Early stage transplantation of bone marrow cells markedly ameliorates copper metabolism and restores liver function in a mouse model of Wilson disease

Abstract

BackgroundRecent studies have demonstrated that normal bone marrow (BM) cells transplantation can correct liver injury in a mouse model of Wilson disease (WD). However, it still remains unknown when BM cells transplantation should be administered. The aim of this study was to investigate the potential impact of normal BM cells transplantation at different stages of WD to correct liver injury in toxic milk (tx) mice.MethodsRecipient tx mice were sublethally irradiated (5 Gy) prior to transplantation. The congenic wild-type (DL) BM cells labeled with CM-DiI were transplanted via caudal vein injection into tx mice at the early (2 months of age) or late stage (5 months of age) of WD. The same volume of saline or tx BM cells were injected as controls. The DL donor cell population, copper concentration, serum ceruloplasmin oxidase activity and aspartate aminotransferase (AST) levels in the various groups were evaluated at 1, 4, 8 and 12 weeks post-transplant, respectively.ResultsThe DL BM cells population was observed from 1 to 12 weeks and peaked by the 4th week in the recipient liver after transplantation. DL BM cells transplantation during the early stage significantly corrected copper accumulation, AST across the observed time points and serum ceruloplasmin oxidase activity through 8 to 12 weeks in tx mice compared with those treated with saline or tx BM cells (all P < 0.05). In contrast, BM cells transplantation during the late stage only corrected AST levels from 4 to 12 weeks post-transplant and copper accumulation at 12 weeks post-transplant (all P < 0.05). No significant difference was found between the saline and tx BM cells transplantation groups across the observed time points (P > 0.05).ConclusionsEarly stage transplantation of normal BM cells is better than late stage transplantation in correcting liver function and copper metabolism in a mouse model of WD.

Macrophage-Derived Exosomes in TLR9-/- Mice Ameliorate Sepsis-Induced Mitochondrial Oxidative Stress and Apoptosis in Cardiomyocytes

“…In addition, 48 male C57BL/6J mice (8-10 weeks old, 24 TLR9 −/− mice and 24 WT mice) were purchased from the Henan Skbex Biotechnology Company. The TLR9 −/− and WT mice were used as donor mice and euthanized with isoflurane, and the myeloid or bone marrow cells were acquired from femur and tibia bones, then the C57/BL mice were irradiated with 5.5 GY, and 6 × 10 7 donor cells [ 22 , 23 ] dissolved in RPMI-1640 were injected via caudal veins for the recipient mice. The recipient mice were administrated with acidified water with 100 mg/L neomycin and 10 mg/L polymyxin B sulfate.…”

Transplantation of ATP7B–Transduced Bone Marrow Mesenchymal Stem Cells Decreases Copper Overload in Rats

“…To confirm that injected MSCs ATP7B had differentiated into normal hepatocytes, GFP/CK-18 double fluorescence intensity was assessed using a previously described protocol [31] . Briefly, liver tissues were embedded in tissue freezing medium (Tissue-Tek OCT Compound, Sakura Finetek, Torrance, CA, USA) and frozen at −80°C.…”

Copper, Iron, Cadmium, and Arsenic, All Generated in the Universe: Elucidating Their Environmental Impact Risk on Human Health Including Clinical Liver Injury

“…In the case of deceased donor liver shortage, living related liver transplantation is an option [ 146 ]. Although promising data were obtained in animal studies, future RCT studies in humans are required to assess innovative approaches directed at hepatocyte transplantation [ 146 , 148 ], the transplantation of bone marrow cells [ 149 ], and gene therapy [ 106 , 146 ]. The indication for a liver transplantation has to be carefully considered in Wilson disease patients with severe psycho-neurological symptoms [ 146 , 147 ].…”