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December 8, 2025BloodOpen Access

Overcoming maturation deficits in iPSC-NK cells through programmable T-bet induction

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Authors

YDYagmur DölalanSMStephan MeinkeFLFredrik Lanner

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Overview

Transcription factor t-bet enhances nk cell differentiation and cytotoxicity in induced pluripotent stem cells, indicating its role in immunotherapy.

Key Points

  • To explore the effects of T-bet induction on the maturation and functional capabilities of NK cells derived from iPSCs.
  • Integrated a doxycycline-inducible T-bet expression cassette into iPSCs using PiggyBac transposition.
  • Differentiated cells into NK cell lineage via a feeder-free embryoid-based protocol.
  • Administered doxycycline during hematopoietic progenitor stage to activate T-bet expression.
  • Assessed lineage progression and maturation through flow cytometry at weeks 3 to 5 and at the end of differentiation.
  • Conducted functional assays including CD107a degranulation against K562, Raji, and Daudi cells.
  • Unmodified iNK cells showed significantly lower expression of NKG2D, CD16, and KIRs compared to pNK cells.
  • T-bet induction resulted in a 6- to 11-fold increase in KIR expression in iNK cells.
  • Modified iNK cells had significantly enhanced co-expression of CD56 and CD94 compared to controls.
  • T-bet iNK cells exhibited a 1.4-fold increase in cytotoxicity against K562 cells.
  • Average 3-fold increase in IFN-γ secretion observed in modified cells across all target cell lines.

Cite This Study

Dölalan et al. (2025) studied this question.

synapsesocial.com/papers/69362f694fa91c937236dee9https://doi.org/10.1182/blood-2025-2356
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