The generation and expansion of tissue-engineered small intestine from human stem/ progenitor cells: a preclinical study of functional translation

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
Award Value: 
Disease Focus: 
Intestinal Disease
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
Public Abstract: 

This proposal aims to complete the preclinical steps to develop tissue-engineered intestine (TESI) as a functional replacement of the small intestine to treat short bowel syndrome (SBS). Common birth conditions especially those associated with prematurity result in SBS wherein 50-75% of the small intestine is gone. SBS children cannot get adequate nutrition and supportive medical care is morbid with liver failure a common problem. Small bowel transplants, the only current salvage therapy have many problems including poor graft survival, rejection, limited donor supply, surgical morbidity, and lifelong immunosuppression. We hypothesize that TESI from the patient's own cells offers a potential, durable human progenitor-cell based treatment option for SBS.

We have shown that TESI forms when autologous cells are implanted on a polymer scaffold, and that TESI exactly recapitulates native intestine: all four differentiated epithelial cell types in conjunction with the key supporting structure such as nerves, and muscle, grow from the transplanted OU. Importantly, Lewis rats recover from massive small bowel resection with TESI. Other regions of the gut can also reengineered via this approach.

Our goal is to translate TESI from rodents to an autologous human cell based therapy. Patients who needed emergency surgery for their intestine, which might leave the remaining amount of intestine too short to absorb enough nutrition could potentially be treated with TESI.

Statement of Benefit to California: 

In the pediatric population, the incidence of SBS is estimated to be 24.5 per 100,000 live births and associated with a 30% 5-year mortality. To put this in perspective, the NCI reports the cumulative incidence of all invasive childhood cancers is 14.5 per 100,000. In addition, cancer, inflammatory bowel disease and mesenteric ischemia put the adult population at risk. In fact, the incidence of SBS is increasing with a striking 30% 5-year mortality. Annual cost per patient in Europe ranges from $100,000 – 150,000 and is double that in the US [1]. SBS is an unsolved problem with unacceptable human and financial cost. An autologous engineered tissue approach would surpass current therapies. Usable engineered intestine would be far less expensive, more durable, and require less maintenance than any current therapy. California would benefit from this research in many ways- we have a large population and improved and less expensive medical care with less suffering for patients would be the most important benefit to the state and to the people of California. In addition, being at the leading edge of this translational approach will make our state and our institutions experts in the translation of stem cell research, a focus point for attracting scientists and innovators to the state and opening up future therapies building on these results. Finally, this approach will generate intellectual property that can be protected and will also benefit the state and its economy.

Progress Report: 

This proposal aims to complete the preclinical steps required to file an IND for tissue-engineered small intestine (TESI) as a functional replacement for patients with short bowel syndrome (SBS) or other intestinal diseases.

Hypothesis: Autologous TESI offers a potentially durable human stem/progenitor-cell based treatment for patients with SBS.

Highlights this year: Progress on design of the device for generating our stem/progenitor cell clusters (OU) in the operating room, generation of the first TESI in a new large animal model, manuscript accepted for publication (AJPGI) detailing correct ultrastructure and function of TESI derived from both murine and human cells, demonstration of a novel mesenchymal stem cell marker in this system (Cell).

Our near-term goal is to translate TESI to an autologous human stem cell-based therapy for SBS.

Summary of overall progress: In the four months since the mid-year report, we have continued to work as planned. Our most recent progress is outlined below.
Briefly, we have continued to work on developing human TESI from varied sources of OU, in all (childhood) age ranges and disease types, with grading of the resulting TESI. Additionally, we are working on the long-term culture of the OU as well as investigating the stem/progenitor cells that ensure growth of these OU. Last, we are working in our large animal model, and have submitted multiple revisions to our animal protocol (and await approval of same) after our initial experiments indicated parameters for optimization.