Noninvasive evaluation of liver repopulation by transplanted hepatocytes using 31P MRS imaging in mice

Abstract

Hepatocyte transplantation (HT) is being explored as a substitute for liver transplantation for the treatment of liver diseases. For the clinical application of HT, a preparative regimen that allows preferential proliferation of transplanted cells in the host liver and a noninvasive method to monitor donor cell engraftment, proliferation, and immune rejection would be useful. We describe an imaging method that employs the creatine kinase (CK) gene as a marker of donor hepatocytes. Creatine kinase is unique among marker genes, because it is normally expressed in brain and muscle tissues and is therefore not immunogenic. Preferential proliferation of transplanted CK-expressing hepatocytes was induced by preparative hepatic irradiation and expression of hepatocyte growth factor using a recombinant adenoviral vector. CK is normally not expressed in mouse liver and its expression by the donor cells led to the production of phosphocreatine in the host liver, permitting 31 P magnetic resonance spectroscopic imaging of liver repopulation by engrafted hepatocytes. In conclusion, this study combined a noninvasive imaging technique to assess donor hepatocyte proliferation with a preparative regimen of partial liver irradiation that allowed regional repopulation of the host liver. Our results provide groundwork for future development of clinical protocols for HT. (HEPATOLOGY 2006;44:1250-1258

Manganese cell labeling of murine hepatocytes using manganese(III)‐transferrin

“…In this case, manganese release from hepatocytes and liver could be exploited as an MR assay of normal liver function. Furthermore, there is also interest in developing MR assays for viability and function of hepatocytes (35) and other cell types (24) incubation of rat liver slices in Mn 2þ , suggest that hepatocytes have three apparently saturable routes for manganese entry. These are (1) a low-affinity mechanism with K ap in the region of 100 mM; (2) a moderately-high-affinity mechanism with K ap in the range of 0.5-2 mM; and (3) a high-affinity mechanism that operates with a K ap of 0.075 mM.…”

Construction of liver tissue in vivo with preparative partial hepatic irradiation and growth stimulus: investigations of less invasive techniques and progenitor cells

“…We measured the levels of serum HGF, which is known as a strong stimulator for hepatocytes growth. Although supplying HGF via an adenovirus vector was demonstrated to induce proliferation of transplanted hepatocytes (10,11,14), PVBL did not increase the levels of HGF, as observed in the clinical PVE study (16). Liver regeneration is regulated by an orchestrated and complex response, involving not only HGF, but also various kinds of mediators.…”

“…Although these results are very attractive, hepatectomy is too invasive to be carried out in patients. Instead of hepatectomy, Fas-mediated apoptosis of host hepatocytes (9) or administration of a recombinant adenovirus vector expressing hepatocyte growth factor (HGF) (10,11) has been successful in inducing massive repopulation of transplanted hepatocytes. However, these strategies appear difficult to implement clinically because of potential toxicity.…”

Translational Regenerative Medicine—Hepatic Systems

“…Transplants performed in rats have used luciferase imaging to view the engrafted cells; however, this treatment option is not translatable to humans due to the thickness of the abdominal wall. One approach is the use of the creatinine kinase gene as a marker for donor hepatocytes, which when expressed produces phosphocreatinine in the liver and allows for P-31 MRS magnetic resonance imaging of the engrafted donor hepatocytes [84]. Finally, improvements in immunosuppression protocols, or the development of cell-transplantation methods that do not require immunosuppression, would greatly accelerate the field of liver cellular therapy.…”