Thalidomide induces apoptosis during early mesodermal differentiation of human induced pluripotent stem cells

  • Saoko Tachikawa
  • Maho Shimizu
  • Kenshiro Maruyama
  • Kiyoshi Ohnuma


Thalidomide was once administered to pregnant women as a mild sedative; however, it was subsequently shown to be strongly teratogenic. Recently, there has been renewed interest in thalidomide because of its curative effects against intractable diseases. However, the teratogenicity of thalidomide is manifested in various ways and is still not fully understood. In the present study, we evaluated the effects of thalidomide on early mesodermal differentiation by examining the differentiation of human induced pluripotent stem cells (hiPSCs). The most common symptom of thalidomide teratogenicity is limb abnormality, which led us to hypothesize that thalidomide prevents early mesodermal differentiation. Therefore, mesodermal differentiation of hiPSCs was induced over a 6-d period. To induce early mesoderm differentiation, 1 d after seeding, the cells were incubated with the small molecule compound CHIR99021 for 3 d. Thalidomide exposure was initiated at the same time as CHIR99021 treatment. After 5 d of thalidomide exposure, the hiPSCs began expressing a mesodermal marker; however, the number of viable cells decreased significantly as compared to that of control cells. We observed that the proportion of apoptotic and dead cells increased on day 2; however, the proportion of dead cells on day 5 had decreased, suggesting that the cells were damaged by thalidomide during early mesodermal differentiation (days 0–2). Our findings may help elucidate the mechanism underlying thalidomide teratogenicity and bring us closer to the safe use of this drug.


Thalidomide Human induced pluripotent cells Early mesodermal differentiation Teratogenicity 


Author contributions

S.T. and K.O. designed the project. S.T. performed all experiments. M.S. and K.M. assisted with S.T.’ s experiments. S.T. and K.O. wrote the manuscript, and all authors reviewed the manuscript.

Funding information

This work was supported in part by grants from the Ministry of Health, Labor, and Welfare of Japan, the Japan Agency for Medical Research and Development (AMED) (to K.O.), and the Foundation for Applied Research and Technological Uniqueness at Nagaoka University of Technology (to S.T.). The funding bodies had no role in the study design, data collection and analysis, the decision to publish, or manuscript preparation.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

11626_2018_234_MOESM1_ESM.docx (106 kb)
ESM 1 (DOCX 105 kb)


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Copyright information

© The Society for In Vitro Biology 2018

Authors and Affiliations

  1. 1.Department of BioengineeringNagaoka University of TechnologyNagaokaJapan
  2. 2.Department of Science of Technology InnovationNagaoka University of TechnologyNagaokaJapan

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