Mouse Liver Failure Treated by Human Cord Blood Stem Cells
Sacramento, CA -
It is known that administration of autologous bone marrow cells into patients with liver failure induces clinical improvement, at least in pilot trials of cirrhotic patients. Mechanistically this may work through the process of transdifferentiation, that is, bone marrow directly differentiating to hepatocytes. Or through indirect mechanisms such as production of cytokines/inhibition of inflammation.
An elegant study was conducted by Zhou et al. (Human progenitor cells with high aldehyde dehydrogenase activity efficiently engraft into damaged liver in a novel model. Hepatology 2009 Feb 2) in which human umbilical cord blood cells, selected for aldehyde dehydrogenase activity (correlates with high stem cell activity) were administered into an immune deficient animal model of liver failure induced by carbon tetrachloride. The recipient animals were NOD-SCID with a deficiency in beta-glucuronidase and the mucopolysaccharidosis type VII phenotype.
The investigators found that the human aldehyde dehydrogenase high expressing, lineage negative, cord blood cells incorporated into the damaged liver at a range of 3% to 14.2%. Most interestingly, the cells expressed several human hepatic markers such as liver-specific alpha1-antitrypsin messenger RNA, albumin and hepatocyte nuclear factor 1 protein.
Fusion between the human and mouse cells was very rare as observed by human versus mouse centromeric fluorescent in situ hybridization analysis.
These data suggest the continued investigation of cord blood and bone marrow cells for the treatment of liver failure. This has already been reported for CD34 positive cells, which have been used in clinical trials for liver failure.
Perhaps a more interesting and easier approach would be administration of the stem cell mobilizer G-CSF, which has been demonstrated to accelerate liver regeneration.
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jonnyboy said...
given all of the work being done in stem cells administered to liver injured animals, I wonder why no one is using stem cells for enhancing transplant efficacy. I mean if the bone marrow or cord blood stem cells can rejuvenate hepatocytes and actually accelerate post carbon tetrachloride healing, would it not make sense that they could actually help increase the quality of a liver transplant graft?
I wonder if just the simple process of G-CSF mobilization of the recipient after transplant of liver could increase survival or decrease need for immune suppression...remember the cleaner the graft is the less danger signals and presumably the less immunogneic it is