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The GABA receptor GABRR1 is expressed on and functional in hematopoietic stem cells and megakaryocyte progenitors

Fangfang Zhu,Mingye Feng,Rahul Sinha,M. Murphy,F. Luo,Kevin S. Kao,K. Szade,J. Seita,I. Weissman

Published 2019 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance GABA not only plays critical roles in the central nervous system but also is involved in various peripheral tissues, such as intestine, stomach, etc. Here, we tried to identity the function of GABA signaling in hematopoietic progenitors. We found GABRR1 is the only GABA receptor expressed in subsets of both human and mouse hematopoietic stem cells and megakaryocyte progenitors. Further studies showed inhibition of GABRR1 with a knockout mouse model, CRISPR-mediated deletion, or GABA antagonist treatment inhibited megakaryocyte and platelet differentiation, while activation of GABRR1 through lentivirus-mediated overexpression or GABA agonist treatment promoted platelet generation. Thus, our work identifies a link between this neural receptor and the hematopoietic system and potentially uncovers a strategy to efficiently generate megakaryocytes and platelets. GABRR1 is a rho subunit receptor of GABA, the major inhibitory neurotransmitter in the mammalian brain. While most investigations of its function focused on the nervous system, its regulatory role in hematopoiesis has not been reported. In this study, we found GABRR1 is mainly expressed on subsets of human and mouse hematopoietic stem cells (HSCs) and megakaryocyte progenitors (MkPs). GABRR1-negative (GR−) HSCs led to higher donor-derived hematopoietic chimerism than GABRR1-positive (GR+) HSCs. GR+ but not GR− HSCs and MkPs respond to GABA in patch clamp studies. Inhibition of GABRR1 via genetic knockout or antagonists inhibited MkP differentiation and reduced platelet numbers in blood. Overexpression of GABRR1 or treatment with agonists significantly promoted MkP generation and megakaryocyte colonies. Thus, this study identifies a link between the neural and hematopoietic systems and opens up the possibility of manipulating GABA signaling for platelet-required clinical applications.

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