Flow, Fatty Acid Biosynthesis, and Hematopoiesis

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(PLEASE KEEP IN WORD, DO NOT PDF) Hematopoietic stem cells (HSCs), which give rise to the full spectrum of hematological cells in the blood, hold tremendous promise as future treatments for hematological and immunological diseases. For example, HSC transplantation can reconstitute the blood system following irradiation or chemotherapy, thus restoring immune function and improving anemia in patients undergoing such treatments. Furthermore, therapies that could modulate the regulatory pathways controlling cell fate could help treat metabolic disorders caused by unrestricted proliferation of HSCs and hematopoietic progenitor cells. Unfortunately, to date scientists have limited capability to expand multipotent HSCs ex vivo from cord blood. Even with sufficient HSCs, if they are not properly engrafted, transplanted HSCs can cause serious morbidity or mortality. Finally, compatibility challenges between HSC donors and recipients create additional difficulty. These challenges impede the broader application of hematopoietic cell transplantation procedures. One attractive alternative is to generate HSCs in vitro using cell engineering. The overall objective of this application is to identify the key molecular mechanisms controlling HSC emergence during embryonic development. This knowledge can be harnessed to guide de novo generation of HSPCs in vitro. Preliminary results have led to the rationale that fatty acid biosynthesis–activated by shear stress imposed on the vascular wall–dictates hematopoietic development. These pilot studies have revealed a novel flow-regulated lipid metabolism program orchestrating hematopoiesis. Based on rigorous preliminary research and previous publications by this team and others, the central hypothesis is that endogenous fatty acid biosynthesis facilitates HSPC fate commitment from human-induced pluripotent stem cells. The central hypothesis will be investigated through two specific aims that will examine whether the natural fatty acid synthesis program controls HSPC fate specification from human-induced pluripotent stem cells. Upon completion of this work, the results will define a critical flow-regulated lipid metabolism pathway that instructs definitive hematopoiesis.