Liver Engraftment by Transplanted Human Progenitor Cells with High Aldehyde Dehydrogenase Activity in a Novel Model, NOD/SCID/MPSVII Mice.

Hematopoietic stem cells (HSC) have been reported to generate cells other than the blood lineage and thus hold enormous promise for repairing damaged tissues. Evidence from our lab and others suggests that hepatocytes can be derived from HSC. However, the frequency of HSC-derived hepatocytes varies tremendously among various studies which use different stem cell subsets and different mouse models. Therefore, the significance of hematopoietic stem cell contribution to the repair of liver damage is still controversial. To further explore this potential, we used the beta-glucuronidase (GUSB)-deficient NOD/SCID/MPSVII mouse model for better identification of engrafted human cells. We and others have previously shown that lineage depleted (lin⁻) human umbilical cord blood-derived cells with high aldehyde dehydrogenase activity (ALDH^hi) are enriched for primitive HSC. In the current studies, ALDH^hi lin⁻ cells were transplanted into irradiated NOD/SCID/MPSVII mice. One month after transplantation, carbon tetrachloride (CCl₄) was administrated into the mice twice a week for 4 weeks to induced liver damage. In this model, ALDH^hi lin⁻ cells gave rise to robust hematopoietic reconstitution (71%±13.1 in bone marrow, 12.8%±4% in peripheral blood and 10.7%±8.8% in spleen) while ALDH^lolin⁻ cells failed to engraft. In the liver, engraftment of human cells in mice tansplanted with ALDH^hi lin⁻ cells was demonstrated by the presence of human Alu DNA using PCR. CD45⁺ cells were detected by both FACS (2.11%±1.1) and by immunohistological staining in the liver sections. GUSB expression was frequently evident in kuffer cells adjacent to blood vessels and to a lesser extent in the liver parenchyma. GUSB⁺ cells were more abundant than CD45⁺ cells. Most interestingly, human liver-specific a-1-antitrypsin mRNA was detected in the recipient murine livers by RT-PCR analysis. Human albumin- expressing cells were also found in these livers, although such cells were rare as compared to human CD45⁺ or GUSB⁺ cells. In contrast, human cells were not detected in the livers of mice tansplanted with ALDH^lolin⁻ cells in any of our assays. Thus, ALDH-expressing progenitor cells demonstrated potent engraftment of variable cellular phenotypes, suggesting that these adult progenitor cells should be further explored in transplantation models of tissue damage. Our data also support the idea that hematopoietic stem cells may home to the injured liver and release trophic factors that hasten tissue repair, while direct differentiation of these stem cells to hepatocytes or fusion of these cells with hepatocytes is rare and contributes to a lesser extent to liver repair.