Mechanosensory Pathways in Angiocrine Mediated Tissue Regeneration - Mechanical and Chemical Signaling in Angiogenesis - page 20

restoration of the function of damaged or diseased organs remains to be elucidated.
This chapter focuses on the role of paracrine (angiocrine) factors derived from
sinusoidal endothelial cells (SECs) on initiating hepatic regeneration, and the
impending role of biomechanical forces in triggering this angiocrine-mediated
regeneration process.
2 Organ Regeneration
Restoration of tissue upon injury or physical loss occurs through the processes of
repair, remodeling, and regeneration. While repair and remodeling generally
restore tissue continuity by synthesizing extracellular matrix (ECM) proteins and
forming scar tissue, regeneration resolves the same issue by recovering the missing
organ mass at the original anatomical site.
Three different strategies potentially lead to organ regeneration. Non-dividing
cells from the injured organ begin to multiply and grow to resynthesize the lost
tissue. Specialized cells dedifferentiate into multipotent cells that replicate, re-
specialize and replace the missing tissue. Lastly, pools of stem cells can divide and
regenerate the lost tissue. The molecular and cellular pathways that regulate
regeneration of adult organs remain largely unknown.
2.1 Liver Regeneration
The liver has a remarkable regenerative capacity and is able to rapidly restore its
original weight and size after surgical resection. Liver regeneration is orchestrated
by a complex interplay of cytokines, growth factors, and metabolic pathways
(reviewed by [ 11 , 12 ]). The ''blood flow'' theory, proposed over 50 years ago,
suggested increased mechanosensory cues caused by increased blood flow to the
liver post-partial hepatectomy (PH) triggered liver regeneration [ 13 ].
Another theory suggests that following liver damage factors such as Lipo-
polysaccharides (LPSs) are produced by the gut and delivered to the liver via the
portal vein. LPS then activates the Complement system, leading to the production
of anaphylatoxins, complement component 3 (C3a), and complement component 5
(C5a). Both C3a and C5a play a central role in the activation of the Complement
system, a part of the innate immune system, which aids antibodies and phagocytic
cells in clearing pathogens. LPS, C3a, and C5a all participate in the activation of
Kupffer cells, mononuclear phagocytic cells found on the hepatic sinusoids,
through Toll-like receptor 4 (TLR4), C3a receptor (C3aR), and C5a receptor
(C5aR). The activation of Kupffer cells is indispensable in directing liver regen-
eration, namely through the production of TNF-a and IL-6, both of which are
involved in priming the hepatocytes from the quiescent G0 to the G1 phase [ 14 ].
The transition of hepatocytes from G1 to M phases of the cell cycle is promoted by