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Somatic to iPS Cell Reprogramming01:29

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Reprogramming alters the gene expression in somatic cells, transforming them into induced pluripotent stem (iPS) cells over several generations. Scientists can reprogram cells by introducing genes for four transcription factors—Oct4, Sox2, Klf4, and c-Myc (OSKM) by viral or non-viral methods. These factors are also known as Yamanaka factors after Shinya Yamanaka, who first generated iPS cells using mouse skin cells. Yamanaka was awarded the Nobel Prize in Physiology or Medicine in 2012...
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Nuclear reprogramming is a process of transforming one cell type into an unrelated cell type by epigenetic changes that alter the cell’s original gene expression pattern. Such epigenetic changes force cells to express a different set of genes, which play a significant role in inducing transformation into other cell types. Nuclear reprogramming offers applications in reproductive cloning for livestock propagation and regenerative medicine — developing patient-specific cells for...
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Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
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Epigenetic predisposition to reprogramming fates in somatic cells.

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  • 1Department of Biochemistry and Molecular Biology, Tel Aviv University, Tel Aviv, Israel.

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Summary

Cellular reprogramming to pluripotency is predetermined and heritable, originating from specific cell subpopulations. Epigenetic heterogeneity influences this potential, which can be modulated to enhance induced pluripotent stem cell (iPSC) generation.

Keywords:
cell fate decisionslive‐cell imagingreprogramming

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Area of Science:

  • Cell Biology
  • Stem Cell Biology
  • Epigenetics

Background:

  • Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is crucial for regenerative medicine but remains inefficient.
  • Fundamental aspects of reprogramming, such as the timing of pluripotency establishment, are poorly understood.

Purpose of the Study:

  • To determine when somatic cells acquire the potential to generate pluripotent progeny.
  • To investigate factors influencing reprogramming efficiency and fate.

Main Methods:

  • Live-cell imaging and a novel statistical approach to trace cell lineages.
  • Analysis of sister cell outcomes before and after reprogramming factor induction.
  • Perturbation of epigenetic states using Ezh2 inhibitors.

Main Results:

  • The potential to reprogram is heritable between sister cells, suggesting predetermination in specific subpopulations.
  • Cellular expansion before induction does not improve reprogramming likelihood.
  • Reprogramming fate is not correlated with neighboring cell identity or factor levels.
  • Ezh2 inhibition modulates the fraction of iPSC-forming lineages, indicating a role for epigenetic heterogeneity.

Conclusions:

  • Reprogramming potential is established early and heritable within cell lineages.
  • Pre-existing epigenetic heterogeneity in somatic cells contributes to reprogramming efficiency.
  • Epigenetic modifications can be targeted to enhance the reprogramming process.