Abstract
Hematopoietic stem cells (HSCs) generate all hematopoietic lineages over the life of an animal and are the basic units of bone marrow transplants used in treatment of hematologic diseases. However, the availability of this therapy is limited by supply of immunologically compatible donor cells. Thus, the ability to generate autologous HSCs from induced pluripotent stem cells (iPSCs) in vitro for use in regenerative therapies is a major biomedical objective. A number of challenges to generating transplantable HSCs capable of high level engraftment and multi-lineage potential have yet to be overcome. In vertebrates, HSCs are specified from hemogenic endothelium (HE) in the floor of the embryonic dorsal aorta (DA). Hematopoietic inductive signals originate from nearby cells, but the identity of the full set of signals remains unknown. Difficulties in generating HSCs in vitro likely stem from a lack of knowledge of key in vivo HSC specification signals and their cognate receptors. Reproducing the full set of in vivo HSC specification signals might help to overcome some of the barriers to in vitro directed differentiation, but requires identifying the full set of inductive signals. We have identified a novel role for the orphan G-protein coupled receptor, Gpr182 in the control of HSC specification. We show that gpr182 is expressed in the axial vasculature and that HSC specification is disrupted when Gpr182 is knocked down. Importantly specification of the DA and HE cells, which is a prerequisite for HSC specification, is unaffected. Our results suggest that Gpr182 is mediating an HSC specification signal that is required proximally for initiation of the hematopoietic program. We have recently demonstrated that migrating trunk neural crest cells (NCCs) mediate HSC specification through an unknown signal(s). Similar to Gpr182, NCC derived signaling is not required for DA or the HE specification. This phenocopy raises the possibility that Gpr182 could be mediating a NCC derived signal. Interrogating the role of Gpr182 in HSC specification will lead to novel insights into the extracellular signals and downstream regulation of HSC specification in the vertebrate embryo.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
