Induced Pluripotent Stem Cells Expressing Elevated Levels of Sox-2, Oct-4, and Klf-4 Are Severely Reduced in Their Differentiation from Mesodermal to Hematopoietic Progenitor Cells

Induced pluripotent stem (iPS) cells have been generated from bone marrow (BM) hematopoietic progenitor cells by ectopic expression of Sox-2, Oct-4, and Klf-4 with the hope that they may differentiate more efficiently than embryonic stem (ES) cells in vitro into hematopoietic cell lineages because of their epigenetic memory. An in vitro culture system has been standardized to allow a quantitative assessment of the capacities of different ES, BM-derived iPS, and fibroblast-derived iPS cell lines developing to erythroid, myeloid, and lymphoid cell lineages. Surprisingly, the efficiency to differentiate BM-derived iPS cells to hematopoietic cells in vitro is severely reduced compared with ES cells and fibroblast-derived iPS cells. Undifferentiated as well as differentiated stages of the BM-derived iPS lines express elevated mRNA levels of the transcription factors Sox-2, Oct-4, and Klf-4 with which the iPS cells have been transduced. Overexpression of the transcription factors inhibits development of Flk-1(+) mesodermal to CD45(+) hematopoietic progenitors. The overexpression of Sox-2 appears to be inversely related to hematogenic potency. These results suggest that iPS cell generation with the aim of developing hematopoietic cells should be controlled and selected for low levels of transduced Sox-2, Oct-4, and Kfl-4 expression.