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Purinergic P2Y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescence
Joonseok Cho, … , David T. Scadden, Byeong Chel Lee
Joonseok Cho, … , David T. Scadden, Byeong Chel Lee
Published June 17, 2014
Citation Information: J Clin Invest. 2014;124(7):3159-3171. https://doi.org/10.1172/JCI61636.
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Research Article

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

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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

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Figure 1

P2Y14 deficiency increases the susceptibility of HSPCs to radiation stress.

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P2Y14 deficiency increases the susceptibility of HSPCs to radiation stre...
(A) Q-PCR analysis of P2ry14 mRNA: mRNA from BM cells bearing the indicated phenotype was analyzed by Q-PCR. The expression was normalized to GAPDH. The expression level in lineage positive (Lin+) cells was arbitrarily set to 1. Q-PCR was done in duplicate. B, B cells (B220+); T, T cells (CD3+); mono, monocytes (CD11b+). (B) Cells were gated as indicated, and the expression of P2Y14 was measured within the gates. The percentage of P2Y14-expressing (P2Y14+) cells in indicated compartments is plotted on the y axis. The data are representative of at least 3 independent experiments, each with 3 mice per group. (C) Mice of the indicated genotypes were exposed to TBI (3 × 5 Gy). Recipients were allowed to recover for 15 days before the next dose was administered. The number of BM cells was counted within the marrow of femur and tibia. (D) The number of LSK cells was measured after TBI (3 × 5 Gy TBI, 15 days apart). Data show representative mice of at least 6 animals analyzed per group. Statistical analyses were carried out using 1-tailed Student’s t test (C and D) and 2-tailed Student’s t test (B). *P < 0.05; **P < 0.01.
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