With sufficiently detailed prompting, adult cells may change their functionality, even their identity. Skin cells, for example, have been known to respond to genetic manipulation and chemical prodding by turning themselves into brain cells. Such conversions, however, have lacked precision. In the case of skin cell/brain cell conversions, tinkering with microRNA expression has resulted in brain cells of different types, even though a uniform result—brain cells of just one type—might have been more convenient.
Now it appears cell conversions may be accomplished with a greater degree of control. According to researchers at Washington University in St. Louis, bolstering the microRNA approach with the right combination of chemical factors can guide the conversion of human postnatal and adult fibroblasts into neurons of a particular type. These researchers report that they have found a way to generate an enriched population of neurons analogous to striatal medium spiny neurons (MSNs), cells known to be affected in Huntington’s disease.
A release issued by Washington University emphasizes that unlike other techniques that turn one cell type into another, the new process does not pass through a stem cell phase, avoiding the production of multiple cell types. By producing cells of just one type, the Washington University researchers raise the possibility that better cell conversion techniques could result in better disease models or even advance regenerative medicine.
Details of the new process appeared October 22 in the journal Neuron, in an article entitled “Generation of Human Striatal Neurons by MicroRNA-Dependent Direct Conversion of Fibroblasts.”
“Coexpression of miR-9/9∗-124 with transcription factors enriched in the developing striatum, BCL11B (also known as CTIP2), DLX1, DLX2, and MYT1L, can guide the conversion of human postnatal and adult fibroblasts,” wrote the authors. “When transplanted in the mouse brain, the reprogrammed human cells persisted in situ for over 6 months, exhibited membrane properties equivalent to native MSNs, and extended projections to the anatomical targets of MSNs.”
“Not only did these transplanted cells survive in the mouse brain, they showed functional properties similar to those of native cells,” said senior author Andrew S. Yoo, Ph.D., assistant professor of developmental biology. “These cells are known to extend projections into certain brain regions. And we found the human transplanted cells also connected to these distant targets in the mouse brain. That’s a landmark point about this paper.”
Dr. Yoo participated in an earlier study that also used microRNAs to accomplish the direct conversion of skin cells to brain cells. This study, which was published online July 13, 2011, in Nature (“MicroRNA-mediated conversion of human fibroblasts to neurons”), demonstrated that microRNAs could stimulate latent sections of DNA to action.
“We think that the microRNAs are really doing the heavy lifting,” said Matheus B. Victor, a graduate student in neuroscience and co-first author of the current study. “They are priming the skin cells to become neurons. The transcription factors we add then guide the skin cells to become a specific subtype, in this case medium spiny neurons. We think we could produce different types of neurons by switching out different transcription factors.”