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Inhibition of MicroRNA-221 and 222 Enhances Hematopoietic Differentiation from Human Pluripotent Stem Cells via c-KIT Upregulation

  • Lee, Ji Yoon (Department of Biomedical Sciences, Stem Cell Institute, CHA University) ;
  • Kim, MyungJoo (Department of Internal Medicine, School of Medicine, Kangwon National University) ;
  • Heo, Hye-Ryeon (Department of Internal Medicine, School of Medicine, Kangwon National University) ;
  • Ha, Kwon-Soo (Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University) ;
  • Han, Eun-Taek (Department of Medical Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University) ;
  • Park, Won Sun (Department of Physiology, School of Medicine, Kangwon National University) ;
  • Yang, Se-Ran (Department of Thoracic & Cardiovascular Surgery, School of Medicine, Kangwon National University) ;
  • Hong, Seok-Ho (Department of Internal Medicine, School of Medicine, Kangwon National University)
  • Received : 2018.06.02
  • Accepted : 2018.10.10
  • Published : 2018.11.30

Abstract

The stem cell factor (SCF)/c-KIT axis plays an important role in the hematopoietic differentiation of human pluripotent stem cells (hPSCs), but its regulatory mechanisms involving microRNAs (miRs) are not fully elucidated. Here, we demonstrated that supplementation with SCF increases the hematopoietic differentiation of hPSCs via the interaction with its receptor tyrosine kinase c-KIT, which is modulated by miR-221 and miR-222. c-KIT is comparably expressed in undifferentiated human embryonic and induced pluripotent stem cells. The inhibition of SCF signaling via treatment with a c-KIT antagonist (imatinib) during hPSC-derived hematopoiesis resulted in reductions in the yield and multi-lineage potential of hematopoietic progenitors. We found that the transcript levels of miR-221 and miR-222 targeting c-KIT were significantly lower in the pluripotent state than they were in terminally differentiated somatic cells. Furthermore, suppression of miR-221 and miR-222 in undifferentiated hPSC cultures induced more hematopoiesis by increasing c-KIT expression. Collectively, our data implied that the modulation of c-KIT by miRs may provide further potential strategies to expedite the generation of functional blood cells for therapeutic approaches and the study of the cellular machinery related to hematologic malignant diseases such as leukemia.

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

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