Purinergic P2Y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescence

Abstract

Purinergic receptors of the P2Y family are G protein-coupled surface receptors that respond to extracellular nucleotides and can mediate responses to local cell damage. P2Y-dependent signaling contributes to thrombotic and/or inflammatory consequences of tissue injury by altering platelet and endothelial activation and immune cell phagocytosis. Here, we have demonstrated that P2Y 14 modifies cell senescence and cell death in response to tissue stress, thereby enabling preservation of hematopoietic stem/progenitor cell function. In mice, P2Y 14 deficiency had no demonstrable effect under homeostatic conditions; however, radiation stress, aging, sequential exposure to chemotherapy, and serial bone marrow transplantation increased senescence in animals lacking P2Y 14 . Enhanced senescence coincided with increased ROS, elevated p16 INK4a expression, and hypophosphorylated Rb and was inhibited by treatment with a ROS scavenger or inhibition of p38/MAPK and JNK. Treatment of WT cells with pertussis toxin recapitulated the P2Y 14 phenotype, suggesting that P2Y 14 mediates antisenescence effects through Gi/o protein-dependent pathways. Primitive hematopoietic cells lacking P2Y 14 were compromised in their ability to restore hematopoiesis in irradiated mice. Together, these data indicate that P2Y 14 on stem/progenitor cells of the hematopoietic system inhibits cell senescence by monitoring and responding to the extracellular manifestations of tissue stress and suggest that P2Y 14 -mediated responses prevent the premature decline of regenerative capacity after injury.

Metabolic perturbation of epigenome by inhibiting S-adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells

“…2 Accumulating evidence indicates that senescence-inducing agents provide equivalent or prolonged survival with less adverse effects compared with other cytotoxic agents. 3 However, one factor limiting this strategy of cancer therapy is the lack of efficient senescence-inducing agents in clinical practice.…”

P2Y 2 Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling

“…Cumulative data over the past decade demonstrate involvement of P2Y 14 R in inducing proliferation and migration of human keratinocytes 53 , chemotaxis of hHSCs 54 and human neutrophils 55 . In addition, P2Y 14 R enhances mouse HSC (mHSC) resistance to stress-induced senescence and maintains regenerative capacity after injury 56 . Future studies will aim to assess whether P2Y 1 R and P2Y 14 R mediate pro-regenerative roles in hCPCs.…”

Reliability of ROS and RNS detection in hematopoietic stem cells − potential issues with probes and target cell population

“…In stem cell redox studies, mitochondrial O 2 • − has been measured by mitochondrial-targeted HE (Mito-HE or MitoSOX) (Cho et al, 2014;Hole et al, 2010;Taniguchi Ishikawa et al, 2012;. MitoSOX reacts with O 2 • − in a similar manner as HE and, therefore, has the same limitations (Winterbourn, 2014).…”