Transplantation of Adipose Tissue-Derived Multi-Lineage Progenitor Cells Reduces Serum Cholesterol in Hyperlipidemic Watanabe Rabbits

Background: Familial hypercholesterolemia (FH) is an autosomal co-dominant disease characterized by high concentrations of pro-atherogenic lipoproteins and premature atherosclerosis. We have examined the response to in situ stem cell therapy using human adipose tissue-derived multi-lineage progenitor stem cells (hADMPC) in the LDL-receptor deficient Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model for homozygous FH. Methods: WHHL rabbits received either normal control rabbit-derived GFP-rabbit-derived or WHHL rabbit-derived ADMPC (normal-ADMPC, GFP-ADMPC and diseased-ADMPC, respectively) via the portal vein. This was followed by 12-week immunosuppressive therapy to avoid allogenic rejection. In situ survival and differentiation of the ADMPC into hepatocytes was examined by immunohistochemical analysis, respectively. Lipid profile was examined before-, and 4-, 8-and 12 weeks after transplantation. LDL clearance was examined at the end of the study by(125)I-LDL turnover. Results: In situ survival of GFP-ADMPC was confirmed after transplantation. The cells integrated into the hepatic parenchyma and co-expressed GFP and hepatocyte markers such as albumin, indicating that the cells were reprogrammed into hepatocytes-like cells in situ. Transplantation of normal-ADMPC but not diseased-ADMPC resulted in a significant reduction of serum total-and LDL-cholesterol after transplantation. I-125-LDL turnover study showed significant improvement in the rate of LDL clearance in the WHHL rabbits with transplanted normal-ADMPC but not in those transplanted with diseased-ADMPC. Conclusion: Transplantation of ADMPC but not diseased ones corrected the metabolic defects in WHHL rabbits, suggesting that ADMPC transplantation is a potentially useful therapy for FH.