Hematopoietic stem cells (HSCs) have the unique ability to self-renewal as well as give rise to all of the mature blood cells in an adult. Currentl, the genetic signaling pathways and the environmental cues that are required to generate HSCs are not completely understood. HSCs are first born from endothelial cells found in the floor of the primitive descending aorta, known as the dorsal aorta in zebrafish. A better understanding of the cellular specification niche that regulates the birth of these cells, might inform attempts to instruct their specification in vitro. Recently, Wnt16, a non-canonical Wnt, was demonstrated to be required for HSC development in zebrafish. Wnt16 signals through a series of relay signals, and the final signal or signals in this process (i.e. the ones that act directly on HSC precursors o turn on the hematopoietic program) remain unknown, but are not among the recognized set of HSC specification signals. In Wnt16 loss of function animals, there is also an earlier defect in the somite (segmented blocks of cells that give rise to multiple adult tissues, including trunk muscle, ribs, and vertebral column). A compartment of the somite-the sclerotome, which may house vascular muscle cells-is incorrectly formed. These results suggest that sclerotome-derived cells might contribute to the regulatory environment, or niche, that directs HSC specification, explaining the failure of HSC specification when this compartment develops incorrectly. In the proposed research the molecular details of how Wnt16 regulates both sclerotome and HSC specification will be dissected, and the formation of the niche-as well as the genetic control of this process-will be directly imaged in novel transgenic animals. These studies will help to determine both the molecular signals that instruct HSC specification, as well as the architectural construction and cellular composition of the physical niche space, both of which are of significant translational interest.

Public Health Relevance

Hematopoietic stem cells (HSCs) are the therapeutic component of bone marrow transplants, which are used in the treatment of leukemia and other blood disorders, but identification of immune-compatible donors remains a problem. One means of overcoming this limitation would be to transform a patient's own non-blood, unaffected tissues to HSCs, a prospect which has been recently made more plausible by the introduction of technologies to restore the capability to become all kinds of cells to differentiated tissues such as skin (iPS technology); however a significant impediment to this enterprise is an imperfect understanding of the normal embryonic processes that lead to HSCs. Here, I propose studies to better understand the construction of the normal cellular environment where HSCs are born, as a means to guide future attempts to generate and expand these cells in vitro.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Welniak, Lisbeth A
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St. Jude Children's Research Hospital
United States
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