Abstract
Tachykinins are a large group of neuropeptides with both central and peripheral activity. Despite the increasing number of studies reporting a growth supportive effect of tachykinin peptides in various in vitro stem cell systems, it remains unclear whether these findings are applicable in vivo. To determine how neurokinin-1 receptor (NK-1R) deficient hematopoietic stem cells would behave in a normal in vivo environment, we tested their reconstitution efficiency using competitive bone marrow repopulation assays. We show here that bone marrow taken from NK-1R deficient mice (Tacr1−/−) showed lineage specific B and T cell engraftment deficits compared to wild-type competitor bone marrow cells, providing evidence for an involvement of NK-1R signalling in adult hematopoiesis. Tachykinin knockout mice lacking the peptides SP and/or HK-1 (Tac1 −/−, Tac4 −/− and Tac1 −/−/Tac4 −/− mice) repopulated a lethally irradiated wild-type host with similar efficiency as competing wild-type bone marrow. The difference between peptide and receptor deficient mice indicates a paracrine and/or endocrine mechanism of action rather than autocrine signalling, as tachykinin peptides are supplied by the host environment.
Highlights
Tachykinins are a group of small neuropeptides, which share the C-terminal motif FXGLM-NH2
While each ligand can interact with all receptors with varying affinity, substance P (SP) and HK-1 are the preferred, endogenous ligands for neurokinin-1 receptor (NK-1R) [1,2], neurokinin A (NKA) preferentially binds to NK-2R, and neurokinin B (NKB) to NK-3R [3]
Embryonic stem cells are pluripotent and able to differentiate into almost all cell types, whereas adult stem cells such as neuronal stem cells or hematopoietic stem cells are more restricted in their potential and are specialized to differentiate into certain cell lineages
Summary
Tachykinins are a group of small neuropeptides, which share the C-terminal motif FXGLM-NH2. Tac encodes substance P (SP) and neurokinin A (NKA) through alternative splicing, Tac produces neurokinin B (NKB), and Tac encodes hemokinin-1 (HK-1). Tachykinins mediate their actions through three G-protein coupled receptors, neurokinin-1 receptor (NK-1R, Tacr1), NK-2R (Tacr2) and NK-3R (Tacr). Embryonic stem cells are pluripotent and able to differentiate into almost all cell types, whereas adult stem cells such as neuronal stem cells or hematopoietic stem cells are more restricted in their potential and are specialized to differentiate into certain cell lineages. For example during adult hematopoiesis, hematopoietic stem cells produce lymphoid and myeloid cells to maintain a steady supply of immune cells
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