Suite of papers shed light on decade-long stem cell mystery

11 December 2017
Fernando Rossello, Anja Knaupp, Jose Polo and Christian Nefzger (credit: Monash University)
A series of studies led by Monash University researcher Associate Professor Jose Polo have this week shed light on vital, yet previously unclear, aspects of cell reprogramming.

Cell reprogramming, in which one type of cell can be turned into almost any other type cell in the human body, is revolutionising medicine. It gives scientists the capacity theoretically to create any tissue to repair damaged organs, for use in transplantation or disease modelling. 

In 2006, the Japanese researchers who made the Nobel Prize–winning discovery of induced Pluripotent Stem (iPS) cells identified a set of four transcription factors as being capable of turning any cell into iPS cells. These iPS cells, as with embryonic stem cells, have the potential to produce any cell of the body. Yet more than a decade later it was still not fully understood precisely how these reprogramming factors work.

Remarkably, and testament to the world-leading research being undertaken in his lab, two of Associate Professor Polo’s studies were published within a week of each other in highly regarded Cell Press journals, unearthing new evidence into how cells are reprogrammed, while a third related study was published late last month in Nature Methods.

The first study, published this week in Cell Reports, is the result of an international collaboration led by Associate Professor Polo and Dr Owen Rackham from Duke-NUS Singapore. It built on landmark research into iPS cells that Associate Professor Polo conducted in 2012 which described a ‘roadmap’ of what was happening in the process of reprogramming fibroblasts (skin cells) into stem cells. In this new work, the team found that the roadmap was not the same for every cell type.

Using fibroblasts, neutrophils (white blood cells) and keratinocytes (another skin cell type) from animal models, the researchers revealed that the route to pluripotency depended on the original cell type.

Monash BDI’s biologist Dr Christian Nefzger, joint first author on the paper with bioinformatician Dr Fernando Rossello, said the findings have important implications for research. “Studying how different cell types convert into pluripotent stem cells revealed that we need to look through different lenses to comprehensively understand and control the process,” Dr Nefzger said.

The second study, published in Cell Stem Cell, led by Associate Professor Polo and Professor Ryan Lister from University of Western Australia, unveiled how the reprogramming transcription factors switch specific genes “on” or “off”, or “open” or “close” them.

The Cell Stem Cell study provides an explanation of how these factors do their job. Genes are part of the chromatin, a complex of DNA and proteins that form chromosomes within the cell nucleus. The scientists were able to explain the mechanisms behind a process in which the reprogramming factors go into areas on the chromatin that open and close.

“This has unveiled areas of the chromatin and transcription factors that previously we didn’t know were important in pluripotency,” Associate Professor Polo said. “Now that we know they’re significant, we can study these areas in more detail and see what role they may play in development, regeneration or even cancer,” he added.

Co-first author, Monash BDI’s Dr Anja Knaupp said: “Through our molecular analyses we are now able to better understand and consequently improve the reprogramming process which is essential if we want to eventually move this technology into clinical applications.” Such findings may pave the way in the future for tissues to be regenerated within the human body rather than in the laboratory, for the production of ‘synthetic cells’ with properties tailored to the needs of researchers or clinicians, or for the production of drugs that mimic these factors.

“Every layer we’re adding to helps us take a step forward,” Associate Professor Polo said.

Associate Professor Jose Polo is a Chief Investigator with Stem Cells Australia; Professor Ryan Lister is an Affiliate Investigator with Stem Cells Australia. 

Source: Monash University

More coverage:
Harry Perkins Institute of Medical Research (11 December 2017)
The University of Western Australia (11 December 2017)