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Tissue-engineered Small Intestine: A Proposed Future Treatment for Short Bowel Syndrome
Kathleen Holoyda, MD, and Tracy C. Grikscheit, MD
Short bowel syndrome (SBS) results from the removal of a significant proportion of a patient’s bowel, or from the loss of function of the bowel that is present. The condition is fairly rare. It affects approximately twenty-two children for every one thousand admitted to the neonatal intensive care unit at birth. How many adults are affected is more difficult to determine. It is estimated, based upon data describing patients requiring long-term home parenteral nutrition (HPN), that in the United States between ten and twenty thousand adults with SBS are receiving HPN therapy.
The most common reason children develop SBS is the removal of a large portion of bowel due to necrotizing enterocolitis. In some premature infants, necrotizing enterocolitis causes so much inflammation that the bowel does not function well, or even perforates, and needs to be removed. In adults, removal of bowel is most commonly due to damage from inflammatory bowel disease, such as Crohn’s disease and radiation enteritis; short bowel infarction; or after there has been trauma to the bowel. In adults and children, the condition can lead to malnutrition and dehydration. Therapy for SBS is designed to manage these issues.
Inside the Small Bowel
The small bowel is where food is digested and nutrients are absorbed. When a large amount of the bowel is lost, the small bowel tries to compensate by dilating and developing a thicker wall. The cells that line the inside of the small bowel, called enterocytes, reproduce more rapidly in this setting. Imagine an individual blade of grass growing in a meadow. As the blade grows quickly in the spring, the soil becomes thicker with tangled roots. The blade of grass can be compared to an enterocyte, and the entire meadow to the epithelium, which lines the inside of the small intestine. As discussed below, the epithelium is made up of several different types of cells in addition to the enterocytes.
The process of increasing the number of enterocytes, increasing the size of the small bowel, and developing a thicker wall is called intestinal adaptation. It occurs mainly in the first two years following loss of the small bowel, and it is controlled by stem cells that live in the wall of the small bowel and which maintain the small bowel’s ability to absorb nutrients. The stem cells live in the crypt, and the crypt lies between villi (plural for "villus;” see figure 1).
Villi are covered with the epithelium of the small intestine, which contains specialized cells called enterocytes, goblet cells, enteroendocrine cells, and Paneth cells. Enterocytes are responsible for the absorption of nutrients. Goblet cells secrete mucus, which protects the intestinal epithelium from mechanical stress. Enteroendocrine cells produce and release hormones into the bloodstream and locally; they have the ability to react to substances within the lumen of the small intestine and aid in digestion and protection. Finally, Paneth cells act as the immune cells of the small intestine by secreting granules that protect the intestine from bacteria. Paneth cells also reside near and help support the intestinal stem cells in the base of the crypts.
There are unique types of small intestine stem cells. As enterocytes get older, one type of stem cell multiplies and replaces them with fresh cells. These are called crypt base columnar cells, or CBCCs. When the small bowel is injured, +4 stem cells, which are normally relatively inactive, respond to this injury and help to replace damaged enterocytes.
Both types of stem cells multiply and become intermediate progenitor cells that differentiate into the specialized cells of the epithelium. Progenitor cells are located in the crypt above the stem cell zone. They multiply approximately four to six times before differentiating. As they differentiate, the cells move up towards the tip of the villi, which is exposed to the lumen of the small intestine, to help protect the small intestine and absorb nutrients. The stem cell populations are crucial in maintaining healthy intestine and responding to bowel injuries. They are also an important part of intestinal adaptation in the setting of SBS.
Current Therapies for SBS
Current therapies for SBS address the malnutrition, electrolyte disturbances, and dehydration associated with the condition. The many people who may be involved in the care of patients with SBS include a neonatologist or pediatrician, a gastroenterologist, a nutrition specialist, and a surgeon. Each team member contributes a unique aspect of care to support the patient. Therapy often involves the placement of a central line so fluids and/or parenteral nutrition (PN) can be provided directly into the patient’s veins.
Other treatments include anti-motility agents, which are designed to slow the transit of food through the small bowel, allowing for greater contact time with the epithelium, increasing absorption. Novel medical therapies are also being developed, such as teduglutide (Gattex®, NPS Pharma), a GLP-2 analog that is administered subcutaneously and promotes repair and growth of the cells that line the small bowel. Several clinical trials have shown increased absorption and decreased need for PN with the administration of teduglutide.
Surgery can also be a therapeutic option for the treatment of SBS. The procedure with the best outcomes is the serial transverse enteroplasty procedure, or STEP. This procedure effectively lengthens the bowel and can help wean patients from PN. It may be repeated multiple times as the bowel heals. It cannot be performed on all patients with SBS, however. As with any surgical procedure, careful patient selection is very important to increase the likelihood of success.
Small bowel transplantation is another surgical treatment for SBS. This procedure essentially replaces the removed small bowel with a donor patient’s small bowel. However, only thirty-seven of one hundred donated small intestine grafts are still functioning five years following transplantation. Patients must also take immunosuppressive medications for the duration of the transplant, which means the patient is more susceptible to infection.
Tissue Engineering of Small Intestine
Many laboratories throughout the world are working to create long-term solutions for SBS patients that do not require daily administration of intravenous fluids or immunosuppression. Our goal is to grow small intestine from the tissue of the patient. This tissue-engineered small intestine, or TESI, would ideally be nearly identical to the patient’s native tissue, thus eliminating the need for immunosuppression. We believe that in the future this may be a suitable treatment for those suffering from SBS.
Our laboratory has successfully grown TESI in several different models. This is possible because of the stem cells present in the epithelium of the small intestine. We take a sample of small intestine and, using enzymes and mechanical means, break the sample into smaller pieces of tissue, or "digested tissue.” This tissue includes the epithelium of the small intestine; the supporting structures of the small intestine, called the mesenchyme; and the small intestine stem cells. This collection of the crucial components is loaded onto a scaffold, a small, semipermeable tube, and given a blood supply. Over a period of four weeks, human TESI develops and grows as a result of the interactions between the intestine stem cells and the other components.
The human TESI produced in the laboratory looks similar to native human small intestine. It contains the basic small intestine lining, including crypts and villi. It also contains the mesenchyme supporting the epithelium that consists of a muscular layer and nervous tissue. The four important cell types of the epithelium—enterocytes, goblet cells, enteroendocrine cells, and Paneth cells, all of which are essential for functional small intestine—are also identified within the human TESI.
At this time, TESI only contains approximately three times the original number of cells that were present in our digested tissue. This is inadequate to replace the small bowel in a patient following removal of a significant proportion of their bowel.
Current work is focused on enhancing the growth of TESI and various factors that encourage growth are under investigation. Testing the function of TESI is another focus. In order for TESI to be a treatment for SBS, it must be able to perform the same function as native small intestine. We are studying the presence of transporters on the luminal side of the TESI bowel and the ability of TESI to absorb fragments of protein and carbohydrates.
While human TESI has been created, many experiments must be performed before patients may benefit from it. We do know that the maturation of digested tissue into organized TESI is controlled by the stem cells of the intestinal epithelium. However, this is a highly regulated process that is still not clearly understood. By understanding the pathways and factors that enhance TESI growth, scientists hope to overcome these limitations so that in the future, TESI may be used as a therapy for SBS.
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