Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells
نویسندگان
چکیده
Familial 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.
منابع مشابه
A Quick update from the Past to Current Status of Human Pluripotent Stem Cell-derived Hepatocyte culture systems
Pluripotent stem cells (PSCs) may be offered as an unlimited cell source for the hepatocyte generation. The generation of hepatocytes from stem cells in vitro would provide an alternative cell source for applications in drug discovery and cell transplantation. In this review, we discuss different approaches to generate pluripotent stem cell-derived hepatocytes, advantages, limitations for each ...
متن کاملCRISPR correction of a homozygous low‐density lipoprotein receptor mutation in familial hypercholesterolemia induced pluripotent stem cells
Familial hypercholesterolemia (FH) is a hereditary disease primarily due to mutations in the low-density lipoprotein receptor (LDLR) that lead to elevated cholesterol and premature development of cardiovascular disease. Homozygous FH patients (HoFH) with two dysfunctional LDLR alleles are not as successfully treated with standard hypercholesterol therapies, and more aggressive therapeutic appro...
متن کاملLarge-Scale Expansion of Human Embryonic and Induced Pluripotent Stem Cells for Cell Therapy Applications
Successful isolation, derivation and culturing of human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced pluripotent stem (hiPSCs) cells in laboratory scale has opened new horizones for cell therapy applications such as tissue engineering and regenerative medicine. However, most of the cell therapy protocols using these unique cells require large number of ...
متن کاملFingolimod Enhances Oligodendrocyte Differentiation of Transplanted Human Induced Pluripotent Stem Cell-Derived Neural Progenitors
Multiple sclerosis (MS) is an autoimmune disease which affects myelin in the central nervous system (CNS) and leads to serious disability. Currently available treatments for MS mainly suppress the immune system. Regenerative medicine-based approaches attempt to increase myelin repair by targeting endogenous progenitors or transplanting stem cells or their derivatives. Fingolimod exerts anti-inf...
متن کاملP-50: Elongating and Elongated Spermatids Manufactured In Vitro from Non-Human Primate Pluripotent Stem Cells
Background: We have recently shown that human embryonic (hESCs) and induced pluripotent stem cells (hiPSCs) can differentiate into advanced spermatogenic cells including round spermatids by in vitro culture (Easley et al., Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells. Cell Reports 2, 440-446 2012) and also, in collaboration, that rhesus spermatogonial ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 8 شماره
صفحات -
تاریخ انتشار 2017