Hematopoietic stem cells (HSCs) are rare cells within human bone marrow that are responsible for the curative effects of hematopoietic cell transplantation (HCT). A major goal of regenerative medicine is to instruct formation of HSCs in vitro from pluripotent precursors. Despite decades of efforts, this goal has not been achieved. An improved understanding of the native mechanisms of HSC specification in the vertebrate embryo is thus required to inform these approaches. Recent studies have conclusively demonstrated that HSCs arise from hemogenic endothelium, a special population of endothelial cells within the ventral wall of the dorsal aorta that transdifferentiate into HSCs. In this application, we will utilize the unique advantages of the zebrafish embryo to provide a better understanding of how HSCs are specified genetically. Our preliminary findings demonstrate that signaling via fibroblast growth factors (FGFs) regulates HSC development at multiple stages. FGF signaling appears to be required initially to instruct HSCs from posterior lateral mesoderm (PLM), and to subsequently regulate their emergence from ventral aortic endothelium. Dissection of the mechanisms involved will lead to improved insight into the molecular cues that specify hemogenic endothelium, the birthplace of HSCs across vertebrate phyla. Our findings will ultimately provide the means to replicate human HSC development in vitro from pluripotent precursors in a precise, robust, and reproducible manner, requirements for eventual clinical utility.

Public Health Relevance

Hematopoietic stem cells (HSCs) are rare cells within human bone marrow that are responsible both for the life-long replenishment of all blood cell lineages and for the curative effects of bone marrow transplantation. The creation of human induced pluripotent cells holds great promise for cellular regeneration therapies, but we cannot currently instruct these cells to specifically generate HSCs in vitro. The overall goal of this application i to determine the molecular cues that instruct the HSC fate in the vertebrate embryo such that these events may ultimately be replicated in vitro for clinical utility.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Thomas, John
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University of California San Diego
Other Basic Sciences
Schools of Medicine
La Jolla
United States
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Lee, Yoonsung; Manegold, Jennifer E; Kim, Albert D et al. (2014) FGF signalling specifies haematopoietic stem cells through its regulation of somitic Notch signalling. Nat Commun 5:5583
Pouget, Claire; Peterkin, Tessa; Simões, Filipa Costa et al. (2014) FGF signalling restricts haematopoietic stem cell specification via modulation of the BMP pathway. Nat Commun 5:5588