Rodent Animal Models for Surrogate Analysis of Cell Therapy in Acute Liver Failure

Abstract

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.

Alpha‐fetoprotein: A biomarker for the recruitment of progenitor cells in the liver in patients with acute liver injury or failure

“…Therefore, the induction of sufficient MH is a critical step in the recovery from massive hepatocyte necrosis resulting from ALI/ALF. Indeed, the progression of LPC proliferation in an in vivo model of liver injury has been shown to inhibit hepatocyte demise and improve patient outcomes . Therefore, agents promoting the differentiation of LPC to MH may be good candidates as therapeutic targets in ALI/ALF patients with a poor prognosis.…”

Mammalian MSC from selected species: Features and applications

“…They prevented disease progress by inhibition of apoptosis and necrosis, and supported liver regeneration by stimulating proliferation of host hepatocytes. Functional cell transplants were found in the host livers for up to seven weeks after transplantation . This indicates that MSC are capable of liver support by functional tissue substitution and paracrine stimulation of tissue regeneration after acute inflammatory insult.…”

“…It is obvious that MSC from most species investigated may interfere with all these levels of immune activation. Yet, a critical review of the single factors is quite mandatory to understand the overarching coherences .…”

Human Bone Marrow Mesenchymal Stem Cell-Derived Hepatocytes Improve the Mouse Liver after Acute Acetaminophen Intoxication by Preventing Progress of Injury

“…Besides these initial effects of APAP-induced hepatotoxicity, pro-inflammatory cytokines like TNFα and IL1β are elevated after APAP treatment and may trigger an inflammatory response, thus potentially augmenting tissue damage [ 49 – 51 ]. Since mesenchymal stem cells display anti-inflammatory and pro-regenerative features [ 15 , 17 , 47 , 52 ], we reasoned that transplantation of MSC into APAP-treated livers might alleviate liver injury. It has been shown for stem cell-derived hepatocytes that after portal injection they are entrapped in the proximal branches of the portal vein and eventually traverse the endothelia to integrate long-term into the portal parenchyma featuring the same qualities as their neighbouring periportal hepatocytes [ 20 , 27 , 53 ].…”