122 Other approaches have looked at transdifferentiation of hepatocytes from other progenitor cell sources. Mesenchymal stem cells,

whether from bone marrow, cord blood, cord lining cells, cord matrix cells, amniotic cells, adipose progenitor and muscle progenitors have been demonstrated to be capable of differentiation into hepatocytes in vitro.110,118 While it would be exhaustive to describe all human transplantation studies to date, a review on liver regeneration would be incomplete if studies relating to the original aims of understanding regeneration are not covered. To date, some 20 human studies have been undertaken, in which attempts were made to enhance liver regeneration. These can be grouped into CH5424802 adult hepatocyte transplantation, fetal hepatocyte transplantation and bone marrow stem cell transplantation. As mature hepatocytes are the main cells that

regenerate the injured liver, roughly 25 patients with acute liver failure Lenvatinib nmr have been transplanted with 107–9 hepatocytes in an attempt to salvage the failing liver.123 Instead of adult hepatocytes, Habibullah et al.124 transplanted 6 patients with acute liver failure with 107 fetal hepatocytes. In these studies, there were transient clinical improvements in encephalopathy and ammonia levels, but there was no overall transplant-free survival benefit. It is likely that the quantity of cells (up to 5% of liver mass) transplanted for each patient may have been too low to register a clinical benefit, and that the window period was too narrow for these cells to regenerate. Although the use

of bone marrow stem cells as candidates for liver regeneration is controversial, the availability of these cells and ease by which they can be harvested has lead to the transplantation of bone marrow stem cells or peripheral blood stem cells in more than 100 tuclazepam patients with cirrhosis. Of note, one small study employed the infusion of AC133+ cells mobilized from the bone marrow after one lobe of the liver has been deliberately embolised, and showed that regeneration in the remaining lobe was augmented.125 Most of these studies are uncontrolled, but clinical improvement in measurable parameters has been claimed.126 The mechanisms by which improvement has occurred are still not known, but studies have shown that remodeling in cirrhotic liver can occur by paracrine signals (metalloproteinases) from bone marrow mesenchymal cells, without actual transdifferentiation into hepatocytes. Whether this work represents true progenitor cell regeneration or the modulation of local environment for native hepatocytes to regenerate, this strategy may yet be promising as long as liver regeneration occurs and clinical outcome is improved.