Direct cell reprogramming is a stochastic process amenable to acceleration

Jacob Hanna, Krishanu Saha, Bernardo Pando, Jeroen van Zon, Christopher J. Lengner, Menno P. Creyghton, Alexander van Oudenaarden & Rudolf Jaenisch

Abstract | Direct reprogramming of somatic cells into induced pluripotent stem (iPS) cells can be achieved by overexpression of Oct4, Sox2, Klf4 and c-Myc transcription factors, but only a minority of donor somatic cells can be reprogrammed to pluripotency. Here we demonstrate that reprogramming by these transcription factors is a continuous stochastic process where almost all

mouse donor cells eventually give rise to iPS cells on continued growth and transcription factor expression.Additional inhibition of the p53/p21 pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell-division-rate-independent manner. Quantitative analyses define distinct cell-division-rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggest that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.

http://www.nature.com/nature/journal/v462/n7273/pdf/nature08592.pdf

Synthetic biology: understanding biological design from synthetic circuits

Shankar Mukherji and Alexander van Oudenaarden

Abstract | An important aim of synthetic biology is to uncover the design principles of natural biological systems through the rational design of gene and protein circuits. Here, we highlight how the process of engineering biological systems — from synthetic promoters to the control of cell–cell interactions — has contributed to our understanding of how endogenous systems are put together and function. Synthetic biological devices allow us to grasp intuitively the ranges of behaviour generated by simple biological circuits, such as linear cascades and interlocking feedback loops, as well as to exert control over natural processes, such as gene expression and population dynamics.

http://www.nature.com/nrg/journal/v10/n12/pdf/nrg2697.pdf

Direct cell reprogramming is a stochastic process amenable to acceleration

Jacob Hanna*, Krishanu Saha*, Bernardo Pando, Jeroen van Zon, Christopher J. Lengner, Menno P. Creyghton, Alexander van Oudenaarden & Rudolf Jaenisch

Abstract | Direct reprogramming of somatic cells into induced pluripotent stem (iPS) cells can be achieved by overexpression of Oct4, Sox2, Klf4 and c-Myc transcription factors, but only a minority of donor somatic cells can be reprogrammed to pluripotency. Here we demonstrate that reprogramming by these transcription factors is a continuous stochastic process where almost all mouse donor cells eventually give rise to iPS cells on continued growth and transcription factor expression. Additional inhibition of the p53/p21 pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell-division-rate-independent manner. Quantitative analyses define distinct cell-division-rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggest that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.

http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature08592.pdf