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Shwachman-Diamond syndrome (SDS) is a genetic disorder characterized by exocrine pancreatic and hematological dysfunction. As hematological complications are major concerns for mortality with limited treatment options, the mechanisms underlying the SDS hematopoietic defects need to be elucidated to advance the development of effective treatments. We hypothesized that the onset of SDS hematopoietic defects occurred in a certain hematopoietic developmental stage. In this study, definitive hematopoietic differentiation of SDS compared to normal hiPSCs showed reduced CFU-GM and BFU-E formation, increased venous and endothelial potential, and reduced viability in embryoid bodies containing hemogenic and vascular endothelia. Over-representation analysis of dysregulated genes in SDS compared to normal hiPSCs showed enrichment for pathways including histones, glycosaminoglycan metabolism, and WNT signaling. This study offers insight into the onset of SDS hematopoietic defects and potentially disrupted pathways in SDS hiPSCs, and provides patient hematopoietic cell resources for drug screening and the potential to improve patient outcome.