Intrapatient Variations in Type 1 Diabetes-specific iPS Cell Differentiation Into Insulin-producing Cells

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 acro...

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Bibliographic Details
Published in:Molecular therapy 2013-01, Vol.21 (1), p.228-239
Main Authors: Thatava, Tayaramma, Kudva, Yogish C, Edukulla, Ramakrishna, Squillace, Karen, De Lamo, Josep Genebriera, Khan, Yulia Krotova, Sakuma, Toshie, Ohmine, Seiga, Terzic, Andre, Ikeda, Yasuhiro
Format: Article
Language:English
Subjects:
Cell Differentiation
Cell Lineage
Cloning
Diabetes
Diabetes Mellitus, Type 1 - metabolism
Diabetes Mellitus, Type 1 - pathology
Disease
Gene expression
Gene Expression Profiling
Genetic Vectors
Humans
Insulin
Insulin - biosynthesis
Karyotyping
Medical schools
Medicine
Morphology
Oligonucleotide Array Sequence Analysis
Original
Pancreas - metabolism
Pancreas - pathology
Patients
Phosphatase
Polymerase Chain Reaction
Stem cells
Stem Cells - metabolism
Stem Cells - pathology
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Summary: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.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2012.245