Mechanism of Tissue Engineered Small Intestine Formation

Mechanism of Tissue Engineered Small Intestine Formation

Funding Type: 
New Faculty II
Grant Number: 
RN2-00946
Award Value: 
$3,211,122
Disease Focus: 
Intestinal Disease
Pediatrics
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
Status: 
Active
Public Abstract: 
Statement of Benefit to California: 
Progress Report: 

Year 1

Short Bowel Syndrome (SBS) is an expensive, morbid condition with an increasing incidence. Fundamental congenital and perinatal conditions such as gastroschisis, volvulus, atresia, and necrotizing enterocolitis (NEC) may lead to SBS. NEC is the most common gastrointestinal emergency in neonates and primarily occurs in premature infants. Rates of prematurity are increasing, as are the numbers of children with SBS and NEC. In addition, prevalence is increasing for other diagnoses such as gastroschisis. Medical and surgical treatments are partial and carry high dollar and human costs including multiple infections and hospitalizations for vascular access, liver failure in conjunction with intravenous nutrition, and death. Tissue-engineered small intestine (TESI) offers a potential durable autologous therapy. In the human, engineered intestine from autologous cells would avoid the problems of transplant: immunosuppression and donor supply. Because engineered small and large intestine, esophagus, stomach and specific portions of the gastrointestinal tract such as the GE junction, form by the same process, in addition to SBS engineered intestine could aid in future treatments of trauma, vascular accidents, and gastrointestinal cancer resection. In this year's work, we were able to identify the donor contributions to TESI in a novel murine model that will allow us to make the formation of tissue-engineered small intestine much more efficient. This progress will help us to progress toward a safe human therapy.

Year 2

Current treatment for children with Short Bowel Syndrome (SBS) has a 30% 5 year mortality rate and serious morbidities that destroy the quality of life. Surgical and medical therapies are inadequate. Tissue- engineered small intestine (TESI) may offer an alternative and superior means for restoring intestinal length and function. We recently transitioned this model in order to make use of the tools available in the mouse. The long-term goal of this project is a human cure for SBS. TESI will be formed from autologous cells, and after formation, be connected to the shortened intestinal tract to salvage patients. In order to meet regulatory requirements and to increase the chance of success in humans, we must define the necessary and sufficient progenitor cell population by defining the fate of transplanted OU. A knowledge of the serial process of TESI formation from the seeded OU will inform us about cell spreading, time of vascularization, when and how mature mucosa forms, and allow us to manipulate these processes for successful TESI formation in larger animals and humans. In addition, we can expand the crucial progenitor(s) prior to implantation. As another strategy to enhance TESI formation, we are investigating the role of FGF10, a necessary molecule during organogenesis, homeostasis, and injury repair in postnatal life. FGF10 may increase the proliferation of intestinal epithelial progenitor cells, and therefore improve the growth of TESI. We are conducting parallel studies with murine and human tissue, with success with each.

Year 3

In order to treat children or adult patients who lose part of their gastrointestinal system from trauma, birth defect, or surgery for cancer, we are working on growing parts of the intestine for replacement. This tissue-engineered intestine is now growing well in our laboratory models, and further studying this model we have found ways to make the tissue grow faster while still confirming that the tissue is still growing in a healthy way. We published these findings and presented them at national and international meetings.

Year 4

Transition to the mouse model for the generation of Tissue-Engineered Small Intestine (TESI) was accomplished in year 1, and in year 2 the efficiency and reproducibility of TESI formation in the mouse was markedly improved. For 2012, the work resulted in 4 invited national lectures, and 10 nationally presented abstracts. The lab also has 1 abstract accepted for presentation in 2013 and three papers in press. In year 4 of this grant, we determined that FGF10 overexpression enhances the formation of tissue-engineered small intestine, and these results were just accepted for publication. We also demonstrated two critical steps toward human therapy: generation of tissue-engineered large and small intestine from human progenitor cells.

Year 5

Transition to the mouse model for the generation of Tissue-Engineered Small Intestine (TESI) was accomplished in year 1, and in year 2 the efficiency and reproducibility of TESI formation in the mouse was markedly improved. In year 3, we showed improved tissue generation with VEGF administration and in year 4 of this grant, we determined that FGF10 overexpression enhances the formation of tissue-engineered small intestine and published those data. We also demonstrated two critical steps toward human therapy: generation of tissue-engineered large and small intestine from human progenitor cells. In Year 5, we further developed and published the generation of tissue-engineered small and large intestine, investigated the role of FGF10 in the homeostasis of the small intestine in order to determine its utility as a growth factor for engineered intestine, and began work on the request for designation to the FDA for future translation. In addition, we developed a body of data that we are submitting for publication showing that we have developed a cryopreservation and storage solution, vitrification, which results in the growth of tissue-engineered intestine with excellent viability post-thaw. We further determined that tissue-engineered intestine demonstrates numerous functional markers that are necessary for human translation. For 2013, the work resulted in 6 invited national lectures, and 13 nationally or internationally presented abstracts. The lab also has 6 abstracts accepted for presentation in 2014 and published 5 papers this year.

Publications

© 2013 California Institute for Regenerative Medicine