Induction of Expandable Tissue-Specific Progenitor Cells from Human Pancreatic Tissue through Transient Expression of Defined Factors

Hirofumi Noguchi, Chika Miyagi-Shiohira, Yoshiki Nakashima, Takao Kinjo, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, A. M.James Shapiro, Tatsuya Kin

Research output: Contribution to journalArticle

Abstract

We recently demonstrated the generation of mouse induced tissue-specific stem (iTS) cells through transient overexpression of reprogramming factors combined with tissue-specific selection. Here we induced expandable tissue-specific progenitor (iTP) cells from human pancreatic tissue through transient expression of genes encoding the reprogramming factors OCT4 (octamer-binding transcription factor 4), p53 small hairpin RNA (shRNA), SOX2 (sex-determining region Y-box 2), KLF4 (Kruppel-like factor 4), L-MYC, and LIN28. Transfection of episomal plasmid vectors into human pancreatic tissue efficiently generated iTP cells expressing genetic markers of endoderm and pancreatic progenitors. The iTP cells differentiated into insulin-producing cells more efficiently than human induced pluripotent stem cells (iPSCs). iTP cells continued to proliferate faster than pancreatic tissue cells until days 100–120 (passages 15–20). iTP cells subcutaneously inoculated into immunodeficient mice did not form teratomas. Genomic bisulfite nucleotide sequence analysis demonstrated that the OCT4 and NANOG promoters remained partially methylated in iTP cells. We compared the global gene expression profiles of iPSCs, iTP cells, and pancreatic cells (islets >80%). Microarray analyses revealed that the gene expression profiles of iTP cells were similar, but not identical, to those of iPSCs but different from those of pancreatic cells. The generation of human iTP cells may have important implications for the clinical application of stem/progenitor cells.

Original languageEnglish
Pages (from-to)243-252
Number of pages10
JournalMolecular Therapy - Methods and Clinical Development
Volume13
DOIs
Publication statusPublished - Jun 14 2019

Keywords

  • iPSCs
  • iTP
  • iTS
  • induced pluripotent stem cells
  • induced tissue-specific progenitor cells
  • induced tissue-specific stem cells
  • pancreas
  • reprogramming factors

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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