This is a tissue-engineered colon generated from cells from a patient with Hirschsprung's disease. Nerve cells (derived from neurospheres) are shown in green. [Children's Hospital Los Angeles]
This is a tissue-engineered colon generated from cells from a patient with Hirschsprung’s disease. Nerve cells (derived from neurospheres) are shown in green. [Children’s Hospital Los Angeles]

Congenital disorders of the digestive tract, while rare, are serious conditions that most often require surgical intervention. In recent years, with advances in tissue engineering scientists have begun to develop systems to grow parts of the GI tract under laboratory conditions. The main goal of which is to have tissue-engineered colons (TECs) potentially replace absent or injured pieces of the intestinal tract. However, little attention has been given to a key component of the GI tract, the enteric nervous system, for TECs.

Now, researchers at Children's Hospital Los Angeles (CHLA) have shown that tissue-engineered colons derived from human cells can develop the many specialized nerves required for function, mimicking the neuronal population found in the native colon. These highly specialized neurons, confined to the gut, form the enteric nervous system, which regulates digestive tract motility, secretion, absorption, and gastrointestinal blood flow.   

“The diversity of neuron types that grew within the human tissue-engineered colon was a revelation to our team, because previously we had only documented that some ganglia were present,” explained senior author Tracy Grikscheit, M.D., pediatric surgeon and researcher at The Saban Research Institute of CHLA. “The next step was to determine if these neuronal elements could be supplied to the tissue-engineered colon that was missing neurons—like in Hirschsprung's disease.”

The findings from this study were published online recently in Tissue Engineering, Part A through an article entitled “Human and murine tissue-engineered colon exhibit diverse neuronal subtypes and can be populated by enteric nervous system progenitor cells when donor colon is aganglionic.”

Within healthy intestines, food is moved along the digestive tract through a series of wave-like contractions dubbed peristalsis. Specialized nerve cells called ganglion cells are required for this movement, but there is also a diverse mixture of other types of neuronal cells. In children with Hirschsprung's disease, these cells are missing and without them, the intestine becomes blocked, requiring surgical removal of the affected segment of colon.

The future goal of the current study is to grow tissue-engineered organs, generating new tissue from a patient's own cells. However, to begin, Dr. Grikscheit and her team first needed to determine what parts of the enteric nervous system were present in the tissue-engineered colon when it is grown from normal human cells.

The investigators initially were able to grow cells from patients with Hirschsprung's disease, as well as from mice with a genetic mutation that causes aganglionosis (the absence of ganglion cells within the colon). In both cases, the TEC derived from these cells did not have all the components of the intestinal nervous system. Though, in a second set of experiments, again testing mouse and human cells, the investigators added neurospheres—clusters of purified neural progenitor cells. The cells had been stained with green fluorescence, so the scientists could visualize and track where the nerve cells ended up in the TEC.

“After growing the colon for four weeks, we saw that the green nerve cells had been incorporated into the colon engineered from human tissue derived from a patient lacking those elements and that the different nerve subtypes were present,” noted lead author Minna Wieck, M.D., investigator and surgical resident at CHLA.

The researchers were excited by their findings and are hopeful that combining tissue-engineering and cellular replacement therapies will provide a new strategy for treating enteric neuropathies, particularly in the case of Hirschsprung Disease.








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