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Histological changes of the liver tissue after extended resection. Hematoxylin-eosin staining of the residual liver tissue 24 hours, 48 hours, and 5 days after extended liver resection of PBS controls (A) and MSC-treated animals (B).
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To prevent posthepatectomy acute liver failure after extended resection by treatment with mesenchymal stem cells (MSCs).
Liver tumors often require extended liver resection, overburdening metabolic and regenerative capacities of the remnant organ. Resulting dysfunction and failure may be improved by the proregenerative characteristics of MSCs.
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... of liver function by MSCs should be verified histologically. Tissue was analyzed at 24 hours, 48 hours, and 5 days after resection by hematoxylin-eosin staining. At 24 hours, hepatocyte volume was enlarged in the PBS group, which became even more prominent 48 hours after liver resection ( Fig. 2A; 24 and 48 hours). At both points in time, nearly normal liver architecture was observed in MSC-treated animals ( Fig. 2B; 24 and 48 hours). In these animals, histology was normal 5 days after liver resection, whereas animals of the PBS group did not survive until that time point ( Fig. 2B; 5 days). This indicated that the preservation of ...
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... was analyzed at 24 hours, 48 hours, and 5 days after resection by hematoxylin-eosin staining. At 24 hours, hepatocyte volume was enlarged in the PBS group, which became even more prominent 48 hours after liver resection ( Fig. 2A; 24 and 48 hours). At both points in time, nearly normal liver architecture was observed in MSC-treated animals ( Fig. 2B; 24 and 48 hours). In these animals, histology was normal 5 days after liver resection, whereas animals of the PBS group did not survive until that time point ( Fig. 2B; 5 days). This indicated that the preservation of liver tissue was associated with a survival advantage for the animals treated with ...
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... even more prominent 48 hours after liver resection ( Fig. 2A; 24 and 48 hours). At both points in time, nearly normal liver architecture was observed in MSC-treated animals ( Fig. 2B; 24 and 48 hours). In these animals, histology was normal 5 days after liver resection, whereas animals of the PBS group did not survive until that time point ( Fig. 2B; 5 days). This indicated that the preservation of liver tissue was associated with a survival advantage for the animals treated with ...
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... after liver resection. Yet, after extended resection, the fat-storing capacity of the residual liver is limited, which might lead to vast steatosis with consecutive functional impairment. In the PBS group, microsteatosis was obvious 24 hours after resection, expanding to massive steatosis after 48 hours as visualized by Sudan III staining ( Fig. 3A; 24 and 48 hours). This was probably one of the reasons for macroscopic hypertrophy of the liver at 48 hours after resection ( Fig. 3A; 48 hours, inset). Lipid droplets in the livers of animals in the MSC-treated group were clearly fewer and smaller than those in the PBS group, at both 24 and 48 hours after resection. Also, the hypertrophy ...
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... from an increase in fatty acids by stimulation of lipolysis in the adipose tissue or may be due to the decrease of hepatic lipid utilization. To explain hepatic lipid metabolism impairment, metabolomic profiling was performed in the liver and blood. Data were first evaluated by a principal component analysis (see Supplemental Digital Content Fig. 2A, available at http://links.lww.com/SLA/A748) and a hierarchical cluster analysis (see Supplemental Digital Content Fig. 2B, available at http://links.lww.com/SLA/A748). These analyses indicated a clear separation between nonresected control and resected animals. Furthermore, liver samples could be differentiated from serum samples. ...
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... lipid utilization. To explain hepatic lipid metabolism impairment, metabolomic profiling was performed in the liver and blood. Data were first evaluated by a principal component analysis (see Supplemental Digital Content Fig. 2A, available at http://links.lww.com/SLA/A748) and a hierarchical cluster analysis (see Supplemental Digital Content Fig. 2B, available at http://links.lww.com/SLA/A748). These analyses indicated a clear separation between nonresected control and resected animals. Furthermore, liver samples could be differentiated from serum samples. However, using this global approach for sample differentiation, the outcome of MSC treatment was not fully represented. ...
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... 6A, C). This shows that MSCs supported liver regeneration by stimulating hepatocyte proliferation. liver function (INR, bilirubin) and liver damage (liver transaminases) were significantly improved, one may assume that MSCs attenuated acute liver failure after resection. This was corroborated by histological analyses showing less tissue damage (Fig. 2) and apoptosis (Fig. 5), and stimulation of regeneration (Fig. 6), by MSC ...
Citations
... Recently, mesenchymal stromal cells (MSCs) were shown to support liver regeneration after extended partial hepatectomy in rodent [15][16][17][18] and pig [19,20] animal models. Mechanistically, MSCs attenuated platelet recruitment to the liver and downstream THBS1mediated TGF-β activation and epithelial disruption. ...
... Thus, we anticipate that MSCs both ameliorate surgery-induced liver injury and support post-operative tissue restoration. Similar findings were reported in rats [17,[38][39][40], pigs [21,41], and mice [18,42,43], indicating the versatility of MSCs in the treatment of post-hepatectomy liver failure [16]. ...
Extended liver resection carries the risk of post-surgery liver failure involving thrombospondin-1-mediated aggravation of hepatic epithelial plasticity and function. Mesenchymal stromal cells (MSCs), by interfering with thrombospondin-1 (THBS1), counteract hepatic dysfunction, though the mechanisms involved remain unknown. Herein, two-thirds partial hepatectomy in mice increased hepatic THBS1, downstream transforming growth factor-β3, and perturbation of liver tissue homeostasis. All these events were ameliorated by hepatic transfusion of human bone marrow-derived MSCs. Treatment attenuated platelet and macrophage recruitment to the liver, both major sources of THBS1. By mitigating THBS1, MSCs muted surgery-induced tissue deterioration and dysfunction, and thus supported post-hepatectomy regeneration. After liver surgery, patients displayed increased tissue THBS1, which is associated with functional impairment and may indicate a higher risk of post-surgery complications. Since liver dysfunction involving THBS1 improves with MSC treatment in various animal models, it seems feasible to also modulate THBS1 in humans to impede post-surgery acute liver failure.
... Typically, the bone marrow, adipose tissue, and umbilical cord, which could be induced to differentiate into hepatocyte-like cells (HLCs) [5], are regarded as the primary sources of mesenchymal stem cells for hepatic repair and regeneration. Also, many studies have shown that MSCs can improve hepatic function, downregulate hepatocyte apoptosis, and promote liver regeneration in animal models of ALF [6][7][8]. ...
Background:
Liver transplantation is limited by the insufficiency of liver organ donors when treating end-stage liver disease or acute liver failure (ALF). Ectodermal mesenchymal stem cells (EMSCs) derived from nasal mucosa have emerged as an alternative cell-based therapy. However, the role of EMSCs in acute liver failure remains unclear.
Methods:
EMSCs were obtained from the nasal mucosa tissue of rats. First, EMSCs were seeded on the gelatin-chitosan scaffolds, and the biocompatibility was evaluated. Next, the protective effects of EMSCs were investigated in carbon tetrachloride- (CCl4-) induced ALF rats. Finally, we applied an indirect coculture system to analyze the paracrine effects of EMSCs on damaged hepatocytes. A three-step nontransgenic technique was performed to transform EMSCs into hepatocyte-like cells (HLCs) in vitro.
Results:
EMSCs exhibited a similar phenotype to other mesenchymal stem cells along with self-renewal and multilineage differentiation capabilities. EMSC-seeded gelatin-chitosan scaffolds can increase survival rates and ameliorate liver function and pathology of ALF rat models. Moreover, transplanted EMSCs can secrete paracrine factors to promote hepatocyte regeneration, targeted migration, and transdifferentiate into HLCs in response to the liver's microenvironment, which will then repair or replace the damaged hepatocytes. Similar to mature hepatocytes, HLCs generated from EMSCs possess functions of expressing specific hepatic markers, storing glycogen, and producing urea.
Conclusions:
These results confirmed the feasibility of EMSCs in acute hepatic failure treatment. To our knowledge, this is the first time that EMSCs are used in the therapy of liver diseases. EMSCs are expected to be a novel and promising cell source in liver tissue engineering.
... Around 1000 MSC-related clinical trials and >400 clinical trials involving ADSCs are currently listed on ClinicalTrails.gov. The therapeutic potential of ADSCs has boosted numerous studies on musculoskeletal [41], cardiovascular [42][43][44], rheumatic [45], urinary [46][47][48][49], hepatic [50,51], corneal [52] and neurological diseases [53][54][55] as well as aesthetic rejuvenation [56] etc. (Figure 1). In addition to promoting tissue repair directly, adipocytes generated from patient-derived ADSCs carry genetic variation cues and help screen personalized antidiabetic drugs [57]. ...
Adipose-derived stem cells (ADSCs) have promising applications in tissue regeneration. Currently, there are only a few ADSC products that have been approved for clinical use. The clinical application of ADSCs still faces many challenges. Here, we review emerging strategies to improve the therapeutic efficacy of ADSCs in tissue regeneration. First, a great quantity of cells is often needed for the stem cell therapies, which requires the advanced cell expansion technologies. In addition cell-derived products are also required for the development of 'cell-free' therapies to overcome the drawbacks of cell-based therapies. Second, it is necessary to strengthen the regenerative functions of ADSCs, including viability, differentiation and paracrine ability, for the tissue repair and regeneration required for different physiological and pathophysiological conditions. Third, poor delivery efficiency also restricts the therapeutic effect of ADSCs. Effective methods to improve cell delivery include alleviating harsh microenvironments, enhancing targeting ability and prolonging cell retention. Moreover, we also point out some critical issues about the sources, effectiveness and safety of ADSCs. With these advanced strategies to improve the therapeutic efficacy of ADSCs, ADSC-based treatment holds great promise for clinical applications in tissue regeneration.
... Liver function is significantly improved after HLCs transplantation in mice with acute liver injury by stimulating anti-inflammatory cytokine secretion [49]. HLC transplantation in a partially hepatectomy-induced acute liver injury model significantly reduced lipid accumulation and restored liver capacity, thereby enhancing hepatocyte survival, preventing apoptosis, and eventually prolonging the survival of the animals [67]. HDCs transplantation also significantly reduced liver fibrosis by upregulating the expression of HGFs and lowering the serum levels of fibronectin and hepatic AFP [68]. ...
Background and Aim: Bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation and their hepatogenic differentiated cells (HDCs) can be applied for liver injury repair by tissue grafting. Regenerative potentiality in liver cirrhosis models was widely investigated; however, immunomodulation and anti-inflammation in acute hepatitis remain unexplored. This study aimed to explore the immunomodulatory and evaluate twice intravenous (IV) or intrahepatic (IH) administration of either BM-MSCs or middle-stage HDCs on aflatoxin (AF) acute hepatitis rat model.
Materials and Methods: BM-MSCs viability, phenotypes, and proliferation were evaluated. Hepatogenic differentiation, albumin, and a-fetoprotein gene expression were assessed. AF acute hepatitis was induced in rats using AFB1 supplementation. The transplantation of BM-MSCs or their HDCs was done either by IV or IH route. Hepatic ultrasound was performed after 3-weeks of therapy. Cytokines profile (tumor necrosis factor-α [TNF-α], interleukin [IL]-4, and IL-10) was assessed. Hepatic bio-indices, serum, and hepatic antioxidant activity were evaluated, besides examining liver histological sections.
Results: Acute AFB1 showed a significant increase in TNF-α (p
... Placenta Rat Migration to damaged site and induction of immunomodulatory effects by secreting paracrine factors in ALF [193] Bone marrow Rat Systemic administration of MSCs reduced ALT, AST, and bilirubin levels [124] Bone marrow Rat Reducing ALF, improving glucose metabolism and survival, and also stimulation of the hepatocyte proliferation by activating AKT/GSK-3β/β-catenin pathway [122] Adipose tissue Rat Normalization of amino acids, sphingolipids, and glycerophospholipids in the liver and blood along with attenuation hepatocyte apoptosis and conversely promoting their proliferation rate [194] Placenta Rat Stimulation of liver repair through the antifibrotic and autophagic mechanisms [149] Umbilical cord Monkey Inhibition of the activity of IL-6 producing monocyte, amelioration of the liver histology, and also animal survival [119] Adipose tissue Rat Suppression of the secondary complications of liver failure [195] Bone marrow Porcine Improving the liver function homeostasis, attenuation of reactive oxygen species (ROS) following efficient homing, and also differentiation into hepatocytes [196] control group (50% vs 12.5%). Notably, the intervention led to a robust decrease in the population of neutrophils in the liver, MPO function, and also the expression of pro-inflammatory factors, including TNF-α, IL-1β, interferon gamma (IFNγ) and CXC chemokine ligands 1/2 (CXCL1/2) [118]. ...
Recently, mesenchymal stromal cells (MSCs) and their derivative exosome have become a promising approach in the context of liver diseases therapy, in particular, acute liver failure (ALF). In addition to their differentiation into hepatocytes in vivo, which is partially involved in liver regeneration, MSCs support liver regeneration as a result of their appreciated competencies, such as antiapoptotic, immunomodulatory, antifibrotic, and also antioxidant attributes. Further, MSCs-secreted molecules inspire hepatocyte proliferation in vivo, facilitating damaged tissue recovery in ALF. Given these properties, various MSCs-based approaches have evolved and resulted in encouraging outcomes in ALF animal models and also displayed safety and also modest efficacy in human studies, providing a new avenue for ALF therapy. Irrespective of MSCs-derived exosome, MSCs-based strategies in ALF include administration of native MSCs, genetically modified MSCs, pretreated MSCs, MSCs delivery using biomaterials, and also MSCs in combination with and other therapeutic molecules or modalities. Herein, we will deliver an overview regarding the therapeutic effects of the MSCs and their exosomes in ALF. As well, we will discuss recent progress in preclinical and clinical studies and current challenges in MSCs-based therapies in ALF, with a special focus on in vivo reports.
... In the liver, MSC attenuated fatty liver diseases 3,4 , acute liver failure after acetaminophen 5,6 , or D-galactosamine intoxication 7 , as well as liver fibrosis and cirrhosis 8 . MSC improved liver function after extended partial hepatectomies (ePHx) in rodent animal models by ameliorating damage and supporting regeneration of the residual liver 9,10 . This is clinically relevant, as partial liver resection is the only cure for patients with liver tumors. ...
Post-surgery liver failure is a serious complication for patients after extended partial hepatectomies (ePHx). Previously, we demonstrated in the pig model that transplantation of mesenchymal stromal cells (MSC) improved circulatory maintenance and supported multi-organ functions after 70% liver resection. Mechanisms behind the beneficial MSC effects remained unknown. Here we performed 70% liver resection in pigs with and without MSC treatment, and animals were monitored for 24 h post surgery. Gene expression profiles were determined in the lung and liver. Bioinformatics analysis predicted organ-independent MSC targets, importantly a role for thrombospondin-1 linked to transforming growth factor-β (TGF-β) and downstream signaling towards providing epithelial plasticity and epithelial-mesenchymal transition (EMT). This prediction was supported histologically and mechanistically, the latter with primary hepatocyte cell cultures. MSC attenuated the surgery-induced increase of tissue damage, of thrombospondin-1 and TGF-β, as well as of epithelial plasticity in both the liver and lung. This suggests that MSC ameliorated surgery-induced hepatocellular stress and EMT, thus supporting epithelial integrity and facilitating regeneration. MSC-derived soluble factor(s) did not directly interfere with intracellular TGF-β signaling, but inhibited thrombospondin-1 secretion from thrombocytes and non-parenchymal liver cells, therewith obviously reducing the availability of active TGF-β.
... In the liver, MSC attenuated fatty liver diseases 3,4 , acute liver failure after acetaminophen 5,6 , or D-galactosamine intoxication 7 , as well as liver fibrosis and cirrhosis 8 . MSC improved liver function after extended partial hepatectomies (ePHx) in rodent animal models by ameliorating damage and supporting regeneration of the residual liver 9,10 . This is clinically relevant, as partial liver resection is the only cure for patients with liver tumors. ...
Post-surgery liver failure is a serious complication for patients after extended partial hepatectomies (ePHx). Previously, we demonstrated in the pig model that transplantation of mesenchymal stromal cells (MSC) improved circulatory maintenance and supported multi-organ functions after 70% liver resection. Mechanisms behind the beneficial MSC effects remained unknown. Here we performed 70% liver resection in pigs with and without MSC treatment, and animals were monitored for 24 h post surgery. Gene expression profiles were determined in the lung and liver. Bioinformatics analysis predicted organ-independent MSC targets, importantly a role for thrombospondin-1 linked to transforming growth factor-β (TGF-β) and downstream signaling towards providing epithelial plasticity and epithelial-mesenchymal transition (EMT). This prediction was supported histologically and mechanistically, the latter with primary hepatocyte cell cultures. MSC attenuated the surgery-induced increase of tissue damage, of thrombospondin-1 and TGF-β, as well as of epithelial plasticity in both the liver and lung. This suggests that MSC ameliorated surgery-induced hepatocellular stress and EMT, thus supporting epithelial integrity and facilitating regeneration. MSC-derived soluble factor(s) did not directly interfere with intracellular TGF-β signaling, but inhibited thrombospondin-1 secretion from thrombocytes and non-parenchymal liver cells, therewith obviously reducing the availability of active TGF-β.
... Surgery-induced stress releases fatty acids from adipose tissue that enter the liver to provide energy substrates for liver regeneration (Lafontan et al., 1997;Walldorf et al., 2010). However, in steatohepatitis and, due to the small liver remnant after extended hepatectomies, excess lipid load occurs and impairs post-hepatectomy regeneration, likely as a consequence of mitochondrial impairment (Hamano et al., 2014;Tautenhahn et al., 2016). Though single cell RNA sequencing revealed a sophisticated atlas of liver zonation and its spatio-temporal regulation (Halpern et al., 2017;Droin et al., 2021), computational modeling has not yet addressed metabolic zonation in the liver or its dynamic regulation by surgical challenges like partial hepatectomy. ...
Liver resection causes marked perfusion alterations in the liver remnant both on the organ scale (vascular anatomy) and on the microscale (sinusoidal blood flow on tissue level). These changes in perfusion affect hepatic functions via direct alterations in blood supply and drainage, followed by indirect changes of biomechanical tissue properties and cellular function. Changes in blood flow impose compression, tension and shear forces on the liver tissue. These forces are perceived by mechanosensors on parenchymal and non-parenchymal cells of the liver and regulate cell-cell and cell-matrix interactions as well as cellular signaling and metabolism. These interactions are key players in tissue growth and remodeling, a prerequisite to restore tissue function after PHx. Their dysregulation is associated with metabolic impairment of the liver eventually leading to liver failure, a serious post-hepatectomy complication with high morbidity and mortality. Though certain links are known, the overall functional change after liver surgery is not understood due to complex feedback loops, non-linearities, spatial heterogeneities and different time-scales of events. Computational modeling is a unique approach to gain a better understanding of complex biomedical systems. This approach allows (i) integration of heterogeneous data and knowledge on multiple scales into a consistent view of how perfusion is related to hepatic function; (ii) testing and generating hypotheses based on predictive models, which must be validated experimentally and clinically. In the long term, computational modeling will (iii) support surgical planning by predicting surgery-induced perfusion perturbations and their functional (metabolic) consequences; and thereby (iv) allow minimizing surgical risks for the individual patient. Here, we review the alterations of hepatic perfusion, biomechanical properties and function associated with hepatectomy. Specifically, we provide an overview over the clinical problem, preoperative diagnostics, functional imaging approaches, experimental approaches in animal models, mechanoperception in the liver and impact on cellular metabolism, omics approaches with a focus on transcriptomics, data integration and uncertainty analysis, and computational modeling on multiple scales. Finally, we provide a perspective on how multi-scale computational models, which couple perfusion changes to hepatic function, could become part of clinical workflows to predict and optimize patient outcome after complex liver surgery.
... Lipids are synthesized in the liver and exported to and from the rest of the body by lipoproteins (12). Lipid metabolism can be significantly altered during liver disease (13) or after liver resection (14)(15)(16)(17)(18)(19), suggesting their potential to be used as biomarkers in the setting of PHLF. However, lipid profiles during PHLF have not been thoroughly examined. ...
... resection while PC plasmalogen can be considered as a failure marker, provided PHLF occurs with the 90% PH group. LPC levels were reported to decrease in the rat serum and liver after extended liver resection (19), which is similar to the observed decrease in this study (Figure 4). On the other hand, although the overall PC levels of the two resection groups were found to decrease in this study ( Figure S3) similar to other report (19), that of PC 32:2 in 90% PH group was increased. ...
... LPC levels were reported to decrease in the rat serum and liver after extended liver resection (19), which is similar to the observed decrease in this study (Figure 4). On the other hand, although the overall PC levels of the two resection groups were found to decrease in this study ( Figure S3) similar to other report (19), that of PC 32:2 in 90% PH group was increased. Decrease in serum LPC levels was reported to be attributed to the resection-induced impairment of the liver, thus, reducing the production of albumin, which transports LPC through blood (41). ...
Background:
Clinical diagnosis of post-hepatectomy liver failure (PHLF) can only be made on or after the 5th postoperative day. Biomarker for early diagnosis is considered as a critical unmet need.
Methods:
Twenty domestic female crossbreed (Yorkshire-landrace and duroc) pigs underwent sham operation (n=6), 70% (n=7) and 90% (n=7) partial hepatectomy (PH). A comprehensive lipidomic analysis was conducted using sera collected at pre-operation (PO), 14, 30, and 48 h after PH using nanoflow ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry.
Results:
Of the 184 quantified lipids, 14 lipids showed significant differences between the two resection groups starting at 30 h after surgery. Four phosphatidylcholine (PC) plasmalogen species (P-16:0/16:0, P-18:0/18:2, P-18:0/20:4, and P-18:0/22:6) and PC 32:2 significantly increased in the 90% PH group while these returned to PO level after 30 h in the 70% PH group, presumably implying the failure markers. In contrast, eight triacylglycerol (TG) species (40:0, 42:1, 42:0, 44:1, 44:2, 46:1, 46:2, and 48:3) and sphingomyelin d18:1/20:0 showed an opposite trend, wherein they significantly decreased in the 90% PH group while these in the 70% PH group were abruptly increased until 30 h but returned to near PO levels at 48 h, implying the recovery markers. Same trends could also be observed in the level of whole lipid classes of PC plasmalogens and TGs, in addition to selected individual lipid species.
Conclusions:
Characteristic lipidomic signatures of PHLF could be identified using large animal models. These candidates have a potential to serve as a tool for early diagnosis and may open new paths to the study to overcome PHLF.
... Targeted metabolomics was conducted using the AbsoluteIDQ p150 kit (BIOCRATES Life Sciences AG, Innsbruck, Austria) as described before [26]. In brief, metabolites were extracted from the livers as descripted above, and prepared according to the manufacturer's protocol [37]. ...
Mesenchymal stromal cell (MSC) transplantation ameliorated hepatic lipid load; tissue inflammation; and fibrosis in rodent animal models of non-alcoholic steatohepatitis (NASH) by as yet largely unknown mechanism(s). In a mouse model of NASH; we transplanted bone marrow-derived MSCs into the livers; which were analyzed one week thereafter. Combined metabolomic and proteomic data were applied to weighted gene correlation network analysis (WGCNA) and subsequent identification of key drivers. Livers were analyzed histologically and biochemically. The mechanisms of MSC action on hepatocyte lipid accumulation were studied in co-cultures of hepatocytes and MSCs by quantitative image analysis and immunocytochemistry. WGCNA and key driver analysis revealed that NASH caused the impairment of central carbon; amino acid; and lipid metabolism associated with mitochondrial and peroxisomal dysfunction; which was reversed by MSC treatment. MSC improved hepatic lipid metabolism and tissue homeostasis. In co-cultures of hepatocytes and MSCs; the decrease of lipid load was associated with the transfer of mitochondria from the MSCs to the hepatocytes via tunneling nanotubes (TNTs). Hence; MSCs may ameliorate lipid load and tissue perturbance by the donation of mitochondria to the hepatocytes. Thereby; they may provide oxidative capacity for lipid breakdown and thus promote recovery from NASH-induced metabolic impairment and tissue injury.
