Mechanosensory Pathways in Angiocrine Mediated Tissue Regeneration - Mechanical and Chemical Signaling in Angiogenesis - page 38

Fig. 11 Id-1-mediated induction of Wnt2 and HGF in LSECs stimulates hepatic regeneration.
a Upregulation of HGF and Wnt2 is impaired in Id1 -/- LSECs after partial hepatectomy (n = 5).
b Intrasplenic transplantation of GFP-marked Id1 -/- LSECs carrying both Wnt2 and HGF
(Id1 -/- Wnt2 + HGF + GFP + ) rescues the regeneration of Id1 -/- liver mass (n = 4). *P \ 0.05;

**P \ 0.01. Error bars, SEM

liver vasculature by intra-splenic transplantation. Only Id1 -/- LSECs carrying
both Wnt2 and HGF (Id1 -/- Wnt2 + HGF + ) restored the regeneration of mass and
liver SEC expansion in the Id1 -/- liver (Fig. 11 b), which suggests a collaborative
effect between HGF and Wnt2. Therefore, Id1-activated LSECs through Wnt2 and
HGF synthesis induce proliferation of juxtaposed hepatocytes (Fig. 12 ).
In the PH study, we have used conditional VEGFR2 knockout, Id1 -/- mice, and
an endothelial cell transplantation model to recognize the essential angiocrine role of
a specialized organ-specific vascular niche cell in orchestrating physiological liver
regeneration. Similar to upregulation of Id1 in the angiogenic tumor vessels, Id1
expression is minimal in normal LSECs, but after activation of VEGFR2 induces
exclusive upregulation of Id1 in the angiogenic LSECs. In the first 3 days after partial
hepatectomy, activation of the VEGFR2-Id1 pathway switches on an inductive
angiogenesis program in non-proliferative VEGFR3 + CD34 - VEGFR2 + Id1 + LSECs.
Through production of angiocrine factors Wnt2 and HGF, this program provokes
hepatic proliferation. Subsequently, as the regenerating liver demands additional
blood supply, VEGFR2-Id1-mediated proliferative angiogenesis of LSECs recon-
stitutes hepato-vascular mass. Therefore, we introduce the concept that SECs support
liver regeneration through a biphasic mechanism: at the early phase immediately
after partial hepatectomy, inductive angiogenic LSECs promote organogenesis
through release of angiocrine factors, whereas proliferative angiogenic LSECs
vascularize and sustain the expanding liver mass.
Our earlier work has shown that transplantation of the Id1 -/- Wnt2 + HGF +
LSECs into Id1 -/- mice initiates and restores liver regeneration. These findings,
and the observation that hepatic proliferation is severely reduced in the VEGFR2