(From the November Research Now)
Two of the most promising therapies for the treatment of intestinal injuries such as necrotizing enterocolitis — the leading cause of death in premature babies — involve stem cells, according to numerous studies published by clinician-scientists at Nationwide Children’s Hospital. The potential treatments include transplantation of either neural stem cells or mesenchymal stem cells in combination with heparin-binding EGF-like growth factor.
The latest research on these therapies, published in the journals Stem Cell Research & Therapy and the Journal of Pediatric Surgery, offers additional support for the ongoing clinical investigations into stem cells led by Gail E. Besner, MD, chief of pediatric surgery at Nationwide Children’s. Although the therapies offer hope for a wide range of intestinal ailments, from ischemia-reperfusion injury to radiation-induced injury, Dr. Besner’s passion lies in developing a cure for NEC.
“The mortality rate of NEC approaches 50 percent in very small premature babies requiring surgery, and the disease results in severe morbidities in many more. This situation is unacceptable,” says Dr. Besner, who also is a principal investigator in the Center for Perinatal Research at The Research Institute. “I hope my work with stem cells and growth factors can eventually give physicians the power to say, ‘I can help your baby,’ when they have to make a diagnosis of NEC.”
Since Dr. Besner’s discovery of heparin-binding EGF-like growth factor (a glycoprotein known as HB-EGF) in the 1990s, her research efforts have uncovered its potential for improving tissue repair after intestinal injury, particularly when combined with stem cell therapy. Her most recent publication on the topic further identified that HB-EGF has a direct effect on amniotic fluid-derived mesenchymal stem cells, improving their effectiveness in healing intestinal tissue in animal models of NEC.
“Our latest study showed that mesenchymal stem cells were more likely to engraft into injured intestine and improve intestinal histology and gut barrier function when HB-EGF was administered at the same time,” Dr. Besner explains. “We demonstrated that amniotic fluid-derived mesenchymal stem cells were more effective than those harvested from bone marrow. We also found that HB-EGF improved the efficacy of stem cell therapy when the growth factor was administered enterally along with stem cell therapy, or when stem cells were genetically engineered to overexpress HB-EGF.”
Dr. Besner and her team are continuing to investigate the best way to administer stem cells and HB-EGF for the treatment of NEC in animal models, with the long-term goal of moving to human trials.
By investigating the pathology of the condition among human patients, Dr. Besner and her team have also confirmed the presence of significant enteric nervous system damage in infants with NEC. Evidenced clinically by intestinal dysmotility, enteric nervous system abnormalities, such as neuronal cell death and structural and functional abnormalities, were discovered in the intestinal tissues of babies with acute NEC and persisted for months after recovery from the acute disease. This pointed to a novel, previously underappreciated possible etiology for the development of the disease, Dr. Besner says. In order to study the potential of stem cell therapies to target the enteric nervous system abnormalities associated with NEC, the team performed the transplantation of neural stem cells in animal models of the disease.
“We found that neurotransplantation resulted in engraftment of the cells in injured intestine and the subsequent improvement of enteric nervous system integrity and intestinal motility,” says Dr. Besner, who also is a professor of pediatrics and surgery at The Ohio State University College of Medicine and holds their H. William Clatworthy Jr. Professorship in Surgery. “Neurotransplantation could become a novel therapeutic to help human infants overcome the enteric nervous system damage of NEC.”
Dr. Besner’s lab is continuing research efforts with both mesenchymal stem cells and neurotransplantation. She is optimistic that these types of therapies could lead to advances in NEC treatment in the near future.
“Both of these potential therapies could offer excellent options for managing NEC and other intestinal injuries,” she says. “As the research evolves, it is my hope that we can use our research findings from the laboratory to save premature babies from this devastating disease.”
Watkins DJ, Zhou Y, Matthews MA, Chen L, Besner GE. HB-EGF augments the ability of mesenchymal stem cells to attenuate intestinal injury. Journal of Pediatric Surgery. 2014 Jun, 49(6):938-44.
Yang J, Su Y, Zhou Y, Besner GE. Heparin-binding EGF-like growth factor (HB-EGF) therapy for intestinal injury: Application and future prospects. Pathophysiology. 2014 Feb, 21(1):95-104.
Zhou Y, Yang J, Watkins DJ, Boomer LA, Matthews MA, Su Y, Besner GE. Enteric nervous system abnormalities are present in human necrotizing enterocolitis: potential neurotransplantation therapy. Stem Cell Research & Therapy. 2013 Dec, 4(6):157.