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Loss of P2Y14 Results in an Arresting Response to Hematological Stress

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Loss of P2Y14 Results in an Arresting Response to Hematological Stress Loss of P2Y14 results in an arresting response to hematological stress Brian S. Garrison, Derrick J. Rossi J Clin Invest. 2014;124(7):2846-2848. https://doi.org/10.1172/JCI76626. Commentary 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 JCI, Cho and Yusuf et al. demonstrate that the purinergic receptor P2Y14 may mediate the hematopoietic stem and progenitor cell regenerative response. Find the latest version: https://jci.me/76626/pdf commentaries rial infections? In view of the critical pro- microbial properties of cells in the urinary links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent tective role played by A-ICs, do their sister tract, such as A-ICs, may become viable mechanism. J Clin Invest. 2005;115(2):468–475. cells, B-ICs, play a complementary role in therapeutic alternatives. 7. Paragas N, et al. α–Intercalated cells defend the uri- combating infection? Despite any linger- nary system from bacterial infection. J Clin Invest. ing questions, the results of this study are Acknowledgments 2014;124(7):2963–2976. 8. Goetz DH, Holmes MA, Borregaard N, Bluhm ME, important and reveal how a specialized kid- The authors were funded by NIH grants Raymond KN, Strong RK. The neutrophil lipocalin ney cell, previously implicated in acid-base U01-AI082107, R01-AI096305, and R56- NGAL is a bacteriostatic agent that interferes with homeostasis, combats bacterial infections DK095198 and by a block grant from siderophore-mediated iron acquisition. Mol Cell. 2002;10(5):1033–1043. of the urinary tract. Duke-NUS, Singapore. 9. Flo TH, et al. Lipocalin 2 mediates an innate Highly specialized epithelial cells are dis- immune response to bacterial infection by seques- persed on various mucous membranes and Address correspondence to: Soman N. trating iron. Nature. 2004;432(7019):917–921. 10. Jaillon S, et al. The humoral pattern recognition are involved in maintaining the integrity of Abraham, Department of Pathology, Duke molecule PTX3 is a key component of innate the mucosal barrier, mediating secretion, University Medical Center, Box 3712, Dur- immunity against urinary tract infection. Immu- selective absorption, or transcellular trans- ham, North Carolina 27514, USA. Phone: nity. 2014;40(4):621–632. port. The revelation by Paragas and col- 919.684.3630; Fax: 919.684.2021; E-mail: 11. Al-Awqati Q. Cell biology of the intercalated cell in the kidney. FEBS Lett. 2013;587(13):1911–1914. laborators that, in addition to maintaining [email protected]. 12. Wall SM. Recent advances in our understanding acid-base homeostasis, kidney A-ICs play a of intercalated cells. Curr Opin Nephrol Hypertens. key role in abrogating bacterial infection in 1. Chromek M, Brauner A. Antimicrobial mecha- 2005;14(5):480–484. nisms of the urinary tract. J Mol Med (Berl). 2008; 13. Chan CY, St John AL, Abraham SN. Mast cell inter- the urinary tract (7), has implications for 86(1):37–47. leukin-10 drives localized tolerance in chronic human renal diseases. For example, human 2. Chromek M, et al. The antimicrobial peptide cat- bladder infection. Immunity. 2013;38(2):349–359. diseases that involve A-IC dysfunction, helicidin protects the urinary tract against invasive 14. Mishra J, et al. Neutrophil gelatinase-associat- such as chronic distal renal tubular acido- bacterial infection. Nat Med. 2006;12(6):636–641. ed lipocalin (NGAL) as a biomarker for acute 3. Spencer JD, et al. Ribonuclease 7 is a potent anti- renal injury after cardiac surgery. Lancet. 2005; sis, are characterized by recurrent UTIs and microbial peptide within the human urinary tract. 365(9466):1231–1238. pyelonephritis (15). As the aged population Kidney Int. 2011;80(2):174–180. 15. DuBose TD, Alpern RJ. Renal tubular acidosis. In: has dramatically grown in recent years, 4. Schilling JD, Martin SM, Hung CS, Lorenz RG, Valle D, et al., eds. The Online Metabolic and Molecular Hultgren SJ. Toll-like receptor 4 on stromal and Bases of Inherited Disease. New York, New York, USA: recurrent UTIs have become a substantial hematopoietic cells mediates innate resistance to McGraw-Hill; 2007:Chapter 195. doi:10.1036/ clinical problem in hospitals and nursing uropathogenic Escherichia coli. Proc Natl Acad Sci ommbid.228. homes (16). Antibiotics are increasingly U S A. 2003;100(7):4203–4208. 16. Raz R, Stamm WE. A controlled trial of intra- 5. Ganz T. Defensins in the urinary tract and other vaginal estriol in postmenopausal women with ineffective for combating UTIs; therefore, tissues. J Infect Dis. 2001;183(suppl 1):S41–S42. recurrent urinary tract infections. N Engl J Med. harnessing and boosting the innate anti- 6. Saemann MD, et al. Tamm-Horsfall glycoprotein 1993;329(11):753–756. Loss of P2Y14 results in an arresting response to hematological stress Brian S. Garrison1,2,3 and Derrick J. Rossi1,2,3,4 1Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. 2Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. 3Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts, USA. 4Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. The regenerative capacity of tissues to recover from injury or stress is depen- gation, cellular senescence is now under- dent on stem cell competence, yet the underlying mechanisms that govern stood to be a complex mechanism that may how stem cells detect stress and initiate appropriate responses are poorly limit cell growth as well as prevent cancer understood. In this issue of the JCI, Cho and Yusuf et al. demonstrate that in vivo and that can be initiated in response the purinergic receptor P2Y14 may mediate the hematopoietic stem and pro- to a variety of cellular stresses, including genitor cell regenerative response. oxidative damage, telomere shortening, DNA damage, and gene deregulation (2–4). Senescence and stem cell decline ard Hayflick and Paul Moorhead, who As with the majority of tissues, the Cellular senescence, a state of permanent observed that normal human fibroblasts hematopoietic system exhibits signs of irreversible growth arrest, was initially cease to replicate after 50 to 60 cellular age-related decline, including immune described over half a century ago by Leon- divisions (1). This barrier to everlasting dysfunction, decreased red blood cell pro- cellular proliferation later became termed duction, increased incidence of malignan- the “Hayflick limit,” denoting the loss of cies, and impaired recovery from injury, Conflict of interest: Derrick Rossi has an ownership proliferative potential even though the cell much of which appears to arise through stake and provides consultation for Moderna Thera- peutics. remains viable and metabolically active. cell autonomous changes in the HSC com- Citation for this article: J Clin Invest. 2014; While this phenomenon was originally partment (5–8). These age-related changes 124(7):2846–2848. doi:10.1172/JCI76626. connected to long-term in vitro cell propa- in the HSC compartment appear to be 2846 The Journal of Clinical Investigation http://www.jci.org Volume 124 Number 7 July 2014 commentaries Figure 1 HSPCs lacking P2Y14 have reduced functionality. Competitive transplantation of WT and P2Y14-deficient HSPCs into an irradiated animal results in equal repopulation of the hematopoietic environment. Following blood reconstitution, P2y14–/– HSPCs exhibit a competitive disadvantage if mice are exposed to additional hematological stress, such as irradiation or serial transplantation. Furthermore, in response to stress, P2Y14- deficient HSPCs show several markers of senescence, including increased ROS, p38 MAPK, p16INK4A, and SA–β-gal. driven by diverse processes, including DNA Under situations of stress, such as irra- mediator of the ROS-response pathway, damage accumulation (9, 10), loss of cell diation or chemotherapy, a portion of the indicating that dysfunctional ROS man- polarity (11), epigenetic changes of DNA HSPC pool may be lost, leading to myelo- agement may be a significant underlying methylation and histone modifications suppression (decreased red cell, white cell, contributor (17). (12, 13), and clonal dominance of lineage- and platelet numbers), and in such cases, HSC function has previously been shown biased HSCs (7). While age-related decline the surviving HSPCs must increase self to diminish as a consequence of ROS dys- in many tissues is thought to coincide renewal and differentiation to repopulate regulation, leading to premature exhaus- with increased cellular senescence of their required cell populations. How HSPCs tion and shortened lifespan. For example, respective stem and progenitor cell popu- integrate stress signals to invoke the appro- mice deficient in ataxia telangiectasia lations (14), in the HSC compartment, it priate stress responses remains unclear. mutated (ATM) experience hematopoietic is unclear whether senescence promotes Cho, Yusuf, and colleagues have revealed failure, which is largely abrogated by NAC physiological aging, though classical senes- that P2Y14 regulates the HSPC response treatment (18). Similarly, deletion of genes cence markers, such as p16INK4A, do not to stress. Specifically, the authors demon- encoding forkhead box transcription fac- appear to be robustly upregulated in aged
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