Scientist Pursues Role Of Possible New Cell Type

These VENT cells have been found in addition to the three sources of cells typically associated with gastrointestinal development, says Dr. Paul Sohal, MCG developmental biologist, who first identified these cells nearly a decade ago.

Identification of VENT - ventrally emigrating neural tube - cells within the stomach and small intestine is another piece in Dr. Sohal's effort to fully define and describe the cells that he first found migrating out from the neural tube of a chick embryo.

If Dr. Sohal's studies are on target, he's found the first source of new cells identified in the embryo since 1868 and what might be the precursor for adult stem cells.

With three National Institutes of Health grants under his belt and a slowly growing body of published evidence, including the recent finding published in the December issue of the International Journal of Developmental Neuroscience, Dr. Sohal definitely believes he's on to something.

"I have a burning desire to find out the role of VENT cells in normal development, their role in congenital malformation as well as their potential in repair and regeneration of adult tissue," he says. "It's an issue that is constantly on my mind."

In his latest study, he labeled VENT cells while they were still in the neural tube, the structure that ultimately forms the brain and spinal cord and the place where he first saw VENT cells migrating out. The neural tube sends a nerve from the developing brain, down though the neck, lungs, heart and, eventually, to the gastrointestinal tract. He watched the labeled VENT cells migrate along the path of this vagus nerve, eventually differentiating into neurons and supporting cells of the gut's enteric nervous system. The labeled cells also became smooth muscle cells and epithelial cells that help form the gut lining as well as interstitial cells of Cajal, which are essentially pacemaker cells that enable the gastrointestinal tract's motility.

"The current belief is that the gastrointestinal tract develops from three sources of cells," Dr. Sohal says. The enteric nervous system, which innervates the gut, is believed to come solely from neural crest cells. Smooth muscle cells are believed to develop from the mesoderm, one of the body's three basic germ layers laid down early in development. The epithelium, the lining of the gut that allows nutrients to be absorbed from food, comes from the endoderm, the innermost germ layer.

"What we have found is the VENT cells give rise to all these cell types," Dr. Sohal says. The finding not only questions the understanding of normal development, but also brings in new factors for consideration in developmental or acquired diseases of the gastrointestinal tract and possibly much more, he says. Examples include diseases such as Hirschsprung's disease, in which a part of the intestines does not get its nerves during formation and consequently its motility; one out of 5,000 children is born with this disease. Also, about 1 in 500 children is born with pyloric stenosis, in which the opening of the stomach is too narrow for much food to pass; its opposite is esophageal reflux disease, in which stomach contents keep moving back up into the esophagus because the opening is too lax.

"Our findings could mean that some congenital malformations and acquired disorders might be as a result of these cells going bad, not the cells people have been looking at," Dr. Sohal says.

His identification of these cells and subsequent tracking to identify specifically where they go and what they do have met with questions and criticism from some colleagues and rejection from some journals.

Undaunted, he continues to move forward, taking logical next steps to document what he admits is a mind-boggling concept. Some feedback from his latest work was that he might have randomly labeled cells from among the known cell types.

The logical progression of science coupled with that type of criticism has him looking for the genes for his VENT cells. "The turning point for us will be when we know the genes of these cells; that these cells have unique genes compared to any other cells," says Dr. Sohal. He believes that gene identification likely will happen this year and says preliminary evidence indicates the presence of unique ones.

Identification of the genes also will allow development of monoclonal antibodies that will enable Dr. Sohal and his research team to tag all VENT cells present during development, rather than the relatively few tagged with a marker gene for the most recent study.

"I would like to know, before I retire, what is the significance of these cells. I think it's tremendous," the 54-year-old scientist says of the VENT cells he has documented coming from the neural tube, which is known for producing multipotential cells. "These cells migrate along nerves and nerves connect every tissue of the body. So here is a mechanism by which you could carry multipotential cells to various target tissues in the body." He noted that sometimes these cells get ahead of the nerves, so they may also cue nerves to make the proper connections with target tissue.

"That is not to say that we already know at this point that they make every cell type in the body, because we don't. But the four tissues of the body are believed to come from different sources of cells … because the (cell) fates are believed to be restricted. What we are finding in these cells is that their fate is not restricted, they are flexible."