Hypoxia protects the liver from Small For Size Syndrome: A lesson learned from the associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure in rats

Dili, Alexandra; Bertrand, C.; Lebrun, Valérie; Pirlot, Boris; Leclercq, Isabelle

doi:10.1111/ajt.15420

Cited by 15 publications

(22 citation statements)

References 50 publications

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“…In recent work, our team proposed experimental evidence that the stimulation of angiogenesis at early time points during regeneration of a small remnant prevented SFSS-induced mortality. Maneuvers, such as hepatic artery ligation concomitant to extended hepatectomy or treatment with DMOG, a prolyl hydroxylase domain inhibitor that activates HIF-1α, triggered an early pro-angiogenic response and prevented the collapse of hepatic sinusoids in the small for size regenerating liver [ 122 ].…”

Section: Role Of Lsec In Extended Hepatectomymentioning

confidence: 99%

Critical Role of LSEC in Post-Hepatectomy Liver Regeneration and Failure

Rudder¹,

Dili

Stärkel

et al. 2021

IJMS

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Liver sinusoids are lined by liver sinusoidal endothelial cells (LSEC), which represent approximately 15 to 20% of the liver cells, but only 3% of the total liver volume. LSEC have unique functions, such as fluid filtration, blood vessel tone modulation, blood clotting, inflammatory cell recruitment, and metabolite and hormone trafficking. Different subtypes of liver endothelial cells are also known to control liver zonation and hepatocyte function. Here, we have reviewed the origin of LSEC, the different subtypes identified in the liver, as well as their renewal during homeostasis. The liver has the exceptional ability to regenerate from small remnants. The past decades have seen increasing awareness in the role of non-parenchymal cells in liver regeneration despite not being the most represented population. While a lot of knowledge has emerged, clarification is needed regarding the role of LSEC in sensing shear stress and on their participation in the inductive phase of regeneration by priming the hepatocytes and delivering mitogenic factors. It is also unclear if bone marrow-derived LSEC participate in the proliferative phase of liver regeneration. Similarly, data are scarce as to LSEC having a role in the termination phase of the regeneration process. Here, we review what is known about the interaction between LSEC and other liver cells during the different phases of liver regeneration. We next explain extended hepatectomy and small liver transplantation, which lead to “small for size syndrome” (SFSS), a lethal liver failure. SFSS is linked to endothelial denudation, necrosis, and lobular disturbance. Using the knowledge learned from partial hepatectomy studies on LSEC, we expose several techniques that are, or could be, used to avoid the “small for size syndrome” after extended hepatectomy or small liver transplantation.

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Section: Role Of Lsec In Extended Hepatectomymentioning

confidence: 99%

Critical Role of LSEC in Post-Hepatectomy Liver Regeneration and Failure

Rudder¹,

Dili

Stärkel

et al. 2021

IJMS

Self Cite

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“…Furthermore, the patient developed reversible liver failure even if graft function was significantly increasing. The functional competition among the native liver and the auxiliary graft was investigated in the past 17,18 in cases of metabolic liver disease transplanted with auxiliary partial graft; this amount of knowledge was recently improved through the scientific advancements on liver partition and portal vein ligation during staged hepatectomy 19,20 …”

Section: Discussionmentioning

confidence: 99%

Heterotopic segmental liver transplantation on splenic vessels after splenectomy with delayed native hepatectomy after graft regeneration: A new technique to enhance liver transplantation

Ravaioli

Brandi

Siniscalchi

et al. 2021

American Journal of Transplantation

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We describe a patient with liver metastases from colorectal cancer treated with chemotherapy and hepatic resection, who developed unresectable multifocal liver recurrence and who received liver transplantation using a novel planned technique: heterotopic transplantation of segment 2‐3 in the splenic fossa with splenectomy and delayed hepatectomy after regeneration of the transplanted graft. We transplanted a segmental liver graft after in‐situ splitting without any impact on the waiting list, as it was previously rejected for pediatric and adult transplantation. The volume of the graft was insufficient to provide liver function to the recipient, so we performed this novel operation. The graft was anastomosed to the splenic vessels after splenectomy, and the native liver portal flow was modulated to enhance graft regeneration, leaving the native recipient liver intact. The volume of the graft doubled during the next 2 weeks and the native liver was removed. After 8 months, the patient lives with a functioning liver in the splenic fossa and without abdominal tumor recurrence. This is the first case reported of a segmental graft transplanted replacing the spleen and modulating the portal flow to favor graft growth, with delayed native hepatectomy.

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“…Although preliminary studies have shown that mitochondrial function, hypoxia signals, and the pathways above are involved in ALPPS-induced regeneration, there is a lack of robust evidence to support the causality (7)(8)(9)(10)15). A deeper understanding of the activation of HSCs and the JNK1/IHH axis has been demonstrated as the first example of an ALPPS-induced molecular event associated with unprecedented regenerative acceleration (7,16).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction attenuates rapid regeneration in livers with toxin-induced fibrosis

Li¹,

Liang²,

Ying³

et al. 2021

Ann Transl Med

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Background: The mechanism of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)-induced rapid liver regeneration remains poorly documented, especially in patients with fibrosis.Therefore, this study aims to investigate the underlying mechanism of ALPPS-induced accelerated regeneration in toxin-induced fibrosis models. Methods:The ALPPS-induced regeneration model was established in livers with thioacetamide (TAA)induced fibrosis to determine the regenerative pathways involved in rapid regeneration. Confirmatory experiments were performed in transforming growth factor beta 1 (TGFβ1)-treated AML12 cells and mice with carbon tetrachloride (CCl 4 )-induced fibrosis. Finally, mitochondrial dysfunction was validated in fibrotic/non-fibrotic patients.Results: In TAA-induced fibrotic mice, ALPPS-induced regeneration was significantly inferior to that of the control group (P=0.027 at day 2 and P<0.001 at day 7). Furthermore, mitochondria-associated genes were significantly downregulated in TAA-challenged mice. Accordingly, the reduced production of ATP and elevated levels of malondialdehyde indicated disturbances in intracellular energy metabolism during the ALPPS-induced regenerative process after TAA treatment. Further investigations were performed in TGF-β1-treated AML12 cells and CCl 4 -treated mice, which indicated that mitochondrial dysfunction attenuated the capacity for rapid regeneration after ALPPS.Conclusions: In summary, this study revealed that mitochondrial dysfunction led to inferior regeneration in livers with toxin-induced fibrosis and identified new therapeutic targets to improve the feasibility and safety of the ALPPS procedure. Further studies in human patients are required in the future.

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Hypoxia protects the liver from Small For Size Syndrome: A lesson learned from the associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure in rats

Cited by 15 publications

References 50 publications

Critical Role of LSEC in Post-Hepatectomy Liver Regeneration and Failure

Critical Role of LSEC in Post-Hepatectomy Liver Regeneration and Failure

Heterotopic segmental liver transplantation on splenic vessels after splenectomy with delayed native hepatectomy after graft regeneration: A new technique to enhance liver transplantation

Mitochondrial dysfunction attenuates rapid regeneration in livers with toxin-induced fibrosis

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