Transcriptional Regulation During the Development of Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) are routinely used in the treatment of hematopoietic malignancies, aplastic anemia, hemoglobinopathies, immunodeficiencies, and inherited metabolic disorders. However their use in the clinic is limited by donor availability.
Thus much effort has been invested in attempting to make patient-specific HSCs from embryonic stem (ES) cells, induced pluripotent stem cells (iPS), or by direct reprogramming from another adult cell type. While significant progress has been made in producing committed hematopoietic progenitors from ESCs or iPSCs, the production of transplantable HSCs has not yet been possible. A factor hindering progress is that we only partially understand how HSCs form in the embryo.

Hematopoietic stem cells (HSCs) differentiate from specialized endothelial cells in the embryo called hemogenic endothelium. The latter then differentiate into preHSCs in major vasculature before they mature into fully functional HSCs. As with all developmental process, the ontogeny of HSCs is driven by a series of gene expression programs over time. Little is known about these gene regulatory programs since HSCs and their precursors are extremely rare and traditionally not amenable to genome-wide studies.

Researchers at the Center for Childhood Cancer Research, led by Kai Tan, PhD, are
developing cutting-edge genomic and computational tools to profile and model the gene regulatory circuitry during HSC development. Studies to date have revealed a repertoire of highly dynamic transcriptional regulatory sequences as well as transcriptional regulators that are previously uncharacterized in adult HSCs.

Additional studies are underway to experimentally test novel regulatory DNA sequences and transcriptional regulators. Ultimately, this may lead to novel molecular markers and pathways that will provide useful reagents/benchmarks and protocols for investigators attempting to generate HSCs ex vivo.

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