The history of reprogramming 3.0

by Alexey Bersenev on April 24, 2012 · 2 comments

in direct reprogramming

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We’ve used a term “reprogramming 3.0” to describe the methodology of induced direct reprogramming (or transdifferentiation) by defined factors in vivo. This is a relatively new and, potentially, groundbreaking technique. It was developed few years ago by researchers working in diabetes field. Let’s look at some important studies in historical context.

2002. Taniguchi proposed to use a transcription factor Pdx-1 to induce insulin production by pancreatic beta-cells. It was quite different from classical gene therapy, because it wasn’t simple replacement of missing gene. Also, researchers didn’t think about changing the fate (reprogram) of cells. Direct intra-organ delivery and over-expression of Pdx-1 boost insulin production by normal mouse pancreas.

2003. Idit Ber used a term “liver-to-pancreas transdifferentiation” to describe the process ectopic expression of Pdx-1, delivered directly into the liver. By applying “induced transdifferentiation in vivo“, the authors were able to fix diabetic hyperglycemia.
Similar approach was used by Hideto Kojima. He used 2 factors Neurod and betacellulin (Btc) to reverse experimental diabetes.
Both groups observed “beta-cells neogenesis” in the liver. Still, it was not clear whether liver cells were transformed into beta-cells completely or were temporary reprogrammed to compensate a function.

2008. Doug Melton’s group used 3 factors (Ngn3, Pdx1 and Mafa) to reprogram pancreatic exocrine cells into insulin-producing beta-(like)-cells. They used a term “in vivo reprogramming” for the first time. Concluding the study, they shaped the future directions:

This study provides an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.

The idea of direct reprogramming in vivo became very attractive. But nobody was able to demonstrate its potential outside of “diabetes field”. Until now.

2012. Srivastava’s group used 3 transcription factors (Gata4, Mef2c and Tbx5) to reprogram scar tissue fibroblast of infarcted heart tissue into beating cardiomyocytes. In the disease model, delivery of these factors in vivo decreased infarct size and improved of heart function.

Reprogramming 3.0 techniques could potentially play significant role in regenerative medicine.

{ 2 comments… read them below or add one }

Nian May 3, 2012 at 3:31 am

I think in vivo reprogramming is a gene therapy in fact, but it is very valuable in regenerative medicine.

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Alexey Bersenev May 3, 2012 at 8:39 pm

Nian,
I think, you can call it so and many people call it “gene therapy”, but there is some differences. Classical gene therapy means “replacement of missing (or nonfunctional) gene”. Traditionally, it used for monogenic hereditary diseases. But cells could be gene-modified with different purposes. For example, suicide genes to control wayward cells in T-cell therapy –
http://hematopoiesis.info/2009/04/05/control-of-wayward-cells-after-transplantation/
Yet another difference is “therapeutic intention”. In case of classical gene therapy – compensation of the function of missing gene, in case of reprogramming – changing a fate of targeted cell population in situ.

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