Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance: mechanisms of

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A Simple Method to Identify Kinases That Regulate Embryonic Stem Cell Pluripotency by High-throughput Inhibitor Screening
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Published on: May 12, 2017

Makoto Hamasaki1, Yoshinobu Hashizume, Yoshinori Yamada

  • 1Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto, Japan.

Stem Cells (Dayton, Ohio)
|September 6, 2012
PubMed

Insights

Fibrodysplasia ossificans progressiva (FOP) hinders induced pluripotent stem cell (iPSC) generation due to overactive activin receptor-like kinase 2 (ALK2). Inhibiting ALK2 successfully restored iPSC production, identifying a potential therapeutic target.

Area of Science:

  • Stem Cell Biology
  • Genetics
  • Rare Diseases

Background:

  • Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder causing progressive soft tissue ossification.
  • FOP is linked to mutations in activin receptor-like kinase 2 (ALK2), leading to dysregulated BMP signaling.
  • Reprogramming FOP-derived cells into induced pluripotent stem cells (iPSCs) is challenging.

Purpose of the Study:

  • To investigate the impact of constitutive activin receptor-like kinase 2 (ALK2) activation on induced pluripotent stem cell (iPSC) generation and maintenance in Fibrodysplasia ossificans progressiva (FOP).
  • To identify potential therapeutic strategies for FOP by exploring the role of ALK2 in iPSC reprogramming.
  • To leverage the iPSC reprogramming defect as a phenotype for drug discovery in FOP.

Main Methods:

  • Generation of induced pluripotent stem cells (iPSCs) from skin fibroblasts of patients with Fibrodysplasia ossificans progressiva (FOP).
  • Assessment of iPSC reprogramming efficiency and maintenance under conditions of suppressed or inhibited activin receptor-like kinase 2 (ALK2) expression.
  • Pharmacological inhibition of ALK2 activity in FOP-derived fibroblasts.

Main Results:

  • Induced pluripotent stem cell (iPSC) generation and maintenance were significantly repressed in Fibrodysplasia ossificans progressiva (FOP)-derived fibroblasts.
  • Suppression of activin receptor-like kinase 2 (ALK2) expression or treatment with an ALK2 inhibitor largely overcame the reprogramming inhibition.
  • Constitutive activation of ALK2 was identified as the cause of impaired iPSC generation and maintenance in FOP.

Conclusions:

  • The constitutive activation of activin receptor-like kinase 2 (ALK2) in Fibrodysplasia ossificans progressiva (FOP) directly inhibits induced pluripotent stem cell (iPSC) generation and maintenance.
  • An ALK2 inhibitor demonstrated efficacy in restoring iPSC production, highlighting its potential as a therapeutic candidate for FOP.
  • The observed defect in iPSC reprogramming serves as a valuable model for studying disease mechanisms and discovering novel drug targets for FOP.

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