http://diposit.ub.edu/dspace/bitstream/2445/120385/1/664909.pdf

Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis

Chronic diseases confer tissue and organ damage that reduce quality of life and are largely refractory to therapy. Although stem cells hold promise for treating degenerative diseases by 'seeding' injured tissues, the regenerative capacity of stem cells is influenced by regulatory networks orchestrated by local immune responses to tissue damage, with macrophages being a central component of the injury response and coordinator of tissue repair. Recent research has turned to how cellular and signaling components of the local stromal microenvironment (the 'soil' to the stem cells' seed), such as local inflammatory reactions, contribute to successful tissue regeneration. This Review discusses the basic principles of tissue regeneration and the central role locally acting components may play in the process. Application of seed-and-soil concepts to regenerative medicine strengthens prospects for developing cell-based therapies or for promotion of endogenous repair.

Preparing the ground for tissue regeneration: from mechanism to therapy

After liver injury, regeneration occurs through self-replication of hepatocytes. In severe liver injury, hepatocyte proliferation is impaired-a feature of human chronic liver disease. It is unclear whether other liver cell types can regenerate hepatocytes. Here we use two independent systems to impair hepatocyte proliferation during liver injury to evaluate the contribution of non-hepatocytes to parenchymal regeneration. First, loss of β1-integrin in hepatocytes with liver injury triggered a ductular reaction of cholangiocyte origin, with approximately 25% of hepatocytes being derived from a non-hepatocyte origin. Second, cholangiocytes were lineage traced with concurrent inhibition of hepatocyte proliferation by β1-integrin knockdown or p21 overexpression, resulting in the significant emergence of cholangiocyte-derived hepatocytes. We describe a model of combined liver injury and inhibition of hepatocyte proliferation that causes physiologically significant levels of regeneration of functional hepatocytes from biliary cells.

/pdf/cholangiocytes-act-as-facultative-liver-stem-cells-during-2181ttugaz.pdf

Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration

Adult Hepatocytes Are Generated by Self-Duplication Rather than Stem Cell Differentiation

Liver regeneration has been studied for many decades and the mechanisms underlying regeneration of the normal liver following resection or moderate damage are well described. A large number of factors extrinsic (such as bile acids and circulating growth factors) and intrinsic to the liver interact to initiate and regulate liver regeneration. Less well understood, and more clinically relevant, are the factors at play when the abnormal liver is required to regenerate. Fatty liver disease, chronic scarring, prior chemotherapy and massive liver injury can all inhibit the normal programme of regeneration and can lead to liver failure. Understanding these mechanisms could enable the rational targeting of specific therapies to either reduce the factors inhibiting regeneration or directly stimulate liver regeneration. Although animal models of liver regeneration have been highly instructive, the clinical relevance of some models could be improved to bridge the gap between our in vivo model systems and the clinical situation. Likewise, modern imaging techniques such as spectroscopy will probably improve our understanding of whole-organ metabolism and how this predicts the liver's regenerative capacity. This Review describes briefly the mechanisms underpinning liver regeneration, the models used to study this process, and discusses areas in which failed or compromised liver regeneration is clinically relevant.

/pdf/liver-regeneration-mechanisms-and-models-to-clinical-4gl23to6a0.pdf

Liver regeneration - mechanisms and models to clinical application.

Regeneration of Liver After Extreme Hepatocyte Loss Occurs Mainly via Biliary Transdifferentiation in Zebrafish

The CCCH-type zinc finger transcription factor Zc3h8 represses NF-κB-mediated inflammation in digestive organs in zebrafish

Capsaicin, a transient receptor potential vanilloid 1 channel agonist, possesses antioxidative properties through activating nuclear factor-erythroid 2-related factor 2 (Nrf2). As oxidative stress is a major contributor to the development of contrast-associated acute kidney injury (CA-AKI), we investigated the protective effect of capsaicin against CA-AKI via Nrf2. C57BL/6J mice were treated with dehydration and iodixanol to establish the model of CA-AKI. For pretreatment, capsaicin (0.3 mg/kg) was given via intraperitoneal injection one hour before iodixanol injection. Nrf2-specific siRNA was given through the tail vein to knock down Nrf2. The CA-AKI mouse model had remarkable mitochondrial fragmentation and dysfunction and apoptosis of tubular cells, overproduction of superoxide in renal tubules, increased renal malondialdehyde, tubular epithelial cell injury, and renal dysfunction. Importantly, pretreatment with capsaicin significantly ameliorated tubular cell injury and renal dysfunction with decreased superoxide, renal malondialdehyde, and apoptotic tubular cells and improved mitochondrial morphology and function in the CA-AKI mouse model. The expression of Nrf2 was increased in the kidney from the CA-AKI mouse model and was further enhanced by capsaicin. Administration of siRNA through the tail vein successfully decreased Nrf2 expression in the kidney, and knockdown of Nrf2 by siRNA abolished the beneficial effects of capsaicin on CA-AKI. The present study demonstrated a protective effect of capsaicin pretreatment against CA-AKI via Nrf2.

/pdf/capsaicin-prevents-contrast-associated-acute-kidney-injury-3qmugu8r.pdf

Capsaicin Prevents Contrast-Associated Acute Kidney Injury through Activation of Nrf2 in Mice

Colorectal cancer (CRC) is a deadly and commonly diagnosed cancer. Cell‐free circulating tumor DNAs (ctDNA) have been used in the diagnosis and treatment of CRC, but there are open questions about the relationship between ctDNAs and CRC. Although mutations of genes detected by ctDNA in CRC have been studied, the quantitative relationship between ctDNA mutations and ctDNA concentration has not been addressed.

The association of blood ctDNA levels to mutations of marker genes in colorectal cancer

The liver plays a very important role in physiological processes of the human body. Liver regeneration has developed into an important area of study in liver disease. The Mtz (metronidazole)/NTR (nitroreductase)-mediated cell ablation system has been widely used to study the processes and mechanisms of liver injury and regeneration. However, high concentrations and toxic side effects of Mtz severely limit the application of the Mtz/NTR system. Therefore, screening new analogs to replace Mtz has become an important means to optimize the NTR ablation system. In this study, we screened five Mtz analogs including furazolidone, ronidazole, ornidazole, nitromide, and tinidazole. We compared their toxicity on the transgenic fish line Tg(fabp10a: mCherry-NTR) and their specific ablation ability on liver cells. The results showed that Ronidazole at a lower concentration (2 mM) had the same ability to ablate liver cells comparable with that of Mtz (10 mM), almost without toxic side effects on juvenile fish. Further study found that zebrafish hepatocyte injury caused by the Ronidazole/NTR system achieved the same liver regenerative effect as the Mtz/NTR system. The above results show that Ronidazole can replace Mtz with NTR to achieve superior damage and ablation effects in zebrafish liver.

Qingliang Zou

Papers

Regeneration of Liver After Extreme Hepatocyte Loss Occurs Mainly via Biliary Transdifferentiation in Zebrafish

The CCCH-type zinc finger transcription factor Zc3h8 represses NF-κB-mediated inflammation in digestive organs in zebrafish

Capsaicin Prevents Contrast-Associated Acute Kidney Injury through Activation of Nrf2 in Mice

The association of blood ctDNA levels to mutations of marker genes in colorectal cancer

Ronidazole Is a Superior Prodrug to Metronidazole for Nitroreductase-Mediated Hepatocytes Ablation in Zebrafish Larvae.