Regulation of Hematopoietic Progenitor Formation in a Shwachman Diamond Syndrome Induced Pluripotent Stem Cell Disease Model

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure disease, with 90% of SDS patients carrying a mutation in the SBDS gene. Due to limited efficacy or toxicity of current treatments available, and the otherwise reduced life expectancy of SDS patients, novel therapeutic strategies are needed. Since the main morbidity and mortality are related to the blood dyscrasia, studying hematopoiesis will help characterize the hematological phenotype. We hypothesized that the definitive wave of hematopoiesis is markedly impaired. We generated SDS iPSCs that recapitulated the human SDS disease, specifically, the reduced blood cell formation. The SDS iPSCs showed a defect in definitive hematopoiesis, with a marked reduction in the hemogenic endothelium population. We did not observe a defect in primitive hematopoiesis. Our study sheds light on the onset and progression of the SDS hematopoietic phenotype, and provides a platform for the development of novel, potential therapeutic targets to improve patient care.M.Sc