How a single molecule turns one immune cell into another

July 30, 2015, Cell Press
Stills from time-lapse video showing transdifferentiation of pre-B cells into yeast-eating macrophages. Green fluorescent pre-B cells surrounded by red fluorescent Candida albicans at different hours after activation of C/EBPa (shown are same fields). Note that transdifferentiated macrophages in green aggregate while taking up the yeast, which now appear orange. Credit: J.L. Sardina and T. Zimmermann

All it takes is one molecule to reprogram an antibody-producing B cell into a scavenging macrophage. This transformation is possible, new evidence shows, because the molecule (C/EBPa, a transcription factor) "short-circuits" the cells so that they re-express genes reserved for embryonic development. The findings appear July 30 in Stem Cell Reports, the journal of the International Society for Stem Cell Research.

Over the past 28 years, researchers have shown that a number of specialized cell types can be forcibly converted into another, but the science of how this change takes place is still emerging. Such transdifferentiations, as they're called, include turning a skin cell into a muscle cell (or a muscle cell into a brown fat cell) with the addition of just one or two . These are molecules that bind to a cell's DNA and cause other genes to be expressed.

"For a long time it was unclear whether forcing by expressing transcription factors in the wrong cell type could teach us something about what happens normally during physiological differentiation," says senior study author Thomas Graf of the Center for Genomic Regulation in Spain. "What we have now found is that the two processes are actually surprisingly similar."

Based on experiments led by the first author of the study, Chris van Oevelen, B cell transdifferentiation takes place when C/EBPa binds to two regions of DNA that act as enhancers. Whereas one of these regions is normally active in immune cells, the other is only turned on when macrophage precursors are ready to differentiate. This indicates that the convergence of these two enhancer pathways can cause the B cell to act like a macrophage precursor, thus triggering the unnatural transdifferentiation.

"This has taught us a great deal about how a transcription factor can activate a new gene expression program (in our case, that of macrophages) but has left us in the dark about the other part of the equation; namely, how the factor silences the B cell program, something that must happen if transdifferentiation is to work," Graf says. "This is one of the questions we are focusing on now."

Graf is interested in this pathway because C/EBPa-induced, B cell-to-macrophage transdifferentiation can convert both human B cell lymphoma or leukaemia cells into functional, non-cancerous macrophages. He believes that induced transdifferentiation could become therapeutically relevant, if a drug could be found that can replace the transcription factor—not to mention that understanding the mechanisms of the process would help labs worldwide who use this transdifferentiation approach to generate "a la carte" for regenerative purposes.

Explore further: Cell transformation a la carte

More information: Stem Cell Reports, van Oevelen et al.: "C/EBPα activates pre-existing and de novo macrophage enhancers during induced pre-B cell transdifferentiation and myeloid lineage specification" dx.doi.org/10.1016/j.stemcr.2015.06.007

Related Stories

Cell transformation a la carte

October 3, 2011

Researchers from the Haematopoietic Differentiation and Stem Cell Biology group at the Centre for Genomic Regulation (CRG), have described one of the mechanisms by which a cell (from the skin, for example) can be converted ...

New insight into stem cell development

May 22, 2014

The world has great expectations that stem cell research one day will revolutionize medicine. But in order to exploit the potential of stem cells, we need to understand how their development is regulated. Now researchers ...

Recommended for you

Tiny 'water bears' can teach us about survival

March 20, 2019

Earth's ultimate survivors can weather extreme heat, cold, radiation and even the vacuum of space. Now the U.S. military hopes these tiny critters called tardigrades can teach us about true toughness.

A decade on, smartphone-like software finally heads to space

March 20, 2019

Once a traditional satellite is launched into space, its physical hardware and computer software stay mostly immutable for the rest of its existence as it orbits the Earth, even as the technology it serves on the ground continues ...

Researchers find hidden proteins in bacteria

March 20, 2019

Scientists at the University of Illinois at Chicago have developed a way to identify the beginning of every gene—known as a translation start site or a start codon—in bacterial cell DNA with a single experiment and, through ...

Turn off a light, save a life, says new study

March 20, 2019

We all know that turning off lights and buying energy-efficient appliances affects our financial bottom line. Now, according to a new study by University of Wisconsin-Madison researchers, we know that saving energy also saves ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.