A mature cell of one type can be turned into a mature cell of another type without the cell having to pass through an earlier stage of development. This is called direct reprogramming, a reliable but notoriously inefficient process. Apparently, direct reprogramming occurs in only a few cells in a cell population. But which cells? Many scientists believe that all cells have equal potential to reprogram. It’s just that the cells are also subject to stochastic or probabilistic mechanisms that restrict reprogramming. Essentially, many scientists believe that in any one cell, reprogramming success is a matter of chance.
Other scientists are more deterministic. They favor the “elite” model of direct reprogramming, which holds that a rare subset of the starting cell population has a predetermined intrinsic bias to complete the reprogramming process. These scientists include Derek van der Kooy, PhD, a professor of molecular genetics who heads a laboratory at the University of Toronto.
A new study from the van der Kooy laboratory presents findings in support of the elite model. Specifically, the study determined that neural crest (NC) stem cells located in the skin and other areas of the body are the source of reprogrammed neurons.
Detailed findings appeared in Stem Cell Reports. In a paper titled, “Neural crest precursors from the skin are the primary source of directly reprogrammed neurons,” van der Kooy and colleagues argued that heterogeneity in developmental lineage and maturity of the starting cell population contributes to direct reprogramming using the conversion of murine fibroblasts into neurons.
“We find that nearly all reprogrammed neurons are derived from the neural crest lineage,” the article’s authors wrote. “Moreover, when rare proliferating NC precursors are selectively ablated, there is a large reduction in the number of reprogrammed neurons.
“Previous interpretations of this paradigm are that it demonstrates a cell fate conversion across embryonic germ layers (mesoderm to ectoderm),” they continued. “Our interpretation is that this is actually directed differentiation of a neural lineage stem cell in the skin that has intrinsic bias to produce neuronal progeny.”
The new findings refute the popular theory in cellular reprogramming that any developed cell can be induced to switch its identity to a completely unrelated cell type through the infusion of transcription factors. “We believed that most cases of cell reprogramming could be attributed to a rare, multipotential stem cell that is found throughout the body and lays dormant within populations of mature cells,” said Justin Belair-Hickey, the first author on the study and a graduate student at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research. “It was not fully understood why reprogramming tends to be an inefficient process. Our data explain this inefficiency by demonstrating that the neural crest stem cell is one of the few stem cells that can produce the desired reprogrammed cell type.”
Neural crest cells, which can be found below the hair follicle in the skin, are genetically predisposed to develop into neurons. This is not unexpected, as many cell types in the skin originate from the same location in the embryo as neurons: the ectodermal germ layer. The ectoderm is the outermost of the three layers of cells that form during embryonic development.
The team was driven to conduct this study through their own questioning of how experimental data from cellular reprogramming research is interpreted in terms of how flexible the identity of a cell is. This includes theories of how mature cells from one embryonic layer can be directly reprogrammed to mature cells of another embryonic layer, even though the three germ layers are separated by different developmental histories. They hypothesized that cellular reprogramming can only occur from a stem cell to a mature cell, where both come from the same germ layer.
“I think claims about direct reprogramming are either overstated or based on inaccurate interpretations of the data,” Belair-Hickey said. “We set out to demonstrate that the identity of a cell is much more defined and stable than the field of cellular reprogramming has proposed. At first glance, it appears that we’ve found skin cells that can be reprogrammed into neurons, but what we’ve actually found are stem cells in the skin that are derived from the brain.”
Neural crest stem cells are found throughout the body, including in skin, bone, and connective tissue. Their distribution throughout the body, ability to be reprogrammed into many types of cells, and accessibility within the skin for collection makes them a high-potential candidate for stem cell transplantation to treat disease.
“Neural crest stem cells may have gone unnoticed by others studying cell reprogramming because, while these cells are widespread throughout the body, they are also rare,” van der Kooy explained. “As such, they may have been mistaken for mature cells of various types of tissue that could be reprogrammed into other cell types. I think what we’ve found is a unique group of stem cells that can be studied to understand the true potential of cell reprogramming.”
