Supportive Hepatocyte Transplantation after Partial Hepatectomy Enhances Liver Regeneration in a Preclinical Pig Model

Abstract

<b><i>Background:</i></b> Hepatocyte transplantation (HTx) is regarded as a potential treatment modality for various liver diseases including acute liver failure. We developed a preclinical pig model to evaluate if HTx could safely support recovery from liver function impairment after partial hepatectomy. <b><i>Methods:</i></b> Pigs underwent partial hepatectomy with reduction of the liver volume by 50% to induce a transient but significant impairment of liver function. Thereafter, 2 protocols for HTx were evaluated and compared to a control group receiving liver resection only (group 1, <i>n</i> = 5). Portal pressure-controlled HTx was performed either immediately after surgery (group 2, <i>n</i> = 6) or 3 days postoperatively (group 3, <i>n</i> = 5). In all cases, liver regeneration was monitored by conventional laboratory tests and the novel noninvasive maximum liver function capacity (LiMAx) test with a follow-up of 4 weeks. <b><i>Results:</i></b> Partial hepatectomy significantly impaired liver function according to conventional liver function tests as well as LiMAx in all groups. A mean of 4.10 ± 1.1 × 10<sup>8</sup> and 3.82 ± 0.7 × 10<sup>8</sup> hepatocytes were transplanted in groups 2 and 3, respectively. All animals remained stable with respect to vital parameters during and after HTx. The animals in group 2 showed enhanced liver regeneration as observed by mean postoperative LiMAx values (621.5 vs. 331.3 μg/kg/h on postoperative day 7; <i>p</i> < 0.001) whereas HTx in group 3 led to a significant increase in mean liver-specific coagulation factor VII (112.2 vs. 54.0% on postoperative day 7; <i>p</i> = 0.003) compared to controls (group 1), respectively. In both experimental groups, thrombotic material was observed in the portal veins and pulmonary arteries on histology, despite the absence of clinical symptoms. <b><i>Conclusion:</i></b> HTx can be performed safely and effectively immediately after a partial (50%) hepatectomy as well as 3 days postoperatively, with comparable results regarding the enhancement of liver function and regeneration.

Interleukin-18 and High-Mobility-Group-Protein B1 are Early and Sensitive Indicators for Cell Damage During Normothermic Machine Perfusion after Prolonged Cold Ischemic Storage of Porcine Liver Grafts

“…After premedication with zolazepam (5 mg/kg bodyweight) and atropine (0.02–0.04 mg/kg bodyweight) via intramuscular injection, anesthesia was induced by intravenously applied propofol (1.5–2.5 mg/kg bodyweight). Upon endotracheal intubation anesthesia and analgesia were maintained with isoflurane (0.8–1.5 vol%) and fentanyl (0.003–0.007 mg/kg bodyweight) as previously reported [ 11 , 12 ]. The procurement of the liver was performed as described in humans [ 13 ].…”

Unveiling the power of microenvironment in liver regeneration: an in-depth overview

“…The other category involves non-surgical injury, primarily caused by drug-induced hepatocyte death from substances such as alcohol allyl (AA), acetaminophen (APAP), CCl4, and 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC). Various animal models have been utilized for studying LR, including zebrafish, mice, rats, rabbits, and pigs ( Liao et al, 2017 ; Daradics et al, 2021 ; Jung et al, 2021 ; Oldhafer et al, 2021 ; Zhang et al, 2021 ). Liver injury induced by drugs and toxins is primarily due to hepatocyte necrosis.…”

Surgical Models of Liver Regeneration in Pigs: A Practical Review of the Literature for Researchers

“…Only two studies considered a hepatotoxic pre-treatment using retrorsine [42] or carbon tetrachloride (CCl4) and alcohol [56]. Regarding the PH, sixteen experiments studied liver regeneration in response to liver resection without any additional procedures, while 20 studies evaluated how the liver regenerative capacity was influenced by SCA [30][31][32]39,41,44,51,[66][67][68], IRI [30,32,39,41,53,61,63,66], PVM [34,45,48,58], PVE [49], liver scaffold application [31,33], bio-artificial liver treatment [43], and application of terlipressin and octreotide [64,65]. The caudate lobe was always preserved.…”

“…Eight articles considered IRI, as shown in Table 1. The preferred way to induce IRI was through 60 min of lasting right hepatic ischemia [30,32,39,41,61,67], while only two studies [53,63] used a 150 min Pringle maneuver. The same two authors were the only ones not to perform a PH.…”