Sensing the stress
The ability of tissues to regenerate and recover from stress, such as radiation, chemotherapy, aging, and bone marrow transplantation, is dependent on the regenerative capacity of the stem cell population. Surface purinergic receptors (P2Y) mediate responses to cell stress and damage, which in extreme cases can cause extensive cell death. Joonseok Cho, Rushdia Yusuf, Sungho Kook, and colleagues of the University of Pittsburgh and Harvard University determined that P2Y14 is an important mediator of the hematopoietic stem/progenitor cell (HSPC) response to stress. Under static conditions, mice lacking P2Y14 had no observable hematopoietic defects, but exposure to a variety hematological stresses, including radiation and serial bone marrow transplantation, resulted in increased cell senescence and reduced capacity for hematopoiesis. Excessive senescence in P2Y14-deficient HSPCs associated with increased ROS production, expression of the cell senescence marker p16INK4a, and hypophosphrylation of Rb. Furthermore, P2Y14-deficent HSPCs were not as effective as WT HSPCs for restoration of hematopoiesis when transplanted into irradiated mice. Together, these results suggest that P2Y14 protects HSPCs from stress-induced senescence and preserves the regenerative capacity of these cells. In their companion Commentary, Brian Garrison and Derrick Rossi of Harvard University indicate that this study advances our understanding of the stress response in HSPCs. The accompanying image shows senescence-associated β-gal (Blue) staining in WT (right) P2Y14 heterozygous, and P2Y14-deficent embryos from mothers exposed to radiation.
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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 P2Y14 modifies cell senescence and cell death in response to tissue stress, thereby enabling preservation of hematopoietic stem/progenitor cell function. In mice, P2Y14 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 P2Y14. Enhanced senescence coincided with increased ROS, elevated p16INK4a 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 P2Y14 phenotype, suggesting that P2Y14 mediates antisenescence effects through Gi/o protein–dependent pathways. Primitive hematopoietic cells lacking P2Y14 were compromised in their ability to restore hematopoiesis in irradiated mice. Together, these data indicate that P2Y14 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 P2Y14-mediated responses prevent the premature decline of regenerative capacity after injury.
Authors
Joonseok Cho, Rushdia Yusuf, Sungho Kook, Eyal Attar, Dongjun Lee, Baehang Park, Tao Cheng, David T. Scadden, Byeong Chel Lee
Abstract
The regenerative capacity of tissues to recover from injury or stress is dependent on stem cell competence, yet the underlying mechanisms that govern how stem cells detect stress and initiate appropriate responses are poorly understood. In this issue of the
Authors
Brian S. Garrison, Derrick J. Rossi
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