Hematopoietic stem cells (HSCs) are the basis of blood formation, responsible for producing all types of blood cells. For research-scientists at Riley Children’s Health and Indiana University School of Medicine, they are amid a study to understand why these cells perform better in low-oxygen environments, a state known as hypoxia, within the bone marrow.
The research, supported by a $2.7 million grant from the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), aims to secure improved treatment options for bone marrow failure and rare blood diseases involving gene-corrected stem cells.
The study, named “Hypoxia’s role in regulating stressed hematopoietic stem cells,” is a four-year project that builds upon earlier findings around hypoxia’s beneficial role in maintaining HSC functions, especially in stem cells from patients with Fanconi anemia, who typically have defective stem cells. Co-leading the study is Reuben Kapur, PhD, director of the Herman B Wells Center for Pediatric Research and Ngoc Tung Tran, PhD, assistant professor of pediatrics at the IU School of Medicine.
“My previous research showed that stem cells with mutations resulting in Fanconi anemia survive and function better in hypoxia versus in higher oxygen conditions,” Dr. Kapur said. “Having a better understanding of these distinctions can potentially improve treatments for diseases caused by problems with defective stem cells in patients.”
Ultimately, the study’s findings will be largely impactful for the patients at Riley Children’s, specifically because bone marrow transplantation is the only curative treatment for bone marrow failure right now, says Kathleen Overholt, MD, pediatric hematologist/oncologist and director of the Bone Marrow Failure Program at Riley Children’s. This transplantation approach, however, has its risks due to DNA repair or maintenance mutations inherent in these conditions.
“Transplantation only cures the blood and immune system, and these diseases affect every cell in the body,” Dr. Overholt said. “This means that despite transplantation, there are still cancer risks in all the other cells.”
While research findings will investigate the relation between hypoxia and stem cells, Drs. Kapur and Tran are also focused on developing strategies to enhance the function of diseased blood stem cells, hoping to improve the outcomes of hematopoietic stem cell transplantation and gene therapy treatments. In pursuing this approach, the defective genes will ideally be corrected without any damage to the cells.
“The technique my lab developed, called the Spacer-Nick-mediated gene correction approach, offers a promising avenue for restoring the functionality of Fanconi anemia blood stem cells while minimizing adverse effects,” Dr. Tran said. “Ultimately, corrected stem cells could be transplanted into patients to address bone marrow failure, a leading cause of early mortality in pediatric patients.”
Ahead of the research study, findings will offer broad clinical implications, promising hope to patients with severe blood diseases. Furthermore, this research reveals the potential of hypoxia in enhancing hematopoietic stem cell function, paving the way for more treatments for pediatric patients.