Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells

Abstract

SummaryFamilial hypercholesterolemia (FH) causes elevation of low-density lipoprotein cholesterol (LDL-C) in blood and carries an increased risk of early-onset cardiovascular disease. A caveat for exploration of new therapies for FH is the lack of adequate experimental models. We have created a comprehensive FH stem cell model with differentiated hepatocytes (iHeps) from human induced pluripotent stem cells (iPSCs), including genetically engineered iPSCs, for testing therapies for FH. We used FH iHeps to assess the effect of simvastatin and proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies on LDL-C uptake and cholesterol lowering in vitro. In addition, we engrafted FH iHeps into the liver of Ldlr−/−/Rag2−/−/Il2rg−/− mice, and assessed the effect of these same medications on LDL-C clearance and endothelium-dependent vasodilation in vivo. Our iHep models recapitulate clinical observations of higher potency of PCSK9 antibodies compared with statins for reversing the consequences of FH, demonstrating the utility for preclinical testing of new therapies for FH patients.

Distinct Gene Expression and Epigenetic Signatures in Hepatocyte-like Cells Produced by Different Strategies from the Same Donor

“…While these studies demonstrate significant advances, it should be noted that iPSC-HLCs and hiHeps were still not as efficient at engrafting as PHHs in FRG mice. This highlights the need to improve hepatic maturation and/or liver preconditioning, prior to cell transplantation in the future ( Fisher and Strom, 2006 , Grompe and Strom, 2013 , Yang et al., 2017 ).…”

Pluripotent stem cell-derived bile canaliculi-forming hepatocytes to study genetic liver diseases involving hepatocyte polarity

“…Patientown cells are the ideal source to study endogenous mutant proteins. The ability to generate induced pluripotent stem cells (iPSC) from patients' cells and to differentiate these to hepatocytes has been a major step towards the study of endogenous mutant proteins, including ATP7B, in physiologically relevant cell types [16][17][18][19][20][21][22][23][24]. However, the potential of iPSC-derived hepatocytes to polarize and form bile canaliculi, and their potential to study the polarized trafficking of endogenously expressed mutant protein, is not known.…”

Radiation-primed hepatocyte transplantation in murine monogeneic dyslipidemia normalizes cholesterol and prevents atherosclerosis

“…Gy preparative HIR but without mitogenic stimulation. 52 The comparatively low repopulation reported in that study could have resulted from an HIR dose that was insufficient to reduce the mitotic potential of the host hepatocytes adequately, a lack of mitotic stimulation or both. This highlights the importance of an optimized regimen combining a sufficiently high radiation dose with mitotic stimulation of transplanted cells.…”