Modeling the development and disease of the human enteric nervous system takes guts… and stem cells

April 17, 2017

Question: What part of the nervous system has over 500 million neurons - the cells that transmit electrical or chemical signals throughout the nervous system and beyond - and regulates important bodily functions? Sounds like the brain, right? What if you knew that this part of the nervous system also spans approximately 30 feet in an average adult? That’s right, it’s the enteric nervous system (ENS). Never heard of it?

An often overlooked but critically important component of the nervous system is the ENS, a highly complex network of neurons that surround the length of the gastrointestinal tract from esophagus to anus. With more neurons than the spinal cord, the ENS influences mood and regulates processes including digestion, especially peristalsis - the synchronized process of passing food and waste through the intestines –and other vital functions of the digestive tract.

The ENS is so vital that defects in its formation and function can be fatal. Hirschsprung disease, a genetic defect also known as aganglionic megacolon, is one such disorder of the ENS, affecting 1 in 5,000 births worldwide.

Hirschsprung disease is typically diagnosed during infancy and is characterized by the absence of the ENS in a variable portion of the digestive tract, commonly, the distal colon. The consequence of this defect is that peristalsis is inhibited and food and waste cannot be efficiently passed along the digestive tract, a potentially fatal condition.

The severity of the symptoms can vary, but treatment can involve surgically removing the affected portion of the gut. However, in both surgically treated patients and those with milder forms, gut function may not be normal and can cause life-long health issues.

The understanding of ENS diseases like Hirschsprung’s has been slowed due to the limitations of existing disease models. Thanks to stem cell research, scientists now have a new tool that will help them understand how genetic defects lead to Hirschsprung disease and to test cellular and drug-based therapies to treat it.

A team of scientists lead by Dr. Lorenz Studer from the Center for Stem Cell Biology at Memorial Sloan Kettering Cancer Center have developed a method to derive ENS cells from human induced pluripotent stem (iPS) cells.

Induced pluripotent stem cells, like embryonic stem cells, cells can give rise to any cell type in the body when grown in the appropriate conditions. However, iPS cells are unique in that they can be derived from patients thus providing scientists with stem cells that contain the same genetic mutations found in patients, an essential tool in understanding the disease. iPS cells can also be used to develop replacement cells, for those that are dead or defective, that would not be subject to rejection by the body’s the immune system.

Dr. Studer’s team demonstrated that the iPS-induced ENS cells could model Hirschsprung disease AND potential therapeutic approaches. When used to model the disease in laboratory tests, iPS-derived human ENS cells from Hirschsprung patients revealed migratory defects consistent with the defects seen in patients. To identify potential drugs to treat this migratory defect, a library of FDA-approved drugs was tested to see which compound, if any, could reverse the effects of the mutation. One of the drugs, Pepstatin A, significantly improved the function of the mutant cells, providing proof-of-principle for this approach.

Finally, to illustrate their therapeutic potential, iPS-derived ENS cells from healthy individuals were transplanted into the defective region of the ENS in an animal model of Hirschsprung disease and shown to not only rescue gut function but also significantly extend the life of the animals that would otherwise die due to the disease.

While there is still much research to be done before these cells could be used clinically, this discovery has stimulated significant scientific and financial investment into this approach. The California Institute of Regenerative Medicine, which is focused on “accelerating stem cell treatments to patients with unmet medical needs” has recently funded a multi-million dollar grant to help move this potential therapy closer to the clinic.