is another significant source of mechanical cues. Contraction
of the actomyosin cytoskeleton triggers cellular responses in the contracting cell as
well as external forces on the surrounding cells. The embryogenesis of Xenopus
laevis also appropriately illustrates cellular responses to cell-generated contractile
forces. It has been shown that during gastrulation, cultured explants of the dorsal
involuting and non-involuting marginal zones of frog embryo, neither of which are
subjected to external forces, converge and expand. This study suggests that tissue
movement related to gastrulation is dictated by the tissue itself, rather than by
surrounding external forces [ 10 ].
Mechanotransduction plays an important role in the signaling of endothelial
cells because of their unique position in the blood vessel lumen. Endothelial cells
have direct contact with blood and so can first sense changes in shear stress caused
by alterations in flow rate. It is well known that endothelial cells perceive and
respond to blood flow by undergoing a series of molecular changes, including
expression of various transcription factors. These molecular alterations guide cell
differentiation and may drive tissue regeneration. Nevertheless, the role of bio-
mechanical

forces in orchestration of tissue regeneration and subsequent