Mechanistic insights into gene regulation driving normal and malignant hematopoietic development from embryonic and induced pluripotent stem cell differentiation.

The hematopoietic system originates from mesodermal cells of the vertebrate embryo, giving rise to pluripotent hematopoietic stem cells (HSCs) from which all mature blood cell types originate for the entire lifespan of the organism. Due to the multitude of diseases of the blood system, such as leukemia and bone marrow failure, it is of utmost importance to understand what regulates the initial formation of this system in the embryo and subsequent cell fate decisions occurring during the development of the different mature blood cell lineages. Research along these lines has been greatly facilitated by the development of embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC)-based methods. Such cells can be genetically altered and produce ample cell numbers, thus being the ideal model to elucidate how our genome controls cell fate decisions. In this review, I summarize work from my laboratory and that of others to highlight how ESC and iPSC-based systems have been used to obtain global information, enhancing our understanding of the genetic basis of hematopoiesis, how specific transcription factors interact with chromatin components to regulate differential gene expression, and how signaling molecules and growth factors modulate this process. I outline how such information can be used to optimize in vitro differentiation into specific cell types for regenerative medicine purposes. Last, but not least, I describe how in vitro systems can inform us about how blood cell development goes astray during disease processes.