GABA gets blood on its hands

In this issue of Blood, Shao et al present evidence that hematopoietic cells coopt the tools of the nervous system to communicate with each and both maintain homeostasis and respond to challenge.¹  More specifically, the authors show that the γ-aminobutyric acid (GABA) receptor, GABBR1, is a key functional regulator of murine and human hematopoietic progenitors. GABA is the main inhibitory neurotransmitter in the central nervous system.²  Although best characterized in this context, GABA receptors are also expressed outside the nervous system in the pancreas, spleen, lung, and even hematopoietic progenitors.^3-5  It has been more than a decade since Steidl et al described the expression of neurotransmitter receptors on human hematopoietic stem cells (HSCs).⁵  However, a functional role for these molecules and their corresponding receptors in the context of hematopoiesis has been heretofore absent.

The authors report that Gabbr1^−/− mice have fewer bone marrow hematopoietic progenitors, especially lymphoid progenitors, relative to Gabbr1^+/+ controls. A deeper look at this lineage further revealed a dramatic disruption of most B-cell progenitor compartments, as well as mature B cells, in Gabbr1^−/− mice. Consistently, transcriptional profiling of Gabbr1^−/− hematopoietic progenitors revealed an upregulation of pathways associated with B-cell differentiation, while Gabbr1^+/+ cells displayed immature signatures, suggesting an accelerated differentiation phenotype that goes hand in hand with a loss of progenitors in the absence of GABRR1.

In addition, although HSCs (Lin⁻Sca1⁺cKit⁺CD48⁻CD150⁺ cells) were grossly unperturbed at steady state, they observed impaired proliferation rates in Gabbr1-deficient hematopoietic progenitors. Surprisingly, Gabbr1^−/− HSCs displayed compromised in vivo repopulating potential when subjected to competitive transplantation. In agreement with their observations during homeostasis, this repopulating effect was almost entirely restricted to the B-cell lineage and exacerbated by serial transplantation. Consistently, Shao et al went on to establish that common lymphoid progenitors (CLPs) express the highest levels of Gabbr1 in the hematopoietic hierarchy, followed by HSCs.

Having established a functional role for this neurotransmitter receptor in the homeostasis of select hematopoietic progenitors, the authors next asked if GABA could be detected in the bone marrow and sought to identify its cellular source. Here, they employed imaging mass spectrometry and demonstrated that GABA molecules are present in the bone marrow, with relatively high intensity in the femur endosteum. Because neurons and stroma cells had already been ruled out as a source of GABA in the bone marrow,^6,7  the authors interrogated different bone marrow cell populations for expression of the glutamate decarboxylase enzymes, GAD1 and GAD2, which convert glutamic acid to GABA.⁸  Surprisingly, they found GAD1 to be highly enriched in B cells. Indeed, GABA was absent from the endosteum of Rag1^−/− mice, confirming a mature lymphoid cell as the likely bone marrow source of GABA. Thus, Shao et al have uncovered a novel feedback loop that regulates B-cell output via direct communication between mature B cells and their progenitors (see figure). Indeed, loss of the GABA receptor in Gabbr1^−/− mice short-circuits this loop, exacerbating the homeostatic phenotype during times of stress (ie, the more severe phenotypes observed in secondary recipients of Gabbr1^−/− HSCs).

Finally, and importantly, Shao et al present evidence that GABA regulation of hematopoietic progenitors may have translational potential: treatment of human umbilical cord blood CD34⁺ cells with Baclofen, a clinically approved GABA agonist,⁹  improved engraftment in xenotransplant models.

In summary, Shao et al have illuminated a functional role for a neurotransmitter, GABA, and its receptor, GABBR1, in B-cell lineage differentiation and HSCs. Although it is known that there are many ways in which the nervous system interacts with HSCs during development and into adulthood,¹⁰  the authors present the provocative model that mature B cells themselves secrete GABA, which acts on bone marrow lymphoid progenitors, creating a signaling feedback loop. It will be interesting to determine if GABA or additional molecules active in the communication between cells of the nervous system function in other lineages to establish similar feedback loops. Indeed, Zhu et al recently reported that the GABA/GABBR1 axis participates in megakaryocyte regulation.⁶  Although Shao et al and Zhu et al report slightly different findings (eg, Zhu et al observed perturbed myeloid repopulation after transplant of Gabbr1^−/− HSPC, while Shao et al mainly observed disrupted lymphoid reconstitution⁶ ), together these 2 studies firmly establish a role for GABA in hematopoiesis and GABBR1 as an attractive new molecular target for pharmacologic or biologic intervention to enhance human HSC engraftment.