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Author Spotlight: Advancements and Challenges in β-Cells Differentiation from Pluripotent Stem Cells
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CDK8/19 inhibition plays an important role in pancreatic β-cell induction from human iPSCs

Kensuke Sakuma1,2, Noriko Tsubooka-Yamazoe3,4, Kiyohiro Hashimoto5

  • 1iPSC-Derived Pancreatic Islet Cell (iPIC) Therapy Department, Orizuru Therapeutics Inc., Fujisawa, Kanagawa, 251-8555, Japan. kensuke.sakuma@orizuru-therapeutics.com.

Stem Cell Research & Therapy
|January 4, 2023
PubMed
Abstract

Insights

Researchers identified a mutagenic risk with a common pancreatic islet cell (iPIC) differentiation factor, activin receptor-like kinase 5 inhibitor II (ALK5iII). A safer alternative using a combination of inhibitors was developed for cell therapy.

Area of Science:

  • Stem cell biology
  • Regenerative medicine
  • Drug discovery

Background:

  • Human-induced pluripotent stem cells (hiPSCs) offer therapeutic potential but require safety assessments for clinical use.
  • Malignant cell transformation is a critical safety concern in hiPSC-derived cell therapies.
  • This study addresses mutagenicity risks in the differentiation protocol for hiPSC-derived pancreatic islet-like cells (iPICs).

Purpose of the Study:

  • To evaluate the mutagenicity of differentiation factors used in hiPSC-derived iPIC generation.
  • To identify and mitigate mutagenic risks associated with specific chemical inducers.
  • To develop a safer protocol for iPIC differentiation for potential cell therapy applications.

Main Methods:

  • Ames mutagenicity assay was used to assess the genotoxicity of differentiation factors.
  • Flow cytometry, immunostaining, and TR-FRET assays were employed for cellular analysis.
  • Single-cell RNA-sequencing and in vivo efficacy studies were conducted to evaluate iPIC function and safety.

Main Results:

  • Activin receptor-like kinase 5 inhibitor II (ALK5iII), a common inducer, demonstrated mutagenic effects.
  • ALK5iII uniquely inhibited cyclin-dependent kinases 8 and 19 (CDK8/19).
  • A combination of a non-mutagenic ALK5 inhibitor (SB431542) and a CDK8/19 inhibitor (senexin B) successfully generated iPICs with comparable efficacy and safety.

Conclusions:

  • A novel risk mitigation strategy for cell therapy involving specific kinase inhibitors was developed.
  • This study advances the understanding of the molecular mechanisms underlying β-cell differentiation.
  • The findings pave the way for safer and more effective hiPSC-based cell therapies.
Keywords:
Activin receptor-like kinase 5 inhibitor IICDK8/19 inhibitorsHuman-induced pluripotent stem cellsMutagenicityPancreatic islet cell

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