Gaucher Disease-Induced Pluripotent Stem Cells Display Decreased Erythroid Potential and Aberrant Myelopoiesis
Authors: Sgambato Judi A. , Park Tea Soon , Miller Diana , Panicker Leelamma M. , Sidransky Ellen , Lun Yu , Awad Ola , Bentzen Søren M. , Zambidis Elias T. , Feldman Ricardo A. 
Published: June 2015

AbstractGaucher disease (GD) is the most common lysosomal storage disease resulting from mutations in the lysosomal enzyme glucocerebrosidase (GCase). The hematopoietic abnormalities in GD include the presence of characteristic Gaucher macrophages that infiltrate patient tissues and cytopenias. At present, it is not clear whether these cytopenias are secondary to the pathological activity of Gaucher cells or a direct effect of GCase deficiency on hematopoietic development. To address this question, we differentiated induced pluripotent stem cells (iPSCs) derived from patients with types 1, 2, and 3 GD to CD34+/CD45+/CD43+/CD143+ hematopoietic progenitor cells (HPCs) and examined their developmental potential. The formation of GD-HPCs was unaffected. However, these progenitors demonstrated a skewed lineage commitment, with increased myeloid differentiation and decreased erythroid differentiation and maturation. Interestingly, myeloid colony-formation assays revealed that GD-HPCs, but not control-HPCs, gave rise to adherent, macrophage-like cells, another indication of abnormal myelopoiesis. The extent of these hematologic abnormalities correlated with the severity of the GCase mutations. All the phenotypic abnormalities of GD-HPCs observed were reversed by incubation with recombinant GCase, indicating that these developmental defects were caused by the mutated GCase. Our results show that GCase deficiency directly impairs hematopoietic development. Additionally, our results suggest that aberrant myelopoiesis might contribute to the pathological properties of Gaucher macrophages, which are central to GD manifestations. The hematopoietic developmental defects we observed reflect hematologic abnormalities in patients with GD, demonstrating the utility of GD-iPSCs for modeling this disease.SignificanceThis study showed that hematopoietic progenitors from patients with Gaucher disease (GD) have intrinsic developmental abnormalities that reflect characteristic clinical manifestations. These abnormalities include decreased erythroid potential and abnormal myelopoiesis. GD hematopoietic progenitors gave rise to aberrant macrophage-like cells, suggesting that abnormal myelopoiesis may contribute to the pathological properties of Gaucher macrophages. All the hematopoietic abnormalities observed were reversed by incubation with recombinant glucocerebrosidase, which is used to treat patients with type 1 GD. The results suggest that enzyme replacement therapy could help normalize clinical parameters in these patients, not only through recombinant glucocerebrosidase uptake by Gaucher macrophages, which are the intended target, but also potentially by acting directly on hematopoietic progenitors. The results shown here provide new insights into the etiology of GD hematopoietic abnormalities, and highlight the utility of GD iPSC for modeling the disease and therapeutic development.