Chapter 3: Chemically Induced Pluripotent Stem Cell

The use of human embryonic stem cells (hESCs) in research and for therapeutic applications is a controversial issue due to a combination of religious, political and ethical considerations. This led researchers to concentrate on adult stem cells as a source of pluripotent cells, however, working with these cells has several drawbacks, which limit their use for practical purposes. The breakthrough  discovery by Yamanaka of the generation of iPSCs from somatic cells by forced ectopic expression of four transcription factors (TFs), Oct4, Sox2, Klf4 and c-Myc (termed OSKM) by viral transduction, has opened new venues for the research of regenerative medicine, disease modeling and drug discovery.

The major drawback of iPSCs is safety concerns from possible tumorigenicity from the viral integration of the transcription factors as well as transgene alternations.

This concern led to the development of alternate methods for the induction of iPSCs by DNA-free methods and methods that introduce external DNA sequences by non-integrative vectors. Nevertheless, these methods are not efficient and stable enough yet for practical purposes and further improvements are needed.

Since small molecules have the ability to modulate gene expression through the regulation of epigenetic mechanisms, which is needed for cellular reprogramming and to improve its efficiency, it was speculated that they might be able to replace some of the Yamanaka TFs.

Indeed, many studies have been published using small molecules to replace one or more Yamanaka factors. A major achievement was reached on 2013 when a chemical-only induction of pluripotency was demonstrated.

The chemical substitution of the reprogramming TFs enables a safer more efficient process for the generation of iPSCs, which brings these cells closer to actual clinical applications.

 

List of Small Molecules

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References:

  1. Ebrahimi, (2016). Chemical-only reprogramming to pluripotency. Frontiers in Biology, 11(2), 75-84.
  2. Hou, , Li, Y., Zhang, X., et al., & Deng, H. (2013). Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science, 341(6146), 651-654.
  3. Lin, , & Wu, S. (2015). Reprogramming with small molecules instead of exogenous transcription factors. Stem cells international, 2015.
  4. Takahashi, , & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Сell, 126(4), 663-676.
  5. Zhang, , Li, W., Laurent, T., & Ding, S. (2012). Small molecules, big roles–the chemical manipulation of stem cell fate and somatic cell reprogramming. J Cell Sci, 125(23), 5609-5620.