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Deterministic direct reprogramming of somatic cells to pluripotency

Yoach Rais1, Asaf Zviran, Shay Geula

  • 1The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.

Nature
|September 20, 2013
PubMed

Insights

Reprogramming somatic cells into induced pluripotent stem (iPS) cells is typically inefficient. Depleting Mbd3 enhances Oct4, Sox2, Klf4, and Myc (OSKM) reprogramming to near 100% efficiency, creating a deterministic and synchronized process.

Area of Science:

  • Stem cell biology
  • Epigenetics
  • Molecular reprogramming

Background:

  • Somatic cell reprogramming into induced pluripotent stem (iPS) cells using Oct4, Sox2, Klf4, and Myc (OSKM) is often inefficient and stochastic.
  • The primary barriers to efficient and synchronous reprogramming remain largely undefined.

Purpose of the Study:

  • To investigate the rate-limiting factors in somatic cell reprogramming.
  • To develop a method for deterministic and synchronized iPS cell generation.

Main Methods:

  • Exogenous expression of OSKM factors in somatic cells.
  • Depletion of Mbd3, a component of the Mbd3/NuRD repressor complex.
  • Reprogramming under naive pluripotency-promoting conditions.

Main Results:

  • Depleting Mbd3 alongside OSKM transduction resulted in deterministic and synchronized iPS cell reprogramming with near 100% efficiency within seven days.
  • Identified a dichotomous function of reprogramming factors: reactivating pluripotency networks and recruiting the Mbd3/NuRD complex to restrain target gene reactivation.
  • Demonstrated that Mbd3/NuRD complex interactions, reduced during early development, contribute to the stochastic nature of in vitro reprogramming.

Conclusions:

  • Mbd3 acts as a key repressor limiting the efficiency and synchronicity of OSKM-mediated reprogramming.
  • The developed deterministic reprogramming approach provides a powerful platform for studying pluripotency establishment.
  • Understanding the role of Mbd3/NuRD offers new insights into controlling cellular reprogramming dynamics.

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