Babies born prematurely : intestine transplant can benefit some patients but also stem cell therapy is poised to become a game-changer

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Babies born prematurely often face intense medical challenges, including intestines that are underdeveloped or diseased.

While an intestine transplant can benefit some patients, many babies are simply too small to endure this procedure.

Children’s Hospital Los Angeles surgeon Tracy Grikscheit, MD, is a leader in the field of tissue engineering – growing intestines from stem cells.

In an article published in the journal Cell Stem Cell, Dr. Grikscheit and co-authors highlight how stem cell therapy is poised to become a game-changer for these babies.

Some premature babies are born with severely underdeveloped gastrointestinal tracts or can develop diseases like necrotizing enterocolitis, which attacks the intestines.

In severe cases, surgical removal of the affected bowels (intestines) must be performed. This can have dire consequences.

Fluorescent image of stem cells and progenitor cells. Cells like these can eventually be grown in the laboratory into small intestines to treat babies with severe gastrointestinal challenges. Photo courtesy of Dr. Grikscheit, Children’s Hospital Los Angeles. Credit: Dr. Grikscheit, Children’s Hospital Los Angeles

Most nutrient and water absorption occurs in the small intestine, so if patients are not left with enough healthy tissue, they can suffer from serious complications like malnutrition or dehydration – also known as short bowel syndrome.

In order to get the proper nutrients, patients may have to be fed through a feeding tube or intravenously- through a needle into the bloodstream.

In the most severe cases of short bowel syndrome, small intestine transplant from donor tissue is the only answer; but this, too, comes with its own list of problems.

Babies must be big enough for this procedure, which often means they need to wait several months.

Even then, the road is not an easy one.

Patients must take anti-rejection medications, which have their own side effects and the success rate of transplantation is only about fifty percent.

With such challenges, the future seems bleak for these babies. To Dr. Grikscheit, this is not acceptable.

She wants more for her patients and she envisions a world in which missing portions of intestines can be grown.

Scientists like Dr. Grikscheit investigate growth of new tissue from stem cells to treat babies with severe intestinal impairments.

Stem cell therapies would really improve upon current options,” she says. “Right now, these babies can either get a transplant, or live on IV nutrition, which really impacts the way they can interact with the world and develop.

There has to be a better way.”

The Cell Stem Cell article was written by Dr. Grikscheit and colleagues as part of INTENS, a European consortium that fosters research to treat children with intestinal failure through tissue engineering.

Tissue engineering is the process of producing new tissue in the laboratory from stem cells. The publication describes the progress researchers have made as well as the challenges scientists face in bringing stem cell therapy to patients.

Stem cells have the capability of developing into any cell type, making them ideal starting material for organ repair.

The paper discusses two main ways in which stem cells could potentially treat babies with these intestinal issues.

Stem cells can either be taken from the patient’s own intestine or “off the shelf—from a stock source of stem cells that can be engineered into intestinal tissue.

The two pathways each offer distinct advantages to patients and the treatment type could depend on the condition each child faces.

Research in this field is showing promise for future therapy. Recent progress has allowed researchers to generate larger amounts of intestinal tissue than ever before.

“We’re not yet at the stage of delivering this therapy to babies but we’re developing the road map,” says Dr. Grikscheit. “We’re getting closer.”


The clinical problem of short bowel syndrome

Short bowel syndrome (SBS) refers to the condition in which limited intestinal mucosa cannot meet the nutritional needs of the patient via enteral absorption (1,2).

The diagnosis of SBS relies on an assessment of the loss of intestinal length (13), in combination with poor enteral absorption (4), dependence on total parenteral nutrition (TPN) (57), or some combination of these factors. (1,2,8).

The epidemiology of SBS remains difficult to define due to variation in diagnostic criteria, study population (pediatric versus adult), and the length of the follow-up period among studies. In one of the largest population-based studies of SBS (3), the overall incidence was found to be 0.02% of all live births, and 2.2% of neonatal intensive care unit (NICU) admissions.

Notably, the incidence among premature infants (<37 weeks gestational age) was 100× higher than among infants >37 weeks. Further, there is an increased incidence associated with low birth weight (0.7 in very low birth weight, and 1.1% in extremely low birth weight) babies (1).

Causes of short bowel syndrome and the need for innovative therapies

Among the pediatric population, leading causes of SBS include necrotizing enterocolitis (NEC), intestinal atresia, gastroschisis, and malrotation with volvulus (2,7,9,10), with NEC representing about 96% of cases in the low birth weight NICU population (1).

Complications of SBS are many, and include cholestasis resulting in liver failure, bowel dilation resulting in bacterial overgrowth, and sepsis with its related complications, which may arise both from central-line associated bacterial infection [CLABSI] and bacterial overgrowth. (2,5,7,1012).

The overall mortality of SBS is estimated at 27.5% to 37.5% over a follow up period of 2–5 years (1,2,7,8,13), with leading causes of death being hepatic failure and sepsis (2,7,9,11,13). Given that the inability to achieve enteral autonomy is one of the leading predictors of mortality (2,7,9), current therapy for SBS aims to restore enteral autonomy. Present treatment options focus on either increasing absorption (via adaptation and intestinal reversal procedures) or restoring intestinal length (via intestinal lengthening procedures and transplant.).

Despite decades of experience with TPN supplementation and optimization of surgical techniques and transplantation, half of all patients with SBS will never attain enteral autonomy.

The annual mortality in SBS is 15–30% (3,8,12.) Given the limited success and high morbidity of current therapy, novel treatment approaches are clearly needed.

As will be reviewed in the following sections, the development of an artificial intestine derived from the patient’s own intestinal stem cells and incorporated into a novel bioscaffold that recruits an endogenous blood supply may represent an attractive option for the treatment of children with SBS.Go to:

Strategies for the development of an artificial intestine

The goals of developing an artificial intestine include the provision of appropriate absorptive epithelium, barrier and immune functions, and motility.

In addition, the artificial intestine would be autologous in order to achieve enteral independence without the need for immunosuppressive drugs. In support of the success of this approach, the modern era of tissue engineering began in 1988 with Joseph Vacanti and Robert Langer demonstrating growth of pancreatic and intestinal tissue on a bioabsorbable scaffold implanted into the omentum of rats (14).

Since this early finding, there has been a large body of research focused on the development of a tissue engineered intestine.

The basic requirements for an engineered intestine include a source of stem cells with the capacity to grow and differentiate into a mature and absorptive mucosal surface (Figure 1), a bioscaffold capable of supporting cellular growth (Figure 24), a niche for engraftment and growth of the tissue, and vascularization of the new tissue.

Additional challenges include meeting the large surface area needed for enteral autonomy and optimization of gastrointestinal motility.

Each of these challenges will be discussed with a focus on successes and opportunities which lie ahead.

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Figure 1
Confocal micrograph revealing the growth of a mini-gut (enteroid) in culture as a precursor to the development of an artificial intestine. Green – ki67, cyan – e-cadherin, red – phalloidin, blue – DAPI.
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Figure 2
Scanning electron micrograph showing a synthetic (Poly(glycerol) sebacate (PGS) scaffold with an architecture that mimics the native intestinal crypt-villus architecture in cross section.
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Figure 4
Scanning electron micrograph showing the intestinal stem cells covering a synthetic villous at the villus base.
a. PGS scaffold supports growth of intestinal epithelium

More information: Hans Clevers et al, Tissue-Engineering the Intestine: The Trials before the Trials, Cell Stem Cell (2019). DOI: 10.1016/j.stem.2019.04.018

Journal information: Cell Stem Cell
Provided by Children’s Hospital Los Angeles

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