What does it take to directly convert an antibody-producing B cell into a scavenging macrophage? The answer: one gene, according to a report in the July 30th issue of Stem Cell Reports. This directly reprogramming is transformation is possible because a transcription factor called C/EBPa can short-circuit the cells so that they re-express genes reserved for embryonic development.
Over the past 65 years, research teams in laboratories all over the world have shown that many different types of specialized cell types can be forcibly reprogrammed into another, but how this occurs is only recently been realized. These “transdifferentiations,” as they’re called, include reprogramming a skin cell into a muscle cell, or a muscle cell into a brown fat cell with the addition of just one or two transcription factors that bind to a cell’s DNA and induce the expression of other genes.
“For a long time it was unclear whether forcing cell fate decisions by expressing transcription factors in the wrong cell type could teach us something about what happens normally during physiological differentiation,” said senior study author Thomas Graf, Ph.D., group leader at the Centre for Genomic Regulation in Spain. “What we have now found is that the two processes are actually surprisingly similar.”
According to lead author of this study, Chris van Oevelen, Ph.D., B cell transdifferentiation occurs when C/EBPa binds to two regions of DNA that act as gene expression enhancers. One of these regions is typically active in immune cells, but the other is only activated when macrophage precursors are ready to differentiate. Thus, the synergism of these two enhancer pathways can cause the B cell to act like a macrophage precursor, which triggers B cell-to-macrophage 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,” Dr. Graf said. “This is one of the questions we are focusing on now.”
Dr. Graf is interested in this pathway because of its potential therapeutic applications. As it turns out, C/EBPa-induced B cell-to-macrophage transdifferentiation can convert both human B cell lymphoma or leukemia cells into functional, non-cancerous macrophages. Graf believes that induced transdifferentiation could become therapeutically relevant if drug researchers can find a molecule that can replace C/EBPa. Additionally, understanding the mechanisms of this process would help labs worldwide who use transdifferentiation approach to generate cells for regenerative purposes.