Hepatic Regenerative Response in Small-Sized Liver Isografts in the Rat

Yao, Ai Hua; Yang, Yan; Li, Xiangcheng; Pu, Li; Zhong, Jie; Liu, Xian Zhong; Yu, Yue; Zhang, Feng; Kong, Lianbao; Wang, Xue Hao

doi:10.1016/j.jss.2009.02.013

Cited by 4 publications

(4 citation statements)

References 42 publications

(49 reference statements)

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“…In cases when the liver is too small as in the Small‐for‐Size Syndrome (60), or when the liver is unable to regenerate properly, as in our study, the organ does not grow large enough to fulfil its function (61). In this case, transaminase levels are increased, reflecting a severe liver injury (62–64) as is the case in our study.…”

Section: Discussionsupporting

confidence: 70%

Matrix Metalloproteinase 2 in Reduced‐Size Liver Transplantation: Beyond the Matrix

Padrissa-Altés

Zaoualí

Franco-Gou

et al. 2010

American Journal of Transplantation

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†S. Padrissa-Altés and M. A. Zaouali contributed equally to this study.We studied the contribution of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) to the beneficial effects of preconditioning (PC) in reduced-size orthotopic liver transplantation (ROLT). We also examined the role of c-Jun N-terminal kinase (JNK) and whether it regulates MMP2 in these conditions. Animals were subjected to ROLT with or without PC and pharmacological modulation, and liver tissue samples were then analyzed. We found that MMP2, but notMMP9, is involved in the beneficial effects of PC in ROLT. MMP2 reduced hepatic injury and enhanced liver regeneration. Moreover, inhibition of MMP2 in PC reduced animal survival after transplantation. JNK inhibition in the PC group decreased hepatic injury and enhanced liver regeneration. Furthermore, JNK upregulated MMP2 in PC. In addition, we showed that Tissue inhibitors of matrix metalloproteinases 2 (TIMP2) was also upregulated in PC and that JNK modulation also altered its levels in ROLT and PC. Our results open up new possibilities for therapeutic treatments to reduce I/R injury and increase liver regeneration after ROLT, which are the main limitations in living-donor transplantation.

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Section: Discussionsupporting

confidence: 70%

Matrix Metalloproteinase 2 in Reduced‐Size Liver Transplantation: Beyond the Matrix

Padrissa-Altés

Zaoualí

Franco-Gou

et al. 2010

American Journal of Transplantation

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“…Many growth factors and cytokines, such as IL‐6, TNF‐α, HGF, or VEGF, play important roles in liver regeneration . Several authors reported that liver regeneration was completed by 5‐7 days after partial liver graft transplantation with a peak level of the bromodeoxyuridine, proliferating cell nuclear antigen, or Ki‐67 labeling index at 1‐3days after operation in rodents . However, our experiment was the first trial to evaluate the possibility of liver regeneration in xenogeneic animals.…”

Section: Discussionmentioning

confidence: 89%

“…2 Several authors reported that liver regeneration was completed by 5-7 days after partial liver graft transplantation with a peak level of the bromodeoxyuridine, proliferating cell nuclear antigen, or Ki-67 labeling index at 1-3days after operation in rodents. 7,[18][19][20] However, our experiment was the first trial to evaluate the possibility of liver regeneration in xenogeneic animals. The results of Ki-67 labeling index suggested that liver regeneration of xenogeneic liver peaked on POD3 and continued even after POD7.…”

Section: Discussionmentioning

confidence: 99%

Auxiliary xenotransplantation as an in vivo bioreactor—Development of a transplantable liver graft from a tiny partial liver

Masano

Yagi

Miyachi

et al. 2019

Xenotransplantation

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Background We established a completely novel method of auxiliary xenogeneic partial liver transplantation and examined whether liver grafts procured from Syrian hamsters regenerated in nude rats, which were used as in vivo bioreactors. Methods The hamsters and the rats were all males (n = 10). Partial liver grafts from hamsters were transplanted into nude rats in an auxiliary manner. We evaluated liver graft injury, rejection, and regeneration during 7 days after auxiliary xenogeneic partial liver transplantation. Results All rats survived until sacrifice on post‐operative day (POD) 1, 3, and 7. HE‐staining showed normal at POD1, mild periportal edema, and slight bile duct and venous endothelial inflammation at POD3, and moderate acute cellular rejection at POD7 without parenchymal necrosis. The liver regeneration rates at POD3 and 7 were 1.54 ± 0.23 and 2.54 ± 0.43, respectively. The Ki‐67 labeling index was also elevated at POD3 (27.5 ± 4.1%). Serum HGF and VEGF were elevated at POD1 and 3. ATP levels of liver grafts recovered at POD7. Conclusions These results revealed that with appropriate immunosuppressive therapy, partial liver graft regeneration occurred in a xenogeneic animal, which suggests liver grafts regenerated in xenogeneic environments, such as an in vivo bioreactor, have potential to be transplantable liver grafts for humans.

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“…Hepatic proliferative response was evaluated by the expression of PCNA, cyclin D1 (CyD1) and cyclin E (CyE). Proliferative cell nuclear antigen (PCNA) is a cell-cycle nuclear protein expressed in late G1 and throughout the S-phase of mitosis, and is a processing factor for DNA polymerase δ [31]. PCNA was barely detectable in sham-operated livers and did not increase in FSG, an indication of minimal regeneration activity.…”

Section: Discussionmentioning

confidence: 99%

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

Pan

Liang

et al. 2014

PLoS ONE

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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.

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Hepatic Regenerative Response in Small-Sized Liver Isografts in the Rat

Cited by 4 publications

References 42 publications

Matrix Metalloproteinase 2 in Reduced‐Size Liver Transplantation: Beyond the Matrix

Matrix Metalloproteinase 2 in Reduced‐Size Liver Transplantation: Beyond the Matrix

Auxiliary xenotransplantation as an in vivo bioreactor—Development of a transplantable liver graft from a tiny partial liver

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

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