Ipscs from Cd34 5410 2 4 D E C E M B E R 2 0 0 9 I V O L U M E 1 1 4 , N U M B E R 2 7 Blood

Content Provider	Semantic Scholar
Author	James, C. David Jp, Le Couedic Ma, Vodyanik Smuga-Otto K. Takahashi Raya Rodriguez-Piza, A. Guenechea G. Choi Ball, Edward D.
Abstract	ϩ cells obtained from healthy controls and MPD patients carrying the JAK2-V617F mutation. While MPD-derived iPSCs retained the JAK2-V617F mutation , they had a normal karyotype, embry-onic stem cell–like phenotype, and pluripotent differentiation potential. When control and diseased iPSCs were differentiated back into CD34 ϩ CD45 ϩ hematopoietic progenitors, the progenitors derived from MPD-iPSCs reca-pitulated the features of somatic CD34 ϩ cells from which the iPSCs were originally derived. Similar to somatic MPD CD34 ϩ cells, iPSC-derived CD34 ϩ CD45 ϩ cells demonstrated enhanced erythropoiesis and up-regulation of genes known to be increased in PV. This study clearly demonstrates how iPSC technology could be used to model acquired blood diseases. This technology would be of particular value for the study of blood disorders such as myelodysplastic syndromes, par-oxysmal nocturnal hemoglobinuria, and others for which animal models are not available or difficult to create. In addition, iPSCs carrying leukemia-specific cytogenetic translocation could be used to analyze how cancer stem cells develop. Importantly, the iPSC-based approach would be helpful in addressing the role of genetic background in manifestation of neo-plastic blood disorders. Because iPSCs are capable of indefinite self-renewal, diseased blood cells can be generated continuously in the laboratory, eliminating the need for a constant supply of hematopoietic progenitors from the patients. In particular, a continuous supply of genetically diverse diseased blood cells for drug screening and discovery could be created. Because multiple types of cells can be generated from iPSCs, interaction of diseased blood cells with endothelial or stromal cells could be modeled in vitro. However, several important issues related to iPSC models of blood diseases remain to be addressed. It is known that the hematopoietic differentiation potential of iPSC lines generated from the same starting material varies significantly. 8 If several clones were generated from iPSCs, which clones should be selected to make an appropriate conclusion regarding differences in differentiation potential? What would be an appropriate control for diseased versus non-diseased iPSCs? For studies of acquired blood diseases, iPSC lines can be generated from hematopoietic cells and fibroblasts or bone marrow mesenchymal stem cells (see figure). In this way, iPSCs with the same genetic background , but different in terms of presence or absence of acquired mutations, will be available for comparative analysis. The majority of disease-specific iPSCs have been made using retroviral vectors. Although the impact of ex-ogenous expression is unclear, the possibility remains that retroviral integration and background …
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