The neurotransmitter receptor Gabbr1 regulates proliferation and function of hematopoietic stem and progenitor cells
| Autor: | Hal E. Broxmeyer, Brian J. Cox, Anthony L. Sinn, Adedamola Elujoba-Bridenstine, Laura M. Sanchez, Lijian Shao, Scott Cooper, Emily Sims, Karen E. Pollok, Barbara J. Bailey, Kostandin V. Pajcini, Katherine E. Zink, Owen J. Tamplin |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Baclofen Stromal cell Immunology Mice SCID Biology Biochemistry Mice 03 medical and health sciences 0302 clinical medicine Bone Marrow Mice Inbred NOD Neurotransmitter receptor Lymphopenia Human Umbilical Vein Endothelial Cells medicine Animals Humans Cell Lineage Stem Cell Niche Progenitor cell Receptor Bone Marrow Transplantation Mice Knockout B-Lymphocytes Cell Biology Hematology Hematopoietic Stem Cells Cell biology Mice Inbred C57BL Transplantation Haematopoiesis 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Receptors GABA-B Radiation Chimera Female Bone marrow Stem cell Cell Division 030217 neurology & neurosurgery |
| Zdroj: | Blood. 137:775-787 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Hematopoietic and nervous systems are linked via innervation of bone marrow (BM) niche cells. Hematopoietic stem/progenitor cells (HSPCs) express neurotransmitter receptors, such as the γ-aminobutyric acid (GABA) type B receptor subunit 1 (GABBR1), suggesting that HSPCs could be directly regulated by neurotransmitters like GABA that directly bind to GABBR1. We performed imaging mass spectrometry and found that the endogenous GABA molecule is regionally localized and concentrated near the endosteum of the BM niche. To better understand the role of GABBR1 in regulating HSPCs, we generated a constitutive Gabbr1-knockout mouse model. Analysis revealed that HSPC numbers were significantly reduced in the BM compared with wild-type littermates. Moreover, Gabbr1-null hematopoietic stem cells had diminished capacity to reconstitute irradiated recipients in a competitive transplantation model. Gabbr1-null HSPCs were less proliferative under steady-state conditions and upon stress. Colony-forming unit assays demonstrated that almost all Gabbr1-null HSPCs were in a slow or noncycling state. In vitro differentiation of Gabbr1-null HSPCs in cocultures produced fewer overall cell numbers with significant defects in differentiation and expansion of the B-cell lineage. To determine whether a GABBR1 agonist could stimulate human umbilical cord blood (UCB) HSPCs, we performed brief ex vivo treatment prior to transplant into immunodeficient mice, with significant increases in long-term engraftment of HSPCs compared with GABBR1 antagonist or vehicle treatments. Our results indicate a direct role for GABBR1 in HSPC proliferation, and identify a potential target to improve HSPC engraftment in clinical transplantation. |
| Databáze: | OpenAIRE |
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