Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.1008618 on February 9, 2009

Published online before print February 9, 2009
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(Journal of Leukocyte Biology. 2009;85:837-843.)
© 2009 Society for Leukocyte Biology

The role of the GPR91 ligand succinate in hematopoiesis

Yaron Hakak1, Karin Lehmann-Bruinsma, Shirley Phillips, Thuy Le, Chen Liaw, Daniel T. Connolly and Dominic P. Behan

Arena Pharmaceuticals, Inc., San Diego, California, USA

1 Correspondence: Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. E-mail: yhakak{at}arenapharm.com

ABSTRACT

Regulation of cellular metabolism by the citric acid cycle occurs in the mitochondria. However, the citric acid cycle intermediate succinate was shown recently to be a ligand for the G-protein-coupled receptor GPR91. Here, we describe a role for succinate and its receptor in the stimulation of hematopoietic progenitor cell (HPC) growth. GPR91 mRNA and protein expression were detected in human bone marrow CD34+ progenitor cells, as well as in erythroid and megakaryocyte cultures and the erythroleukemic cell line TF-1. Treatment of these cell cultures with succinate resulted in increased proliferation rates. The proliferation response of TF-1 cells was pertussis toxin (PTX)-sensitive, suggesting a role for Gi signaling. Proliferation was also blocked when TF-1 cells were transfected with small interfering RNA specific for GPR91. Succinate stimulated activation of the Erk MAPK pathway and inositol phosphate accumulation in a PTX-sensitive manner. Pretreatment of TF-1 cells with the Erk1/2 kinase (MEK) inhibitor PD98059 blocked the proliferation response. Succinate treatment additionally protected TF-1 cells from cell death induced by serum deprivation. Finally, in vivo administration of succinate was found to elevate the levels of hemoglobin, platelets, and neutrophils in a mouse model of chemotherapy-induced myelosuppression. These results suggest that succinate-GPR91 signaling is capable of promoting HPC development.

Key Words: hematopoietic progenitor cells • erythroid • megakaryocyte