P2Y-like receptor, GPR105 (P2Y₁₄), identifies and mediates chemotaxis of bone-marrowhematopoietic stem cells

Abstract

Hematopoiesis in mammals undergoes a developmental shift in location from fetal liver to bone marrow accompanied by a gradual transition from highly proliferative to deeply quiescent stem cell populations. P2Y receptors are G-protein-coupled nucleotide receptors participating in vascular and immune responses to injury. We identified a P2Y-like receptor for UDP-conjugated sugars, GPR105 (P2Y 14 ), with restricted expression on primitive cells in the hematopoietic lineage. Anti-GPR105 antibody selectively isolated a subset of hematopoietic cells within the fetal bone marrow, but not in the fetal liver, that was enriched for G0 cell cycle status and for in vitro stem-cell-like multipotential long-term culture capability. Conditioned media from bone marrow stroma induced receptor activation and chemotaxis that was sensitive to G␣i and anti-receptor antibody inhibition. GPR105 is a G-protein-coupled receptor identifying a quiescent, primitive population of hematopoietic cells restricted to bone marrow. It mediates primitive cell responses to specific hematopoietic microenvironments and extends the known immune system functions of P2Y receptors to the stem cell level. These data suggest a new class of receptors participating in the regulation of the stem cell compartment. G-protein-coupled receptors (GPRs) have a broad repertoire of activating ligands ranging from photons to chemokines and induce an array of cellular events in virtually every physiologic system. Yet there remains a large proportion of GPR without known ligands or with limited known functions. A group of GPRs responsive to nucleotides (termed P2Y receptors) has been defined mediating cell-cell communication in the nervous system and in modulating vascular tone . A well-defined effect of nucleotides on platelet activation and vascular smooth muscle migration and growth has suggested participation of P2Y receptors in the response to injury. More recently, these receptors have been noted to affect cellular constituents of the innate immune system altering functional characteristics of monocytes, eosinophils, and dendritic cells and to play a critical role in terminating the inflammatory response in vivo (Mutini et al. 1999;Ferrari et al. 2000;Idzko et al. 2001;Santiago-Perez et al. 2001;Warny et al. 2001;Wilkin et al. 2001). The P2Y receptor specificity originally thought to be restricted to purine (adenine) nucleotides has been extended to pyrimidine nucleotides (uridine) and more recently to a receptor with specificity for UDP, but only when conjugated to glucose or related sugars (Chambers et al. 2000). This receptor, GPR105 (recently designated P2Y 14 ; Abbracchio et al. 2003), was originally noted to be expressed in rat brain tegmentum, but has no known function apart from being the presumed basis for UDP-glucose to induce diaphragmatic contraction or neural action potentials (Pastoris et al. 1979(Pastoris et al. , 1981. We provide evidence that this receptor participates in regulation of hematopoietic cells with stem cell characteristics.

UDP-glucose promotes neutrophil recruitment in the lung

“…5). Collectively, these results strongly suggest that UDP-glucose released into CF-like diseased airways acts as a pro-inflammatory mediator, via stimulation of the P2Y 14 R. P2Y 14 R mRNA is expressed in human [45] and murine [46] lungs [17,46] and inflammatory cells [17][18][19][20][21], but the identity of the cell type(s) potentially sensing UDP-glucose in airway surface liquids is not known. We observed no P2Y 14 R mRNA amplification in well-differentiated primary cultures of bronchial epithelial cells (data not shown).…”

“…UDP also is an agonist of this receptor, but ATP, UTP, or other naturally occurring nucleoside 5′-di-or triphosphates have no P2Y 14 R activity [13][14][15][16]. P2Y 14 R mRNA expression has been reported in the brain and several peripheral tissues [13], including the lung, circulating neutrophils, and other immune/inflammatory cells [17][18][19][20][21].…”

Endoplasmic Reticulum/Golgi Nucleotide Sugar Transporters Contribute to the Cellular Release of UDP-sugar Signaling Molecules

“…P2Y 14 receptor transcripts are expressed in several human tissues, including placenta, stomach, intestine, adipose, brain, lung, spleen, heart, and circulating leukocytes (3,(5)(6)(7). UDPsugar-promoted signaling has been reported in astrocytes and microglial cells (8,9), lung epithelial cells (10), bone marrow hematopoietic stem cells (11), and multiple types of peripheral immune cells, including neutrophils, lymphocytes, and dendritic cells (6,7,12,13). These observations suggest that UDPsugars, high energy donor substrates in biosynthetic reactions, potentially are released from cells in a regulated fashion to perform autocrine/paracrine signaling.…”

“…P2Y receptors belong to the superfamily of G protein-coupled receptors. At least eight human P2Y receptor species have been identified, seven of which (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , and P2Y 13 ) are activated by adenine and/or uridine nucleoside di-and triphosphates (2). The P2Y 14 receptor was identified as the eighth member of the P2Y family (3,4).…”

Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

“…Such paracrine factors include ATP and adenosine and their respective receptor subtypes. P2Y14 receptors expressed by bone marrow HSCs induce migration of these cells to the localization of injury followed by induction of differentiation at the site mediated by activation of other purinergic receptors [49] (Fig. 2).…”