Chapter 2: Improving Reprogramming Efficiency

Induced pluripotent stem cells (iPSCs) hold several advantages over embryonic stem cells (ESCs), including avoiding the ethical issues involved with ESCs, the availability of an “endless” cells source and the ability to generate genetically matching cells, which are important for disease modeling and stem cells transplantation.

However, the efficiency of the original Yamanaka method is very low, with levels of about 0.1% for mouse ESCs (mESCs) and 0.01% for human ESCs (hESCs). This low level of conversion efficiency became an obstacle for practical applications using iPSCs.

Since basic mechanisms were found to be similar between ESCs and iPSCs, it was expected that small molecules that affect fundamental pathways in ESCs will also have similar effects in iPSCs. Indeed, it was found that small molecules can enhance the reprogramming efficiency, alone, or in combinations that simultaneously target several pathways and processes.

Molecules that were found to enhance reprogramming efficiency modulate various cellular processes. These include:

  • Molecules that affect enzymes (such as histone deacetylases, histone demethylases, and DNA methyltransferases), which influence the cellular transcriptional level, DNA epigenetic changes and histone modifications that take place during the reprogramming process.
  • Molecules that affect signaling pathways, such as the Wnt and the TGF-β pathways.
  • Molecules that regulate cell senescence, which can lead to low efficiency in cellular reprogramming.

Constant efforts are being conducted to discover new small molecules that can play a further role in improving reprogramming efficiency.

List of Small Molecules

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References:

  1. Lin, , & Wu, S. (2015). Reprogramming with small molecules instead of exogenous transcription factors. Stem cells international, 2015.
  2. Masip, , Veiga, A., Belmonte, J. C. I., & Simón, C. (2010). Reprogramming with defined factors: from induced pluripotency to induced transdifferentiation. Molecular human reproduction, 16(11), 856-868.
  3. Schmole, C., Hubner, R., Beller, M., Rolfs, A., & J Frech, M. (2013). Small molecules in stem cell research. Current pharmaceutical biotechnology, 14(1), 36-45.