Sulfur Based Stem Cell Therapeutics in Necrotizing Enterocolitis

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This investigator's proposal describes a 5-year project designed to study mesenchymal stem cells derived from inducible pluripotent stem cells as a treatment modality for necrotizing enterocolitis (NEC). NEC is a devastating intrabdominal emergency in the neonatal population that often requires the surgical resection of intestine, thereby leaving infants with a suboptimal length of bowel to absorb nutrition. It occurs in roughly 10% of preterm infants, carries a 40-50% mortality rate, and costs $1.3 billion in medical costs annual. There has been lack of advancement in treatment modalities over the last decade for NEC, and cellular therapy may provide beneficial improvements in outcomes. Investigators hypothesize that hydrogen sulfide (H2S) is a key paracrine factor in mesenchymal stem cell mediated intestinal protection during necrotizing enterocolitis. To more readily study the effects of hydrogen sulfide, they propose the development of a near infrared H2S specific probe to more accurately quantify H2S in biological systems. Further proposed studies overexpress hydrogen sulfide producing enzymes in iPSC derived MSCs and aim to identify the secreted polysulfides which likely serve as intracellular signaling molecules. Finally, they assess the role of Cys440 on eNOS as a critical residue that interacts with hydrogen sulfide to promote mesenteric vasodilation and improved clinical outcomes in experimental NEC. The investigators propose three Specific Aims: 1) To define the role of hydrogen sulfide signaling from MSCs during cellular therapy for NEC, 2) To develop and validate a hydrogen sulfide probe to effectively measure H2S in biological systems, and 3) To evaluate the interaction of iPSC derived MSCs, H2S, and Nitric Oxide (NO) on the mesenteric endothelium during experimental NEC. The investigator is a pediatric surgeon scientist who was formally funded through the NIDDK as a K08 awardee. This grant support expired in May 2022. He is now seeking out his first R01 award as an Early Stage Investigator. His career goals are to use this R01 to further develop cellular therapy as a viable treatment for necrotizing enterocolitis. Dr. Markel has a long standing collaborative and mentor relationship with Dr. Ken Olson at Notre Dame/IU Southbend. He is an international expert in hydrogen sulfide signaling and will continue to assist Dr. Markel with assays designed to further quantify the secreted polysulfide pool. Dr. Markel has also collaborated with Dr Ben Gaston at his local institution who is an expert on nitric oxide signaling, as well as Dr. Tim Lescun, a large animal veterinarian at Purdue University, who has assisted in establishing a piglet model of NEC in Dr. Markel's laboratory. In summary, this research aims to understand the mechanism that iPSC derived MSCs use to provide protection in NEC. The proposal is highly innovative and the investigator has the appropriate support, collaborations, and infrastructure in place to carry out the study. Results of this study will be used to provide final preclinical data before human clinical trials can ensue.