Cellular and Molecular Responses to Mechanical Expansion of Tissue

Abstract

The increased use of tissue expander in the past decades and its potential market values in near future give enough reasons to sum up the consequences of tissue expansion. Furthermore, the patients have the right to know underlying mechanisms of adaptation of inserted biomimetic, its bioinspired materials and probable complications. The mechanical strains during tissue expansion are related to several biological phenomena. Tissue remodeling during the expansion is highly regulated and depends on the signal transduction. Any alteration may lead to tumor formation, necrosis and/or apoptosis. In this review, stretch induced cell proliferation, apoptosis, the roles of growth factors, stretch induced ion channels, and roles of second messengers are organized. It is expected that readers from any background can understand and make a decision about tissue expansion.

Keywords: apoptosis; focal adhesion complex; growth factors; ion channels; secondary messengers; tissue expansion.

Figure 1

(A) Effects of tissue expansion on surrounding tissues. (B) Tissue expander before implantation and implanted in rat. Pictures taken from ongoing research in author's lab.

Figure 2

Physiological and cellular response of skin to mechanical stress. It is most likely that mechanical stress beyond the limit of tolerance of elasticity might induce necrosis and/or apoptosis at the cellular level (Modified from Siegert et al., 1993).

Figure 3

Possible signaling pathways activated in response to mechanical stretch. Upon application of forces, extracellular matrix deformed and the plasma membrane altered resulting activation of the ion channel and activate the integrins, G-protein coupled receptors, tyrosine kinase receptors and others membrane bound signaling pathways.

Figure 4

Signaling pathways activated by mechanical stretch leading to either cell proliferation or apoptosis. The integrins organize the cytoskeleton according the physical properties of the extracellular matrix (ECM). The membrane bound ion channels, G-protein, tyrosine kinase receptor and other molecules activate specific pathways to proliferation. In case of apoptosis, receptor-like molecules such as integrins, focal adhesion proteins become activated and these molecules in turn activate a limited number of protein kinase pathways (p38 MAPK, PI3K/Akt, JNK etc.), which amplify the signal and activate enzymes (caspases) that promote apoptosis. Activation of death receptors (Fas and/or TNFR) leads to the formation of a death-inducing signaling complex (DISC), resulting in the cleavage of procaspase-8 to its active form. Caspase-8 in turn activates downstream proteins that lead to apoptosis. Bax, induces the release of cytochrome c from the mitochondria and promotes apoptosis. Moreover, cytochrome c complexes with apaf-1 and procaspase-9 to form an apoptosome. This leads to the activation of caspase-9, which in turn activates effector caspases (3, 6, and 7) and subsequent apoptosis. Among the stretch-activated ion channels, rapid influx of Ca²⁺ activate several pathways including signal transduction cascades leading to cell proliferation, apoptosis, cell contraction, activation of potassium channel. Potassium channels play roles in maintaining optimal membrane potentials. Mechanical forces and calcium influx also open chloride channels which act as apoptotic agents through a delineated mechanism.