In a breakthrough for regenerative medicine and tissue engineering, researchers have developed a tool that will help scientists directly transform human cells from one type to another. They see the breakthrough as bringing regenerative medicine a step closer to growing whole organs from patients’ own cells.
In a Nature Genetics paper, the team – led by scientists from the University of Bristol in the UK – notes that the current method for directly reprogramming human cells from one type to another – called “cell transdifferentiation” – takes a long time because it relies on trial and error to find the correct transcription factors.
Transcription factors are proteins that – among other things – help to regulate gene expression. All the cells of our body carry the same genes, but different genes are expressed and silenced in different cell types.
To transdifferentiate one cell into another, you have to change the arrangement of which genes are switched on and which are switched off – and for this, you need a unique set of transcription factors, depending on which genes you are dealing with.
There is another way to create new cells of a certain type, and that is to go via pluripotent stem cells – immature or precursor cells that have not yet “decided” which type of cell they are. But, as Julian Gough – professor of bioinformatics at Bristol – explains, their predictive system means you do not have to go down this path:
“The barrier to progress in this field is the very limited types of cells scientists are able to produce. Our system, Mogrify, is a bioinformatics resource that will allow experimental biologists to bypass the need to create stem cells.”
Pluripotent stem cells can be used to treat many different medical conditions and diseases. There are two types: embryonic and artificial. Embryonic stem cells are derived from embryos, and while they are the best quality stem cells, there are ethical concerns about their use – plus, the process of harvesting them from embryos for therapeutic use is expensive and difficult.
The first human artificial pluripotent stem cells were created nearly a decade ago by a team led by Shinya Yamanaka, of Kyoto University in Japan. It took them a long time – using trial and error – to find the four transcription factors that allowed them to reprogram fibroblasts from the skin of mice into pluripotent stem cells. Since then, scientists have only been able to discover further conversions for human cells a handful of times.
‘Atlas of cellular reprogramming’
Prof. Gough says Mogrify predicts which transcription factors to use in order to create any human cell type from any other cell type directly.
With Prof. Jose Polo, of Monash University in Australia, the Bristol team tested the system on two new human cell conversions – and succeeded first time in both cases. Prof. Gough notes:
“The speed with which this was achieved suggests Mogrify will enable the creation of a great number of human cell types in the lab.”
It took the Bristol team 5 years to construct the algorithm by bringing together information on gene expression with that of transcriptional regulatory networks. They used data from the FANTOM international consortium (based at RIKEN, Japan), of which Prof. Gough is a long-time member.
The paper notes how the team “applied Mogrify to 173 human cell types and 134 tissues, defining an atlas of cellular reprogramming,” and that the algorithm “correctly predicts the transcription factors used in known transdifferentiations.”
Prof. Gough sums up the implications of their work:
“The ability to produce numerous types of human cells will lead directly to tissue therapies of all kinds, to treat conditions from arthritis to macular degeneration, to heart disease. The fuller understanding, at the molecular level of cell production leading on from this, may allow us to grow whole organs from somebody’s own cells.”
In an effort to accelerate progress in the field, the team has made Mogrify available online for other researchers and scientists to use.
In November 2015, Medical News Today reported a study where scientists directly reprogrammed human skin cells into serotonin-releasing neurons. The team identified a cluster of six transcription factors for directing the cell differentiation.