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

Tayaramma Thatava, Yogish C Kudva, Ramakrishna Edukulla, Karen Squillace, Josep Genebriera De Lamo, Yulia Krotova Khan, Toshie Sakuma, Seiga Ohmine, Andre Terzic, Yasuhiro H Ikeda

Research output: Contribution to journalArticle

57 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)228-239
Number of pages12
JournalMolecular Therapy
Volume21
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

Induced Pluripotent Stem Cells
Type 1 Diabetes Mellitus
Cell Differentiation
Clone Cells
Insulin
Gastrula
Therapeutic Equivalency
Precision Medicine
Endoderm
Glucagon
Islets of Langerhans
Transcriptome
Genes
Transcription Factors
Embryonic Structures
Glucose
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Thatava, T., Kudva, Y. C., Edukulla, R., Squillace, K., De Lamo, J. G., Khan, Y. K., ... Ikeda, Y. H. (2013). Intrapatient Variations in Type 1 Diabetes-specific iPS Cell Differentiation into Insulin-producing Cells. Molecular Therapy, 21(1), 228-239. https://doi.org/10.1038/mt.2012.245

Intrapatient Variations in Type 1 Diabetes-specific iPS Cell Differentiation into Insulin-producing Cells. / Thatava, Tayaramma; Kudva, Yogish C; Edukulla, Ramakrishna; Squillace, Karen; De Lamo, Josep Genebriera; Khan, Yulia Krotova; Sakuma, Toshie; Ohmine, Seiga; Terzic, Andre; Ikeda, Yasuhiro H.

In: Molecular Therapy, Vol. 21, No. 1, 01.2013, p. 228-239.

Research output: Contribution to journalArticle

Thatava, T, Kudva, YC, Edukulla, R, Squillace, K, De Lamo, JG, Khan, YK, Sakuma, T, Ohmine, S, Terzic, A & Ikeda, YH 2013, 'Intrapatient Variations in Type 1 Diabetes-specific iPS Cell Differentiation into Insulin-producing Cells', Molecular Therapy, vol. 21, no. 1, pp. 228-239. https://doi.org/10.1038/mt.2012.245
Thatava, Tayaramma ; Kudva, Yogish C ; Edukulla, Ramakrishna ; Squillace, Karen ; De Lamo, Josep Genebriera ; Khan, Yulia Krotova ; Sakuma, Toshie ; Ohmine, Seiga ; Terzic, Andre ; Ikeda, Yasuhiro H. / Intrapatient Variations in Type 1 Diabetes-specific iPS Cell Differentiation into Insulin-producing Cells. In: Molecular Therapy. 2013 ; Vol. 21, No. 1. pp. 228-239.
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