Multisystem, Induced Pluripotent Stem Cell (iPSC) Modeling Reveals a Role for Growth Differentiation Factors (GDFs) in the Etiology of β Thalassemia and Ineffective Erythropoiesis

β Thalassemia is one of the most common monogenic diseases in man encompassing a heterogeneous group of naturally occurring, inherited mutations characterized by abnormal globin gene expression. Iron overload is the principle cause of morbidity and mortality in β thalassemia. The hepatic hormone hepcidin regulates iron homeostasis modulating iron concentration in the plasma and its distribution in tissues throughout the body. Dysregulation of hepcidin production underlies many iron disorders with emerging evidence suggesting that deficiency of the hormone may result from the strong suppressive effect of high erythropoietic activity on hepcidin expression. Current treatment modalities for iron overload include phlebotomy and iron chelation. In β thalassemia, phlebotomy is not feasible and regular chelation is the principal treatment for iron overload. Iron chelators have side effects ranging from mild to very serious, and compliance is often suboptimal. Hepcidin diagnostics and the development of novel therapeutic options are clearly desirable and may help in the management of patients with β thalassemia. Hepcidin dysregulation, along with the ineffective erythropoiesis and anemia noted in β thalassemia highlight the need for a model capable of recapitulating the multisystem complexity of this clinically variable disease. Using induced pluripotent stem cell (iPSC) technology, cell lines can be established that are genetically identical to the individual from whom they are derived, allowing for disease modeling and the development of novel therapeutics in the exact genetic context of the patient. We have generated disease-specific iPSC lines from patients with β thalassemia major. Harnessing the pluripotency of iPSCs, we demonstrate the modeling of this multisystem disease through the directed differentiation of patient-specific iPSCs into hepatocytes that produce hepcidin as well as erythroblasts produced via a platform that allows for exponentially greater production of blood cells in comparison to existing methodologies (Smith et. al, Blood, 2013). We demonstrate that β thalassemia iPSC-derived erythroblasts secrete greater amounts of GDFs 11 and 15, and that exposure of the patient’s own iPSC-derived hepatocytes to disease-specific erythroblast supernatants results in a marked decrease in hepcidin expression recapitulating essential aspects of the disease in vitro. Furthermore, exposure of developing iPSC-derived erythroblasts to recombinant GDFs results in the production of immature cells that fail to reach maturity, providing a potential novel mechanism contributing to the development of ineffective erythropoiesis. Taken together, these results validate this iPSC-based, patient-specific in vitro system as a platform for testing new diagnostic approaches as well as novel therapeutic strategies targeting the correction of hepcidin dysregulation. Disclosures No relevant conflicts of interest to declare.