Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Top
  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal
  • Top
  • Abstract
  • Senescence and stem cell decline
  • Loss of P2Y14 leads to reduced HSC potential in response to stress
  • Conclusions and future directions
  • Acknowledgments
  • Footnotes
  • References
  • Version history
  • Article usage
  • Citations to this article

Advertisement

Commentary Free access | 10.1172/JCI76626

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.

Address correspondence to: Derrick J. Rossi, 200 Longwood Ave., Warren Alpert Building, Room #149e, Boston, Massachusetts 02115, USA. Phone: 617.713.8900; Fax: 617.713.8910; E-mail: derrick.rossi@childrens.harvard.edu.

Find articles by Garrison, B. in: PubMed | Google Scholar

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.

Address correspondence to: Derrick J. Rossi, 200 Longwood Ave., Warren Alpert Building, Room #149e, Boston, Massachusetts 02115, USA. Phone: 617.713.8900; Fax: 617.713.8910; E-mail: derrick.rossi@childrens.harvard.edu.

Find articles by Rossi, D. in: PubMed | Google Scholar

Published June 17, 2014 - More info

Published in Volume 124, Issue 7 on July 1, 2014
J Clin Invest. 2014;124(7):2846–2848. https://doi.org/10.1172/JCI76626.
Copyright © 2014, American Society for Clinical Investigation
Published June 17, 2014 - Version history
View PDF

Related article:

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
Research Article

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

  • Text
  • PDF
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 JCI, Cho and Yusuf et al. demonstrate that the purinergic receptor P2Y14 may mediate the hematopoietic stem and progenitor cell regenerative response.

Senescence and stem cell decline

Cellular senescence, a state of permanent irreversible growth arrest, was initially described over half a century ago by Leonard Hayflick and Paul Moorhead, who observed that normal human fibroblasts cease to replicate after 50 to 60 cellular divisions (1). This barrier to everlasting cellular proliferation later became termed the “Hayflick limit,” denoting the loss of proliferative potential even though the cell remains viable and metabolically active. While this phenomenon was originally connected to long-term in vitro cell propagation, cellular senescence is now understood to be a complex mechanism that may limit cell growth as well as prevent cancer in vivo and that can be initiated in response to a variety of cellular stresses, including oxidative damage, telomere shortening, DNA damage, and gene deregulation (2–4).

As with the majority of tissues, the hematopoietic system exhibits signs of age-related decline, including immune dysfunction, decreased red blood cell production, increased incidence of malignancies, and impaired recovery from injury, much of which appears to arise through cell autonomous changes in the HSC compartment (5–8). These age-related changes in the HSC compartment appear to be driven by diverse processes, including DNA damage accumulation (9, 10), loss of cell polarity (11), epigenetic changes of DNA methylation and histone modifications (12, 13), and clonal dominance of lineage-biased HSCs (7). While age-related decline in many tissues is thought to coincide with increased cellular senescence of their respective stem and progenitor cell populations (14), in the HSC compartment, it is unclear whether senescence promotes physiological aging, though classical senescence markers, such as p16INK4A, do not appear to be robustly upregulated in aged HSCs (13, 15). It should be noted that there is evidence of p16INK4A-dependent modulation of HSC potential under conditions of extreme hematopoietic stress, such as serial transplantation (16).

Loss of P2Y14 leads to reduced HSC potential in response to stress

In this issue, Cho, Yusuf, and colleagues provide evidence that stress-induced senescence in hematopoietic stem progenitor cells (HSPCs) is regulated through the G-coupled cell-surface receptor P2Y14 (17). HSCs give rise to all blood effector cells for the life of an individual, and the capacity to constantly replenish the hematopoietic compartment requires a careful balance among HSC fate decisions, including self renewal, quiescence, apoptosis, and multilineage differentiation. In contrast with HSCs, differentiated effector populations frequently have a short life span, measured in days, resulting in a huge daily cell turnover that necessitates tight homeostatic control of the upstream HSPC populations, where transit amplification occurs. Under situations of stress, such as irradiation or chemotherapy, a portion of the HSPC pool may be lost, leading to myelosuppression (decreased red cell, white cell, and platelet numbers), and in such cases, the surviving HSPCs must increase self renewal and differentiation to repopulate required cell populations. How HSPCs integrate stress signals to invoke the appropriate stress responses remains unclear. Cho, Yusuf, and colleagues have revealed that P2Y14 regulates the HSPC response to stress. Specifically, the authors demonstrate that HSPCs lacking P2Y14 are not at a disadvantage for restoring hematopoietic populations when cotransplanted with equivalent WT HSPCs in lethally irradiated mice under steady state conditions; however, under various stress conditions, including serial transplantation, radiation, and chemotherapy, cells lacking P2Y14 were less competitive than WT cells. As a result of the stress-induced loss of competitiveness, there was a decline in P2Y14-deficient HSPCs and total peripheral blood chimerism (Figure 1). Interestingly, the loss of functionality in P2Y14-deficient cells occurred concurrently with increased detection of several classical senescence biomarkers, including p16INK4A, greater β-gal (SA–β-gal) activity, and increased ROS, implicating cellular senescence as a possible consequence of P2Y14 deficiency during stress. Furthermore, Cho, Yusuf, and colleagues demonstrated that the enhanced susceptibility to irradiation stress in P2Y14-deficient HSPCs could be alleviated through administration of the ROS scavenger N-acetyl-cysteine (NAC) or inhibition of p38 MAPK, an important mediator of the ROS-response pathway, indicating that dysfunctional ROS management may be a significant underlying contributor (17).

HSPCs lacking P2Y14 have reduced functionality.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.

HSC function has previously been shown to diminish as a consequence of ROS dysregulation, leading to premature exhaustion and shortened lifespan. For example, mice deficient in ataxia telangiectasia mutated (ATM) experience hematopoietic failure, which is largely abrogated by NAC treatment (18). Similarly, deletion of genes encoding forkhead box transcription factors (FoxOs) has been shown to negatively affect HSC function and numbers through increased ROS production and subsequent HSC apoptosis (19–21). Together, these results indicate that increased ROS levels diminish HSC function; therefore, it is likely that the increased ROS detected in P2Y14-deficient HSPCs is playing an integral role in the observed phenotypes through cellular oxidative damage and perhaps apoptosis, although future work will be needed to elucidate the exact connection between the P2Y14 receptor and ROS management.

Conclusions and future directions

Cho, Yusuf, and colleagues have shown that HSPCs lacking the P2Y14 receptor are compromised in their ability to withstand and recover from several types of stress. The authors make a strong biochemical case for a senescence-based mechanism explaining the diminished function of P2Y14-deficient HSPCs during stress, though the development of functional assays that uncouple senescence from other processes that diminish HSC potential, such as apoptosis, will likely be required to definitively elucidate how P2Y14 mediates the HSPC stress response (10, 22). If PY214-deficient HSCs within the animal model system developed by Cho, Yusuf, and colleagues do indeed prove to be functionally senescent, then this could be an exciting model system for studying the onset of stress-induced senescence within the HSC compartment. A better understanding of the regulators of HSC stress response has important implications for regenerative medicine.

Acknowledgments

D.J. Rossi is a New York Stem Cell Foundation Robertson Investigator.

Address correspondence to: Derrick J. Rossi, 200 Longwood Ave., Warren Alpert Building, Room #149e, Boston, Massachusetts 02115, USA. Phone: 617.713.8900; Fax: 617.713.8910; E-mail: derrick.rossi@childrens.harvard.edu.

Footnotes

Conflict of interest: Derrick Rossi has an ownership stake and provides consultation for Moderna Therapeutics.

Reference information: J Clin Invest. 2014;124(7):2846–2848. doi:10.1172/JCI76626.

See the related article at Purinergic P2Y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescence.

References
  1. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.
    View this article via: PubMed CrossRef Google Scholar
  2. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8(9):729–740.
    View this article via: PubMed CrossRef Google Scholar
  3. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010;24(22):2463–2479.
    View this article via: PubMed CrossRef Google Scholar
  4. Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev. 2014;28(2):99–114.
    View this article via: PubMed CrossRef Google Scholar
  5. Rossi DJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A. 2005;102(26):9194–9199.
    View this article via: PubMed CrossRef Google Scholar
  6. Dykstra B, Olthof S, Schreuder J, Ritsema M, de Haan G. Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J Exp Med. 2011;208(13):2691–2703.
    View this article via: PubMed CrossRef Google Scholar
  7. Beerman I, et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A. 2010;107(12):5465–5470.
    View this article via: PubMed CrossRef Google Scholar
  8. Pang WW, et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci U S A. 2011;108(50):20012–20017.
    View this article via: PubMed CrossRef Google Scholar
  9. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007;447(7145):725–729.
    View this article via: PubMed CrossRef Google Scholar
  10. Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell. 2014;:pii:S1934-5909(14)00153-2.
    View this article via: PubMed Google Scholar
  11. Florian MC, et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell. 2012;10(5):520–530.
    View this article via: PubMed CrossRef Google Scholar
  12. Beerman I, et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell. 2013;12(4):413–425.
    View this article via: PubMed CrossRef Google Scholar
  13. Sun D, et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell. 2014;14(5):673–688.
    View this article via: PubMed CrossRef Google Scholar
  14. Sperka T, Wang J, Rudolph KL. DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol. 2012;13(9):579–590.
    View this article via: PubMed CrossRef Google Scholar
  15. Attema JL, Pronk CJ, Norddahl GL, Nygren JM, Bryder D. Hematopoietic stem cell ageing is uncoupled from p16 INK4A-mediated senescence. Oncogene. 2009;28(22):2238–2243.
    View this article via: PubMed CrossRef Google Scholar
  16. Janzen V, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006;443(7110):421–426.
    View this article via: PubMed Google Scholar
  17. Cho J, et al. Purinergic P2Y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescence. J Clin Invest. 2014;124(7):3159–3171.
    View this article via: JCI CrossRef Google Scholar
  18. Ito K, et al. Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes. J Immunol. 2007;178(1):103–110.
    View this article via: PubMed CrossRef Google Scholar
  19. Tothova Z, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007;128(2):325–339.
    View this article via: PubMed CrossRef Google Scholar
  20. Miyamoto K, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell. 2007;1(1):101–112.
    View this article via: PubMed CrossRef Google Scholar
  21. Yalcin S, et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J Biol Chem. 2008;283(37):25692–25705.
    View this article via: PubMed CrossRef Google Scholar
  22. Shao L, et al. Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner. Blood. 2014;123(20):3105–3115.
    View this article via: PubMed CrossRef Google Scholar
Version history
  • Version 1 (June 17, 2014): No description
  • Version 2 (July 1, 2014): No description

Article tools

  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal

Related posts

  • Sensing the stress

Metrics

  • Article usage
  • Citations to this article

Go to

  • Top
  • Abstract
  • Senescence and stem cell decline
  • Loss of P2Y14 leads to reduced HSC potential in response to stress
  • Conclusions and future directions
  • Acknowledgments
  • Footnotes
  • References
  • Version history
Advertisement
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts