Genomics of liver transplant injury and regeneration

Abstract

While improved surgical techniques, post-operative care, and immunosuppression regimens have reduced morbidity and mortality associated with orthotopic liver transplantation (OLT), further improvement of outcomes requires personalized treatment and a better understanding of genomic mechanisms involved. Gene expression profiles of ischemia/reperfusion (I/R) injury, regeneration, and rejection, may suggest mechanisms for development of better predictive tools and treatments. The liver is unique in its regenerative potential, recovering lost mass and function after injury from ischemia, resection, and rejection. I/R injury, an inevitable consequence of perfusion cessation, cold storage, and reperfusion, is regulated by the interaction of the immune system, inflammatory cytokines, and reduced microcirculatory blood flow in the liver. Rejection, a common postoperative complication, is mediated by the recipient's immune system through T-cell-dependent responses activating proinflammatory and apoptotic pathways. Characterizing distinctive gene expression signatures for these events can identify therapies to reduce injury, promote regeneration, and improve outcomes. While certain markers of liver injury and regeneration have been observed in animals, many of these are unverified in human studies. Further investigation of these genomic signatures and mechanisms through new technology offers promise, but continues to pose a significant challenge. An overview of the current fund of knowledge in this area is reviewed.

Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms

“…Downregulated miRNAs involved in apoptosis include miRNA‐200b and miRNA‐183. Upregulated miRNAs involved in liver regeneration include miRNA‐27a, −494, −1224 and ‐149 . These findings indicate an important role for miRNA in the regulation of hepatic IRI.…”

Parkin deficiency elevates hepatic ischemia/reperfusion injury accompanying decreased mitochondrial autophagy, increased apoptosis, impaired DNA damage repair and altered cell cycle distribution

“…Previous studies have investigated HIRI-induced liver damage with insufficient energy supply, which may be exacerbated by the degradation of mitochondrial autophagy (20). It is well established that mitochondrial autophagy and its derivatives potently and reversibly decrease mitochondrial transmembrane potentials and inhibit cell death in a concentration-dependent manner.…”

“…Livers without injury have been demonstrated to exhibit decreased apoptosis compared with their counterparts, following HIRI and a direct effect of apoptosis on tissues is the suppression of energy production by mitochondria (21). At the gene expression level, certain studies (20) have reported that Bcl-2 secured correct rejoining of the DNA broken end to protect DNA integrity as DNA damage response post-HIRI, indicating that Bcl-2-associated regulatory mechanisms serve an important role in HIRI; this may explain why Bcl-2 downregulation results in increased sensitivity to HIRI. These previous studies suggest that the downregulation of anti-apoptotic genes and a subsequent increase in apoptosis may impair cell survival post HIRI (12).…”

Exogenous vascular endothelial growth factor delivery prior to endothelial precursor cell transplantation in orthotopic liver transplantation–induced hepatic ischemia/reperfusion injury

“…ASC activity also decreases antiapoptotic BCL2 expression while increasing proapoptotic caspase 3 expression . In addition, HIRI also activates expression of HO‐1 (also known as HSP32), which provides protection against HIRI through carbon monoxide (CO) generation . Mechanistically, HO‐1 promotes the expression of several antiapoptotic proteins through CO generation, including BCL2 and HSP70 .…”

“…VEGF stimulates hepatocyte proliferation through VEGFR‐1–induced HGF up‐regulation . Specifically, VEGF's binding to LSECs triggers the release of pro‐HGF, which is then cleaved to form HGF . HGF then activates the release of TGF‐α and other downstream signals that promote cell‐cycle transition .…”