As the debate continues on the ethics and therapeutic potential of embryonic versus mature stem cells, Medical College of Georgia researchers are exploring a third group of cells that appears critical to development and capable of making all major types of human tissue.
"VENT cells are a unique category of multi-potent cells," Dr. Douglas P. Dickinson, molecular biologist, says of this cell type that escapes from the bottom of the neural tube early in development, after the tube closes to form the brain.
VENT cells then travel along nerve paths, eventually getting ahead of the nerves, and dispersing throughout the body. "They travel in association with the cranial nerves to target tissues, disperse into those tissues, then, at what is perhaps an endpoint for their stay during development, they differentiate into the same cell type as their neighbors. So they potentially just vanish into the crowd," says Dr. Dickinson who first heard of these cells last year when their discoverer, MCG Developmental Biologist Paul Sohal, gave a lecture at the MCG School of Dentistry. Dr. Dickinson thought these cells might be used to establish a human cell line to enable his studies of the development and function of salivary glands.
While the jury remains out on that question, the cells have helped Dr. Dickinson find new direction in his research: working to learn more about the cells Dr. Sohal first saw in 1995 traveling out of the neural tube of a three-day-old chick embryo.
Dr. Dickinson got a baptism by immersion as lead author on an invited review article published this month in the Journal of Anatomy that examines the near 10-year history of VENT cell research.
The August review article chronicles the cells' discovery and documentation of their presence in every tissue that Dr. Sohal's research team has examined, including the gastrointestinal tract, heart, liver, blood vessels, inner ear and skull. "There aren't a huge number of them in most tissues," says Dr. Dickinson. "But what is exciting about VENT cells is that if you interfere with VENT cells arriving at those target tissues, you appear to cause major disruptions in development."
Now Dr. Dickinson is part of the team answering additional questions such as the origin of VENT cells, the exact role they play in target tissues and if they are the source of undifferentiated adult stem cells kept in reserve by all tissues
In fact, Dr. Dickinson already has applied for a National Institutes of Health grant to further explore the role of VENT cells in craniofacial development and the genes that distinguish VENT cells from others. To help explore their multi-potential status, he wants to answer questions such as: "Can you take VENT cells from elsewhere in the embryo, move them to the craniofacial area and supplement function?"
The contributions of VENT cells challenges long-held notions about what type of cells form what type of tissue. For example, with the gastrointestinal tract, future scientists and physicians learn that the enteric nervous system, which innervates the tract, comes from neural crest cells. Smooth muscle cells come from one of the body's three basic germ layers laid down early in development called the mesoderm. The lining of the gut, the epithelium, comes from the endoderm, another germ layer. Now the science is showing that VENT cells contribute to all these tissues as well.
Challengers say VENT cells are not distinctive, rather artifacts or aberrations. But Dr. Dickinson says the review paper addresses detractors by showing how VENT cells help make the body's four tissue types - nerve, muscle, connective and epithelial tissues. It also clearly points out how the cells are identified using four distinct labeling mechanisms and points to potential technical problems in two reports where scientists looked in vain for VENT cells.
"This tells us that VENT cells are remarkable cells. They are important. If you take them away you have heart defects, craniofacial defects, gut defects and so on," Dr. Dickinson says. "So you need them, " he says of VENT cells, the first source of new cells identified in the embryo since 1868.
Many questions remain about what the cells do, but the MCG scientists consider their existence no longer up for debate.
"They clearly migrate through the cranial nerves. They reach target tissue. What they do there, that is the exciting part. We don't know yet," Dr. Dickinson says. "We know where they end up and that they are doing something very important along the way," noting that the effect of their removal seems disproportionate with their relatively small numbers.
"It's not that these cells are providing a cell type that is not available from any other source," Dr. Sohal says. "So why have a population of cells which does not follow established principles of development? Why have a cell population that is multi-potential, that is capable of forming every kind of tissue in our body?"
The researchers say it's because VENT cells have a role in every tissue, the first of which may be connecting the central nervous system with its target tissues, noting how the cells travel with nerves then move ahead of them as if showing the way. "Nerves could be following certain cues left behind by VENT cells," Dr. Sohal says. "That is what we think. We have to experimentally test that."
They also think that VENT cells may work like the Federal Reserve System works for banks: as a centralized source that supplies stem cells to all tissues. "We have a pool of stem cells in every tissue but we don't know the source of these cells in adults," Dr. Sohal says. "VENT cells would be a simple way of providing stem cells to various tissues because nerves connect to every tissue and you would not be dependent on every muscle, every nerve, every bone to make sure you keep a small reserve," Dr. Sohal says. The work to date has been in chicken, quail and duck embryos and one of many projects is to move into the mouse model to enable detailed genetic studies.
Dr. Sohal's research is funded by three NIH grants.