Mechanosensory Pathways in Angiocrine Mediated Tissue Regeneration - Mechanical and Chemical Signaling in Angiogenesis - page 30

4.2 Liver Regeneration
Liver regeneration has also been linked to the proliferation of hepatocytes post
partial hepatectomy, which coincides with the secretion of a variety of growth
factors and cytokines, such as interleukin-6 (IL-6), hepatocyte growth factor
(HGF), and tumor necrosis factor (TNF). It has previously been shown that growth
factors and cytokines produced by hepatocytes play an important role in orches-
trating the process of liver regeneration. In fact, it seems both parenchymal cells
(particularly hepatocytes) and nonparenchymal cells (Kupffer cells, SECs, hepatic
stellate cells, and billiary epithelial cells) are involved in producing cytokines for
liver regeneration [ 56 ]. Hepatic SECs are the second most common liver cells after
hepatocytes [ 57 ]. They compose a functionally unique capillary network that
vascularizes organs such as bone marrow and liver. Hepatic SECs play a vital role
in providing nutrients and growth factors to proliferating hepatocytes via the
formation of new vessels during regeneration. Bone marrow SECs in adult mice
support hematopoietic regeneration through expression of specific angiocrine
trophogens, such as Notch ligands [ 58 , 59 ]. The hepatic circulation is also largely
lined by LSECs [ 60 , 61 ], with each hepatocyte dwelling in cellular proximity to
ECs. However, the lack of a suitable definition of liver ECs and scarcity of
relevant mouse angiogenic genetic models [ 14 , 16 ] have hampered studies of the
role of LSECs in regulation of hepatic regeneration [ 62 - 64 ].
As early as 1965, portal venous blood flow has been identified as an important
factor in liver regeneration [ 13 ]. Liver mass is significantly reduced post-PH (due
to liver resection), and the remaining hepatic segments are subjected to increased
portal blood flow and pressure. The earliest and most notable change following PH
is the drastic increase in liver blood flow, with an increase in liver blood flow of up
to 10-fold. Considering that hepatic SECs respond to shear stress and radical
increases in blood flow, hepatic SECs must play a role in the initiation of liver
regeneration.
5 Partial Hepatectomy Model
Recently, we have used a PH model to examine the instructive role of LSECs in
hepatic regeneration (Fig. 3 )[ 65 ]. In this model, resection of 70 % of the liver
mass without perturbing the integrity of the residual liver vasculature activates
hepatocyte regeneration [ 11 , 63 , 66 ]. This method is in contrast to the adminis-
tration of hepatotoxic chemicals, which impair the organization of LSECs and
causes tissue hypoxia, cell death, and inflammation [ 16 , 60 , 67 ]. This approach
offers an instructive model for examining the role of structurally and functionally
intact LSECs in supporting liver regeneration.
Growth factors such as those in the VEGF family play a significant role in the
regeneration of bone marrow SECs [ 68 ]. As such, we hypothesized that two VEGF