Rodent animal models for surrogate analysis of cell therapy in acute liver failure

Without therapeutic intervention acute liver failure (ALF) is the consequence of a progredient destruction of the liver parenchyma due to metabolic exhaustion of the hepatocytes. Perivenous hepatocytes are responsible for the detoxification of noxious compounds via the cytochrome P450 enzyme system. Liver transplantation is the only remaining therapeutic option in the end-stage of the disease. Assuming that metabolic capacity could be provided by healthy hepatocytes and thus substitute for the genuine parenchymal cells hepatocyte transplantation since quite some time is considered to be an alternative to whole liver transplantation. While this hypothesis achieved proof-of-concept in animal trials clinical breakthrough is still awaiting success, the reasons of which are ongoing matter of debate. In recent times mesenchymal stem cells (MSC) came into focus as a transplantable cell source to treat ALF. Interestingly, as demonstrated in various rodent animal models their mode of action is rather based on trophic support of hepatocytes remaining in the damaged host parenchyma rather than substitution of tissue loss. Mechanistically, either direct or indirect paracrine effects from the transplanted cells acting pro-proliferative, anti-apoptotic, and anti-inflammatory seem to trigger the regenerative response of the residual healthy hepatocytes in the otherwise lethally injured liver parenchyma. Thus, allogeneic MSC may be the best choice for the treatment of ALF taking advantage of their short-term benefit to sustain the critical phase of the acute insult avoiding long-term immunosuppression

Mesenchymal Stem Cell-Derived Hepatocytes for Functional Liver Replacement

Mesenchymal stem cells represent an alternate cell source to substitute for primary hepatocytes in hepatocyte transplantation because of their multiple differentiation potential and nearly unlimited availability. They may differentiate into hepatocyte-like cells in vitro and maintain specific hepatocyte functions also after transplantation into the regenerating livers of mice or rats both under injury and non-injury conditions. Depending on the underlying liver disease their mode of action is either to replace the diseased liver tissue or to support liver regeneration through their anti-inflammatory and anti-apoptotic as well as their pro-proliferative action

Human Mesenchymal Stromal Cells Resolve Lipid Load in High Fat Diet-Induced Non-Alcoholic Steatohepatitis in Mice by Mitochondria Donation

Mesenchymal stromal cells (MSC) increasingly emerge as an option to ameliorate non-alcoholic steatohepatitis (NASH), a serious disease, which untreated may progress to liver cirrhosis and cancer. Before clinical translation, the mode of action of MSC needs to be established. Here, we established NASH in an immune-deficient mouse model by feeding a high fat diet. Human bone-marrow-derived MSC were delivered to the liver via intrasplenic transplantation. As verified by biochemical and image analyses, human mesenchymal stromal cells improved high-fat-diet-induced NASH in the mouse liver by decreasing hepatic lipid content and inflammation, as well as by restoring tissue homeostasis. MSC-mediated changes in gene expression indicated the switch from lipid storage to lipid utilization. It was obvious that host mouse hepatocytes harbored human mitochondria. Thus, it is feasible that resolution of NASH in mouse livers involved the donation of human mitochondria to the mouse hepatocytes. Therefore, human MSC might provide oxidative capacity for lipid breakdown followed by restoration of metabolic and tissue homeostasis

Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH

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

Computational Modeling in Liver Surgery

The need for extended liver resection is increasing due to the growing incidence of liver tumors in aging societies. Individualized surgical planning is the key for identifying the optimal resection strategy and to minimize the risk of postoperative liver failure and tumor recurrence. Current computational tools provide virtual planning of liver resection by taking into account the spatial relationship between the tumor and the hepatic vascular trees, as well as the size of the future liver remnant. However, size and function of the liver are not necessarily equivalent. Hence, determining the future liver volume might misestimate the future liver function, especially in cases of hepatic comorbidities such as hepatic steatosis. A systems medicine approach could be applied, including biological, medical, and surgical aspects, by integrating all available anatomical and functional information of the individual patient. Such an approach holds promise for better prediction of postoperative liver function and hence improved risk assessment. This review provides an overview of mathematical models related to the liver and its function and explores their potential relevance for computational liver surgery. We first summarize key facts of hepatic anatomy, physiology, and pathology relevant for hepatic surgery, followed by a description of the computational tools currently used in liver surgical planning. Then we present selected state-of-the-art computational liver models potentially useful to support liver surgery. Finally, we discuss the main challenges that will need to be addressed when developing advanced computational planning tools in the context of liver surgery.Peer Reviewe

Identification of pathways in liver repair potentially targeted by secretory proteins from human mesenchymal stem cells

Background: The beneficial impact of mesenchymal stem cells (MSC) on both acute and chronic liver diseases has been confirmed, although the molecular mechanisms behind it remain elusive. We aim to identify factors secreted by undifferentiated and hepatocytic differentiated MSC in vitro in order to delineate liver repair pathways potentially targeted by MSC. Methods: Secreted factors were determined by protein arrays and related pathways identified by biomathematical analyses. Results: MSC from adipose tissue and bone marrow expressed a similar pattern of surface markers. After hepatocytic differentiation, CD54 (intercellular adhesion molecule 1, ICAM-1) increased and CD166 (activated leukocyte cell adhesion molecule, ALCAM) decreased. MSC secreted different factors before and after differentiation. These comprised cytokines involved in innate immunity and growth factors regulating liver regeneration. Pathway analysis revealed cytokine-cytokine receptor interactions, chemokine signalling pathways, the complement and coagulation cascades as well as the Januskinase-signal transducers and activators of transcription (JAK-STAT) and nucleotide-binding oligomerization domain-like receptor (NOD-like receptor) signalling pathways as relevant networks. Relationships to transforming growth factor beta(TGF-beta) and hypoxia-inducible factor 1-alpha (HIF1-alpha) signalling seemed also relevant. Conclusion: MSC secreted proteins, which differed depending on cell source and degree of differentiation. The factors might address inflammatory and growth factor pathways as well as chemo-attraction and innate immunity. Since these are prone to dysregulation in most liver diseases, MSC release hepatotropic factors, potentially supporting liver regeneration

Direct CP violation and the ΔI=1/2 rule in K→ππ decay from the standard model

We present a lattice QCD calculation of the ΔI=1/2, K→ππ decay amplitude A0 and ϵ′, the measure of direct CP violation in K→ππ decay, improving our 2015 calculation [1] of these quantities. Both calculations were performed with physical kinematics on a 323×64 lattice with an inverse lattice spacing of a-1=1.3784(68)  GeV. However, the current calculation includes nearly 4 times the statistics and numerous technical improvements allowing us to more reliably isolate the ππ ground state and more accurately relate the lattice operators to those defined in the standard model. We find Re(A0)=2.99(0.32)(0.59)×10-7  GeV and Im(A0)=-6.98(0.62)(1.44)×10-11  GeV, where the errors are statistical and systematic, respectively. The former agrees well with the experimental result Re(A0)=3.3201(18)×10-7  GeV. These results for A0 can be combined with our earlier lattice calculation of A2 [2] to obtain Re(ϵ′/ϵ)=21.7(2.6)(6.2)(5.0)×10-4, where the third error represents omitted isospin breaking effects, and Re(A0)/Re(A2)=19.9(2.3)(4.4). The first agrees well with the experimental result of Re(ϵ′/ϵ)=16.6(2.3)×10-4. A comparison of the second with the observed ratio Re(A0)/Re(A2)=22.45(6), demonstrates the standard model origin of this “ΔI=1/2 rule” enhancement.We present a lattice QCD calculation of the $\Delta I=1/2$, $K\to\pi\pi$ decay amplitude $A_0$ and $\varepsilon'$, the measure of direct CP-violation in $K\to\pi\pi$ decay, improving our 2015 calculation of these quantities. Both calculations were performed with physical kinematics on a $32^3\times 64$ lattice with an inverse lattice spacing of $a^{-1}=1.3784(68)$ GeV. However, the current calculation includes nearly four times the statistics and numerous technical improvements allowing us to more reliably isolate the $\pi\pi$ ground-state and more accurately relate the lattice operators to those defined in the Standard Model. We find ${\rm Re}(A_0)=2.99(0.32)(0.59)\times 10^{-7}$ GeV and ${\rm Im}(A_0)=-6.98(0.62)(1.44)\times 10^{-11}$ GeV, where the errors are statistical and systematic, respectively. The former agrees well with the experimental result ${\rm Re}(A_0)=3.3201(18)\times 10^{-7}$ GeV. These results for $A_0$ can be combined with our earlier lattice calculation of $A_2$ to obtain ${\rm Re}(\varepsilon'/\varepsilon)=21.7(2.6)(6.2)(5.0) \times 10^{-4}$, where the third error represents omitted isospin breaking effects, and Re$(A_0)$/Re$(A_2) = 19.9(2.3)(4.4)$. The first agrees well with the experimental result of ${\rm Re}(\varepsilon'/\varepsilon)=16.6(2.3)\times 10^{-4}$. A comparison of the second with the observed ratio Re$(A_0)/$Re$(A_2) = 22.45(6)$, demonstrates the Standard Model origin of this "$\Delta I = 1/2$ rule" enhancement