title: Multisystemic Disease Modeling of Liver-Derived Protein Folding Disorders Using Induced Pluripotent Stem Cells (iPSCs).
abstract: Familial transthyretin amyloidosis (ATTR) is an autosomal dominant protein-folding disorder caused by over 100 distinct mutations in the transthyretin (TTR) gene. In ATTR, protein secreted from the liver aggregates and forms fibrils in target organs, chiefly the heart and peripheral nervous system, highlighting the need for a model capable of recapitulating the multisystem complexity of this clinically variable disease. Here, we describe detailed methodologies for the directed differentiation of protein folding disease-specific iPSCs into hepatocytes that produce mutant protein, and neural-lineage cells often targeted in disease. Methodologies are also described for the construction of multisystem models and drug screening using iPSCs.
authors: School of Medicine and the Center for Regenerative Medicine (CReM), Boston University, Boston, MA, USA.
authors: Amy
authors: A
authors: Leung
authors: School of Medicine and the Center for Regenerative Medicine (CReM), Boston University, Boston, MA, USA. gjmurphy@bu.edu.
authors: George J
authors: GJ
authors: Murphy
mesh_terms: D028341:Activins / Q000494:pharmacology; D028227:Amyloid Neuropathies, Familial / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival; D065150:Cellular Reprogramming; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D015870:Gene Expression; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007797:Laminin / Q000737:chemistry; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D061251:Primary Cell Culture; D017510:Protein Folding; D011509:Proteoglycans / Q000737:chemistry; D017457:Receptors, Albumin / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D060508:Wnt3 Protein / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004338:Drug Combinations; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007797:Laminin; D011509:Proteoglycans; D017457:Receptors, Albumin; C555507:WNT3 protein, human; D060508:Wnt3 Protein; C422405:activin A; C091986:transthyretin receptor; D028341:Activins; C059485:matrigel; D014212:Tretinoin; C579455:BDNF protein, human; D003094:Collagen
keywords: Amyloidosis; Directed differentiation; Disease modeling; Drug screening; Induced pluripotent stem cells; Protein folding disorders