Activation of the vitamin D receptor transcription factor stimulates the growth of definitive erythroid progenitors.

The pathways that regulate the growth of erythroid progenitors are incompletely understood. In a computational analysis of gene expression changes during erythroid ontogeny, the () nuclear hormone receptor transcription factor gene was identified in fetal and adult stages, but not at the embryonic stage of development. was expressed in definitive erythroid (EryD) progenitors and was downregulated during their maturation. Activation of Vdr signaling by the vitamin D3 agonist calcitriol increased the outgrowth of EryD colonies from fetal liver and adult bone marrow, maintained progenitor potential, and delayed erythroid maturation, as revealed by clonogenic assays, suspension culture, cell surface phenotype, and gene expression analyses. The early (cKitCD71), but not the late (cKitCD71), EryD progenitor subset of LincKit cells was responsive to calcitriol. Culture of cKitCD71 progenitors in the presence of both vitamin D3 and glucocorticoid receptor ligands resulted in an increase in proliferation that was at least additive compared with either ligand alone. Lentivirus shRNA-mediated knockdown of expression abrogated the stimulation of early erythroid progenitor growth by calcitriol. These findings suggest that has a cell-intrinsic function in early erythroid progenitors. Targeting of downstream components of the Vdr signaling pathway may lead to new approaches for the expansion of erythroid progenitors ex vivo.