Suppression of Graft Regeneration, Not Ischemia/Reperfusion Injury, Is the Primary Cause of Small-for-Size Syndrome after Partial Liver Transplantation in Mice

Abstract

BackgroundIschemia/reperfusion injury (IRI) is commonly considered to play a crucial role in the pathogenesis of small-for-size syndrome (SFSS) after liver transplantation. Rapid regeneration is also considered essential for the survival of SFS grafts.MethodsMouse models of full-size orthotopic liver transplantation, 50% partial liver transplantation and 30% partial liver transplantation were established. Survival rate and serum alanine aminotransferase were observed. IRI was assessed by hepatic pathologic alterations, apoptosis and necrosis. Regeneration response was detected by mitotic index, BrdU incorporation and PCNA, Cyclin D1 and Cyclin E expression. The expression of mTOR, AKT, ERK, JNK2 and p70S6K, also involved in regeneration signaling pathways, were analyzed as well.Results30% partial liver graft resulted in a significantly low 7-day survival rate (P = 0.002) with no marked difference in tissue injury compared with the 50% partial graft group. Serum alanine aminotransferase levels were not significantly different between partial transplantation and full-size transplantation. Western blot analysis of caspase-3 and TUNEL staining also indicated no significant difference in apoptosis response between 30% partial transplantation and half-size or full-size transplantation (P = 0.436, P = 0.113, respectively). However, liver regeneration response indicators, mitotic index (P<0.0001) and BrdU (P = 0.0022), were markedly lower in 30% LTx compared with 50% LTx. Suppressed expression of PCNA, cyclin D1, cyclin E, mTOR, JNK2, AKT, ERK and p70S6K was also detected by western blot.ConclusionsLiver regeneration is markedly suppressed in SFSS, and is more likely the primary cause of SFSS, rather than ischemia/reperfusion injury. Therapy for recovering graft regeneration could be a potentially important strategy to reduce the incidence of SFSS.

Factors associated with low graft regeneration in the early phase after living donor liver transplantation

“…Appropriate graft regeneration after LDLT is crucial to avoid small‐for‐size syndrome (SFSS) . Clinical features of SFSS include graft dysfunction and failure, massive ascites, gastrointestinal bleeding, increased infection, renal dysfunction, hepatocyte ischemia and degeneration, enhanced cholestasis, delayed protein synthesis and coagulopathy, and increased surgical complications .…”

Wnt agonist stimulates liver regeneration after small‐for‐size liver transplantation in rats

“…The mechanisms of SFSG failure remain unclear. Previous studies have shown that liver regeneration is inhibited in SFSG, which plays a key role in the failure of partial liver grafts after transplantation …”

“…Previous studies have shown that liver regeneration is inhibited in SFSG, which plays a key role in the failure of partial liver grafts after transplantation. [6][7][8][9] Liver regeneration is regulated by a variety of signaling cascades involving genes, transcription factors, cytokines and growth factors. Energy status and nutritional factors also affect this process.…”

“…However, many studies have reported that defective liver regeneration in small grafts is associated with an inhibition of expression of cyclin D1, which is a key cell cycle-associated gene critical for the initiation of cell proliferation. [6][7][8] In hepatocytes, cyclin D1 plays an important role in driving proliferation and cyclin D1 overexpression was shown to be sufficient to promote hepatocyte replication and liver growth in vivo. 10 Defective energy production was also involved in the suppression of regeneration of SFSG.…”

Ischemic Preconditioning Affects Long-Term Cell Fate through DNA Damage–Related Molecular Signaling and Altered Proliferation

“…Moreover, issues of DNA damage could be a serious problem after small-for-size liver transplantation, given the failure of liver regeneration in this setting. 28 Our cell transplantation model of liver repopulation additionally elicited information on whether hepatocytes exposed to IR and IP can actually divide and produce daughter cells, because in that situation transplanted cell numbers should have increased. In the retrorsineePH liver repopulation model, 22 native hepatocytes are damaged by DNA adducts of retrorsine and by oxidative DNA damage induced by PH, which culminate in proliferation advantages to transplanted healthy cells.…”