Tumor-free transplantation of Patient-Derived induced pluripotent stem cell progeny for customized islet regeneration

Moustafa M. El Khatib, Seiga Ohmine, Egon J. Jacobus, Jason M. Tonne, Salma G. Morsy, Sara J. Holditch, Claire A. Schreiber, Koji Uetsuka, Noemi Fusaki, Dennis A. Wigle, Andre Terzic, Yogish C. Kudva, Yasuhiro Ikeda

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Human induced pluripotent stem cells (iPSCs) and derived progeny provide invaluable regenerative platforms, yet their clinical translation has been compromised by their biosafety concern. Here, we assessed the safety of transplanting patient-derived iPSC-generated pancreatic endoderm/ progenitor cells. Transplantation of progenitors from iPSCs reprogrammed by lentiviral vectors (LV-iPSCs) led to the formation of invasive teratocarcinoma-like tumors in more than 90% of immunodeficient mice. Moreover, removal of primary tumors from LV-iPSC progeny-transplanted hosts generated secondary and metastatic tumors. Combined transgene-free (TGF) reprogramming and elimination of residual pluripotent cells by enzymatic dissociation ensured tumor-free transplantation, ultimately enabling regeneration of type 1 diabetes-specific human islet structures in vivo. The incidence of tumor formation in TGF-iPSCs was titratable, depending on the oncogenic load, with reintegration of the cMYC expressing vector abolishing tumor-free transplantation. Thus, transgenefree cMYC-independent reprogramming and elimination of residual pluripotent cells are mandatory steps in achieving transplantation of iPSC progeny for customized and safe islet regeneration in vivo.

Original languageEnglish (US)
Pages (from-to)694-702
Number of pages9
JournalStem Cells Translational Medicine
Volume5
Issue number5
DOIs
StatePublished - 2016

Keywords

  • Insertional mutagenesis
  • Integration
  • Teratoma
  • Type 1 diabetes
  • iPS cells

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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