For the first time ever, scientists have been able to artificially create an organoid—a mass of cells and tissues—that accurately reproduces a naturally developed human colon. The research was conducted at Cincinnati Children’s Hospital Medical Center, and senior study investigator James Wells, PhD believes that this technology opens the door to an unprecedented understanding of the gastrointestinal (GI) tract.
Colitis, colon cancer, and Irritable Bowel Syndrome are but a few prevalent diseases that affect the colon, sometimes referred to as the large intestine. As the final part of the GI tract, the colon is responsible for absorbing water and storing waste material as feces. Colitis, an inflammation of the colon, can cause a wide range of physical discomforts and other painful symptoms.
Until now, studies conducted upon the GI tract have taken place in mice, or other animals that closely resemble the human GI tract. Unfortunately, these models fail to precisely represent the effects that human diseases can have in the human GI tract. They are close enough to be effective, but with the ability to engineer the human colon, studies can be performed directly on the human colon itself.
With the ability to engineer the human colon also comes the possibility of one day being able to grow entire GI tracts to be transplanted into patients suffering from gastrointestinal diseases. Other areas of the GI tract have proven easier to recreate than the colon, with the greatest challenges surrounding the colon being overcome in the recent study.
Engineering the Gastrointestinal Tract
Wells serves as director of the Cincinnati Children’s Pluripotent Stem Cell Center. He and his team of researchers have been publishing studies on human pluripotent stem cells (hPSCs) since 2009.
A pluripotent stem cell is an immature cell that, upon development, can grow into and become one of several different cell types. All cells in the human body begin as stem cells, which develop and grow during the embryonic stage of development. They are coaxed into assuming the form of the desired cells by scientists who replicate the conditions of growth that the cells would undergo in standard embryonic development.
In their studies, Wells and his researchers have been able to grow embryonic-stage organoids into many different components of the human stomach, including the small intestines. These artificial organs are engineered to have functioning nervous systems, and go on to function exactly the same way that the natural organ would in relation to the rest of the human body. It is for this reason that researchers are able to study the effects of GI tract diseases upon artificially generated organs.
That being said, the colon presented researchers with a challenge. Embryonic development of the colon has not been as clearly understood as other regions of the GI tract, and so part of the challenge came in determining how to recreate the conditions that stem cells experience in the embryonic stages of development.
Understanding Embryonic Development in Animals
In order to understand the embryonic development of the human colon, researchers turned to frogs and mice. Humans, frogs, and mice share a remarkable similarity in their expression of a specific DNA-binding protein called SATB2, which researchers identified as a key marker in the hindgut of humans, frogs, and mice.
SATB2 is short for special AT-rich sequence-binding protein, and its function is to organize the genetic makeup of chromosomes in the nucleus of cells. Scientists knew that there must be molecular signals regulating SATB2 in frogs and mice, and theorized that if they could identify the proper signals in frogs and mice, they could apply the same molecular signal to human stem cells and trigger the growth of the human colon.
They found an answer in another protein, the bone morphogenetic protein (BMP), which scientists found to be highly active in posterior regions where SATB2 was also highly active. Researchers were able to determine that BMP signals the establishment of SATB2 in the development of the gut region that houses the colon.
By adding BMP proteins to human pluripotent stem cell cultures, a HOX genetic code was activated in the posterior region. The HOX code controls the development of an embryo from head to toe, and researchers found that the cultures successfully expressed the SATB2 proteins, giving form to properly functioning human colon organoids.
Potential for GI Tract Transplantation
Once the GI tissues were engineered, scientists continued their research into testing the performance of the organoid colons in living organisms. If these organoids are to have any therapeutic or transplant potential, they need to survive and properly function in the same capacity as the human colon.
The research team collaborated with the Division of Surgery and transplanted the engineered colons into immunocompromised mice. For six to ten weeks, researchers studied the in vivo colons, searching for signs that the cells in the posterior region were producing the same hormones that are produced from naturally developed human colons.
Over time, the transplanted colons began to assume all of the same structures, forms, and both the molecular and cellular properties of naturally developed human colons. This exciting success brings with it the possibility for direct study of gastrointestinal diseases of the human colon, as well as opportunities to test new pharmaceutical drugs before the clinical trials of the drugs begin.
First author of the study Jorge Munera, PhD, writes that “by exposing human colonic organoids to inflammatory triggers, we can now learn how the cell lining of the colon and the supporting cells beneath cooperate to respond to inflammation.” Munera believes these studies will most directly benefit those with Crohn’s disease or colitis, common gastrointestinal diseases that have until this point been researched primarily through animal testing.
Munera also foresees applications into understanding the relationship between bacteria that live in the gastrointestinal tract, hoping that further researcher will lead to a greater understanding of the roles of these bacteria in health and disease. Munera states that “because the microbiome, the organisms that live in our guts, are most concentrated in the colon, the organoids potentially could be used to model the human microbiome in health and disease."
The bottom line
Engineering and transplanting fully functioning gastrointestinal tracts into human beings is still some ways away, but these breakthroughs have suggested that full transplants may one day be possible for patients with severe gastrointestinal diseases. The fact that transplants have already been successfully conducted in animals is a sign that stem cell research may lead to solutions previously unimaginable.
Wells and his team of researchers continues to study the organoid colons, and the benefits of direct research on the human colon are sure to soon reveal further treatment options and therapies for individuals living with a gastrointestinal disease.