The Potential of Bone Marrow Stem Cells to Correct Liver Dysfunction in a Mouse Model of Wilson's Disease

Abstract

Metabolic liver diseases are excellent targets for correction using novel stem cell, hepatocyte, and gene therapies. In this study, the use of bone marrow stem cell transplantation to correct liver disease in the toxic milk (tx) mouse, a murine model for Wilson's disease, was evaluated. Preconditioning with sublethal irradiation, dietary copper loading, and the influence of cell transplantation sites were assessed. Recipient tx mice were sublethally irradiated (4 Gy) prior to transplantation with bone marrow stem cells harvested from normal congenic (DL) littermates. Of 46 transplanted tx mice, 11 demonstrated genotypic repopulation in the liver. Sublethal irradiation was found to be essential for donor cell engraftment and liver repopulation. Dietary copper loading did not improve cell engraftment and repopulation results. Both intravenously and intrasplenically transplanted cells produced similar repopulation successes. Direct evidence of functionality and disease correction following liver repopulation was observed in the 11 mice where liver copper levels were significantly reduced when compared with mice with no liver repopulation. The reversal of copper loading with bone marrow cells is similar to the level of correction seen when normal congenic liver cells are used. Transplantation of bone marrow cells partially corrects the metabolic phenotype in a mouse model for Wilson's disease.

Correction of copper metabolism is not sustained long term in Wilson’s disease mice post bone marrow transplantation

“…Irradiation results in hepatocyte death during mitosis and thus reduces hepatocyte proliferation in response to liver damage [22], creating the opportunity for donor cells to be recruited to assist in liver repair. Without irradiation, we found no engraftment of DL BM cells in the liver of tx mice [1], suggesting that potential liver damage from irradiation is a prior requirement for liver engraftment. Fig.…”

“…The mouse has an equivalent point mutation in the WND gene to humans, causing a mild liver disease of copper overload [10][11][12]. Until our own recent results using the toxic milk mouse (tx mouse) [1], the only mouse model of metabolic liver disease to demonstrate liver disease correction following BM transplantation was the fumarylacetoacetate hydrolase (FAH -/-) knockout mouse [4]. Without treatment of the metabolic derangement, liver disease in the FAH mouse model is lethal.…”

“…Bone marrow (BM) provides a more readily available source of cells and we have shown previously that they can effect disease correction in the tx mouse over the short term [1].…”

MR Tracking of Magnetically Labeled Mesenchymal Stem Cells in Rat Kidneys with Acute Renal Failure

“…Dysfunction or necrosis of the renal tubular episues, such as those of the kidney, heart, and liver, etc. (1,14,17,23). Although MSCs can differentiate into renal thelial cells is the most common pathologic feature of ARF.…”

Therapeutic Potential of Adult Bone Marrow Stem Cells in Liver Disease and Delivery Approaches

“…Liver function improvement and liver copper levels decrease were observed, indicating that transplantation of BMSCs partially corrects the metabolic phenotype in this model [60].…”