Role of Gpr56 in mammalian haematopoiesis
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Date
31/07/2021Author
Maglitto, Antonio
Metadata
Abstract
Haematopoietic stem cells (HSCs) can differentiate into all blood cell types, making
HSC transplantation a promising treatment for many blood-related disorders.
Allogenic heathy HSCs can be transplanted into patients, although this approach is
limited by availability and compatibility of the donor. Moreover, there are no protocols
available to generate transplantable HSCs from pluripotent stem cells (PSC), or expand
HSCs ex vivo, as the molecules involved in HSC ontogeny remain poorly understood.
Embryonically, HSCs derive from a subset of aortic endothelial cells that undergo
endothelial-to-hematopoietic transition to become HSCs. During this dynamic
process, Gpr56 is the most upregulated receptor in emerging HSCs. The Gpr56 protein
is a cell-surface receptor that is likely involved in the regulation of HSC function.
However, its role in mammalian haematopoiesis remains unknown.
In this study, we examine the function of Gpr56 during in vivo and in vitro HSC
development. To explore the effect of Gpr56 loss-of-function, we characterize the
functional role of mouse embryonic stem cell (ESC) derived hematopoietic stem and
progenitor cells (HSPCs) and in vivo mouse HSCs that lack Gpr56. Gpr56-deficient
HSPCs have a differentiation bias towards myeloid cells and the upregulation of
another GPCR, Gpr97 appeared to compensate for Gpr56 deletion. The simultaneous
deletion of Gpr56 and Gpr97 severely impaired the production of HSPCs, suggesting
that both GPCRs are required in vitro for HSPC generation. Conversely, Gpr56
overexpression during human in vitro PSC differentiation resulted in an important
HSPC expansion. In summary, these data demonstrate that the lack of Gpr56 alters the
HSPC differentiation output, while its overexpression enhances human in vitro HSPCs
generation. This work represents the most comprehensive and current study of Gpr56
in mammalian haematopoiesis and these findings will improve novel strategies to
generate de novo HSC and/or promote their ex vivo expansion.