title: Intrapatient variations in type 1 diabetes-specific iPS cell differentiation into insulin-producing cells.
abstract: Nuclear reprogramming of adult somatic tissue enables embryo-independent generation of autologous, patient-specific induced pluripotent stem (iPS) cells. Exploiting this emergent regenerative platform for individualized medicine applications requires the establishment of bioequivalence criteria across derived pluripotent lines and lineage-specified derivatives. Here, from individual patients with type 1 diabetes (T1D) multiple human iPS clones were produced and prospectively screened using a battery of developmental markers to assess respective differentiation propensity and proficiency in yielding functional insulin (INS)-producing progeny. Global gene expression profiles, pluripotency expression patterns, and the capacity to differentiate into SOX17- and FOXA2-positive definitive endoderm (DE)-like cells were comparable among individual iPS clones. However, notable intrapatient variation was evident upon further guided differentiation into HNF4α- and HNF1β-expressing primitive gut tube, and INS- and glucagon (GCG)-expressing islet-like cells. Differential dynamics of pluripotency-associated genes and pancreatic lineage-specifying genes underlined clonal variance. Successful generation of glucose-responsive INS-producing cells required silencing of stemness programs as well as the induction of stage-specific pancreatic transcription factors. Thus, comprehensive fingerprinting of individual clones is mandatory to secure homogenous pools amenable for diagnostic and therapeutic applications of iPS cells from patients with T1D.
authors.affiliation: Department of Molecular Medicine, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Tayaramma
authors.initials: T
authors.lastname: Thatava
authors.forename: Yogish C
authors.initials: YC
authors.lastname: Kudva
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Edukulla
authors.forename: Karen
authors.initials: K
authors.lastname: Squillace
authors.forename: Josep Genebriera
authors.initials: JG
authors.lastname: De Lamo
authors.forename: Yulia Krotova
authors.initials: YK
authors.lastname: Khan
authors.forename: Toshie
authors.initials: T
authors.lastname: Sakuma
authors.forename: Seiga
authors.initials: S
authors.lastname: Ohmine
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D002454:Cell Differentiation; D019070:Cell Lineage; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D005822:Genetic Vectors; D006801:Humans; D007328:Insulin / Q000096:biosynthesis*; D007621:Karyotyping; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D007328:Insulin