Implanted Adipose-Derived Stem Cells Attenuate Small-for-Size Liver Graft Injury by Secretion of VEGF in Rats

Abstract

Graft injury after small-for-size liver transplantation impairs graft function and threatens the survival of the recipients. The use of adipose-derived stem cells (ADSCs) for liver injury protection and repair is promising.Our aim was to investigate the role of vascular endothelial growth factor (VEGF) secreted by ADSCs in the treatment of small-for-size liver graft injury. Studies were performed using ADSCs with VEGF secretion blocked by RNA interference. In vitro, ADSCs prevented apoptosis of freshly isolated liver sinusoidal endothelial cells (LSECs) by secretion of VEGF. Syngeneic 35% orthotopic liver transplantation followed by implantation of syngeneic ADSCs through the portal vein system was performed using Wistar rats. We found VEGF secreted by implanted ADSCs improved graft microcirculatory disturbances, serum liver function parameters and survival. The improved microcirculatory status was also reflected by reduced hepatocellular damage, especially LSEC apoptosis and improved liver regeneration. These effects were accompanied by decreased expression of endothelin receptor type A, increased Bcl-2/Bax ratio, decreased expression of Bad and elevated proportion of phosphorylated Bad. In conclusion, implanted syngeneic ADSCs attenuated small-for-size liver graft injuries and subsequently enhanced liver regeneration in a rat 35% liver transplantation model. The VEGF secreted by implanted ADSCs played a crucial role in this process.

Mesenchymal Stem Cells Overexpressing C-X-C Chemokine Receptor Type 4 Improve Early Liver Regeneration of Small-for-Size Liver Grafts

“…In response to liver damage, bone marrow–derived stem cells proliferate and mobilize to the peripheral blood and finally migrate to the damaged liver for participation in regeneration by a direct differentiation process . MSCs also can secrete cytokines and growth factors, some of which are known to have antiapoptotic, anti‐inflammatory, immunosuppressive, and liver regeneration–promoting effects . Therefore, MSC transplantation may be a feasible alternative to RSLT.…”

“…6,11,12,26,[36][37][38] MSCs also can secrete cytokines and growth factors, some of which are known to have antiapoptotic, anti-inflammatory, immunosuppressive, and liver regeneration-promoting effects. 7,8,16,17,39,40 Therefore, MSC transplantation may be a feasible alternative to RSLT. For cell transplantation therapy, it is important that cells migrate specifically to damaged tissues.…”

Adipose-Derived Stem Cells in Tissue Regeneration: A Review

“…VEGF secretion by ASCs is significantly upregulated in vitro upon metabolic induction of ischemia [328] and ischemic limbs in diabetic nude mice treated with ASCs show earlier and more abundant neovessel formation, together with increased levels of plasma VEGF [303]. Inhibition of VEGF secretion by ASCs through RNA interference (RNAi), followed by their transplantation into syngeneic models of small-for-size liver injury results in significant disturbances to graft microcirculation, serum liver functional parameters, and graft survival [329]. Finally, recent studies suggest that AKT/c-myc signaling pathways may mediate increased VEGF secretion in ASCs as the injection of constitutively active AKT/v-myc-expressing ASCs promote better wound healing compared to normal controls [330].…”

Protective effect of eNOS overexpression against ischemia/reperfusion injury in small-for-size liver transplantation

“…A small-for-size liver graft is defined as a graft involving <40% of the standard liver volume or a graft to recipient weight ratio of 0.8–1.0% (2). In recent years, the demand for partial liver grafts from either deceased or living donors has been increasing worldwide, due to the severe shortage of donor organs (3).…”