Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard.
Alkylating Agents
/ toxicity
Apoptosis
/ drug effects
Biomarkers
/ metabolism
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Cells, Cultured
Cellular Senescence
/ drug effects
Chemical Warfare Agents
/ toxicity
Chemokines
/ genetics
Cytokines
/ genetics
Humans
Hydrogen Peroxide
/ toxicity
Mesenchymal Stem Cells
/ cytology
Mustard Gas
/ toxicity
Skin
/ drug effects
Wound Healing
/ drug effects
Chemical warfare agents
Mesenchymal stem cells
Senescence
Sulfur mustard
Wound healing disorder
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
27
07
2020
accepted:
28
10
2020
pubmed:
26
1
2021
medline:
8
9
2021
entrez:
25
1
2021
Statut:
ppublish
Résumé
Wound healing is a complex process, and disturbance of even a single mechanism can result in chronic ulcers developing after exposure to the alkylating agent sulfur mustard (SM). A possible contributor may be SM-induced chronic senescent mesenchymal stem cells (MSCs), unable to fulfil their regenerative role, by persisting over long time periods and creating a proinflammatory microenvironment. Here we show that senescence induction in human bone marrow derived MSCs was time- and concentration-dependent, and chronic senescence could be verified 3 weeks after exposure to between 10 and 40 µM SM. Morphological changes, reduced clonogenic and migration potential, longer scratch closure times, differences in senescence, motility and DNA damage response associated genes as well as increased levels of proinflammatory cytokines were revealed. Selective removal of these cells by senolytic drugs, in which ABT-263 showed initial potential in vitro, opens the possibility for an innovative treatment strategy for chronic wounds, but also tumors and age-related diseases.
Identifiants
pubmed: 33491125
doi: 10.1007/s00204-020-02946-5
pii: 10.1007/s00204-020-02946-5
pmc: PMC7870771
doi:
Substances chimiques
Alkylating Agents
0
Biomarkers
0
Chemical Warfare Agents
0
Chemokines
0
Cytokines
0
Hydrogen Peroxide
BBX060AN9V
Mustard Gas
T8KEC9FH9P
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
727-747Références
Abreu-Blanco MT, Watts JJ, Verboon JM, Parkhurst SM (2012) Cytoskeleton responses in wound repair. Cell Mol Life Sci 69:2469–2483
doi: 10.1007/s00018-012-0928-2
Alessio N, Del Gaudio S, Capasso S et al (2015) Low dose radiation induced senescence of human mesenchymal stromal cells and impaired the autophagy process. Oncotarget 6:8155–8166. https://doi.org/10.18632/oncotarget.2692
doi: 10.18632/oncotarget.2692
pubmed: 25544750
Augustin M, Maier K (2003) Psychosomatic aspects of chronic wounds. Dermatol Psychosom/Dermatol Psychosom 4:5–13. https://doi.org/10.1159/000070529
doi: 10.1159/000070529
Baar MP, Brandt RMC, Putavet DA et al (2017) Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169:132-147.e16. https://doi.org/10.1016/j.cell.2017.02.031
doi: 10.1016/j.cell.2017.02.031
pubmed: 28340339
pmcid: 5556182
Baker DJ, Wijshake T, Tchkonia T et al (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236. https://doi.org/10.1038/nature10600
doi: 10.1038/nature10600
pubmed: 22048312
pmcid: 22048312
Baker DJ, Childs BG, Durik M et al (2016) Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530:184–189. https://doi.org/10.1038/nature16932
doi: 10.1038/nature16932
pubmed: 26840489
pmcid: 4845101
Behboudi H, Noureini SK, Ghazanfari T, Ardestani SK (2018) DNA damage and telomere length shortening in the peripheral blood leukocytes of 20 years SM-exposed veterans. Int Immunopharmacol 61:37–44. https://doi.org/10.1016/j.intimp.2018.05.008
doi: 10.1016/j.intimp.2018.05.008
pubmed: 29803135
Behravan E, Moallem SA, Kalalinia F et al (2018) Telomere shortening associated with increased levels of oxidative stress in sulfur mustard-exposed Iranian veterans. Mutat Res Toxicol Environ Mutagen 834:1–5. https://doi.org/10.1016/j.mrgentox.2018.06.017
doi: 10.1016/j.mrgentox.2018.06.017
Borodkina AV, Deryabin PI, Giukova AA, Nikolsky NN (2018) “Social Life” of Senescent Cells: What Is SASP and Why Study It? Acta Naturae 10:4–14
doi: 10.32607/20758251-2018-10-1-4-14
Brandl A, Meyer M, Bechmann V et al (2011) Oxidative stress induces senescence in human mesenchymal stem cells. Exp Cell Res 317:1541–1547. https://doi.org/10.1016/j.yexcr.2011.02.015
doi: 10.1016/j.yexcr.2011.02.015
pubmed: 21376036
Brimfield AA, Soni SD, Trimmer KA et al (2012) Metabolic activation of sulfur mustard leads to oxygen free radical formation. Free Radic Biol Med 52:811–817. https://doi.org/10.1016/j.freeradbiomed.2011.11.031
doi: 10.1016/j.freeradbiomed.2011.11.031
pubmed: 22206978
Bruder SP, Kurth AA, Shea M et al (1998) Bone regeneration by implantation of purified, culture-expanded human mesenchymal stem cells. J Orthop Res 16:155–162. https://doi.org/10.1002/jor.1100160202
doi: 10.1002/jor.1100160202
pubmed: 9621889
Bukowiecki A, Hos D, Cursiefen C, Eming S (2017) Wound-healing studies in cornea and skin: parallels, differences and opportunities. Int J Mol Sci 18:1257. https://doi.org/10.3390/ijms18061257
doi: 10.3390/ijms18061257
pmcid: 5486079
Byun HO, Lee YK, Kim JM, Yoon G (2015) From cell senescence to age-related diseases: differential mechanisms of action of senescence-associated secretory phenotypes. BMB Rep 48:549–558
doi: 10.5483/BMBRep.2015.48.10.122
Carlos Sepúlveda J, Tomé M, Eugenia Fernández M et al (2014) Cell senescence abrogates the therapeutic potential of human mesenchymal stem cells in the lethal endotoxemia model. Stem Cells 32:1865–1877. https://doi.org/10.1002/stem.1654
doi: 10.1002/stem.1654
Chang J, Wang Y, Shao L et al (2016) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 22:78–83. https://doi.org/10.1038/nm.4010
doi: 10.1038/nm.4010
pubmed: 26657143
pmcid: 26657143
Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130:223–233. https://doi.org/10.1016/j.cell.2007.07.003
doi: 10.1016/j.cell.2007.07.003
pubmed: 17662938
Coppé J-P, Patil CK, Rodier F et al (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868. https://doi.org/10.1371/journal.pbio.0060301
doi: 10.1371/journal.pbio.0060301
pubmed: 19053174
pmcid: 19053174
Cullumbine H (1947) Medical aspects of mustard gas poisoning. Nature 159:151–153. https://doi.org/10.1038/159151a0
doi: 10.1038/159151a0
pubmed: 20285648
Demaria M, Ohtani N, Youssef SA et al (2014) An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 31:722–733. https://doi.org/10.1016/j.devcel.2014.11.012
doi: 10.1016/j.devcel.2014.11.012
pubmed: 25499914
pmcid: 4349629
Dörr JR, Yu Y, Milanovic M et al (2013) Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501:421–425. https://doi.org/10.1038/nature12437
doi: 10.1038/nature12437
pubmed: 23945590
Emadi SN, Mortazavi M, Mortazavi H (2008) Late cutaneous manifestations 14 to 20 years after wartime exposure to sulfur mustard gas: a long-term investigation. Arch Dermatol 144:1059–1061. https://doi.org/10.1001/archderm.144.8.1059
doi: 10.1001/archderm.144.8.1059
pubmed: 18711087
Etemad L, Moshiri M, Balali-Mood M (2019) Advances in treatment of acute sulfur mustard poisoning—a critical review. Crit Rev Toxicol 49:191–214. https://doi.org/10.1080/10408444.2019.1579779
doi: 10.1080/10408444.2019.1579779
pubmed: 31576778
Fuhrmann-Stroissnigg H, Ling YY, Zhao J et al (2017) Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun 8:422. https://doi.org/10.1038/s41467-017-00314-z
doi: 10.1038/s41467-017-00314-z
pubmed: 28871086
pmcid: 5583353
Grezella C, Fernandez-Rebollo E, Franzen J et al (2018) Effects of senolytic drugs on human mesenchymal stromal cells. Stem Cell Res Ther 9:108. https://doi.org/10.1186/s13287-018-0857-6
doi: 10.1186/s13287-018-0857-6
pubmed: 29669575
pmcid: 5907463
Hassan ZM, Ebtekar M (2002) Immunological consequence of sulfur mustard exposure. Immunol Lett 83:151–152. https://doi.org/10.1016/S0165-2478(02)00076-7
doi: 10.1016/S0165-2478(02)00076-7
pubmed: 12095704
Janssens R, Struyf S, Proost P (2018) The unique structural and functional features of CXCL12. Cell Mol Immunol 15:299–311
doi: 10.1038/cmi.2017.107
John H, Koller M, Worek F et al (2019) Forensic evidence of sulfur mustard exposure in real cases of human poisoning by detection of diverse albumin-derived protein adducts. Arch Toxicol 93:1881–1891. https://doi.org/10.1007/s00204-019-02461-2
doi: 10.1007/s00204-019-02461-2
pubmed: 31069408
Jun J-I, Lau LF (2010) The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol 12:676–685. https://doi.org/10.1038/ncb2070
doi: 10.1038/ncb2070
pubmed: 20526329
pmcid: 2919364
Kearney AY, Anchang B, Plevritis S, Felsher DW (2015) ARF: connecting senescence and innate immunity for clearance. Aging (Albany NY) 7:613–615. https://doi.org/10.18632/aging.100813
doi: 10.18632/aging.100813
Kilic E, Ortatatli M, Sezigen S et al (2018) Acute intensive care unit management of mustard gas victims: the Turkish experience. Cutan Ocul Toxicol 37:332–337. https://doi.org/10.1080/15569527.2018.1464018
doi: 10.1080/15569527.2018.1464018
pubmed: 29648477
Kim YH, Choi YW, Lee J et al (2017) Senescent tumor cells lead the collective invasion in thyroid cancer. Nat Commun 8:15208. https://doi.org/10.1038/ncomms15208
doi: 10.1038/ncomms15208
pubmed: 28489070
pmcid: 28489070
Krizhanovsky V, Yon M, Dickins RA et al (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134:657–667. https://doi.org/10.1016/j.cell.2008.06.049
doi: 10.1016/j.cell.2008.06.049
pubmed: 18724938
pmcid: 3073300
Lee DE, Ayoub N, Agrawal DK (2016) Mesenchymal stem cells and cutaneous wound healing: novel methods to increase cell delivery and therapeutic efficacy. Stem Cell Res Ther 7:37. https://doi.org/10.1186/s13287-016-0303-6
doi: 10.1186/s13287-016-0303-6
pubmed: 26960535
pmcid: 4784457
Ma S, Xie N, Li W et al (2014) Immunobiology of mesenchymal stem cells. Cell Death Differ 21:216–225. https://doi.org/10.1038/cdd.2013.158
doi: 10.1038/cdd.2013.158
pubmed: 24185619
Malaquin N, Martinez A, Rodier F (2016) Keeping the senescence secretome under control: molecular reins on the senescence-associated secretory phenotype. Exp Gerontol 82:39–49. https://doi.org/10.1016/j.exger.2016.05.010
doi: 10.1016/j.exger.2016.05.010
pubmed: 27235851
Minieri V, Saviozzi S, Gambarotta G et al (2015) Persistent DNA damage-induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells. J Cell Mol Med 19:734–743. https://doi.org/10.1111/jcmm.12387
doi: 10.1111/jcmm.12387
pubmed: 25619736
pmcid: 4395188
Nelson G, Wordsworth J, Wang C et al (2012) A senescent cell bystander effect: senescence-induced senescence. Aging Cell 11:345–349. https://doi.org/10.1111/j.1474-9726.2012.00795.x
doi: 10.1111/j.1474-9726.2012.00795.x
pubmed: 22321662
pmcid: 3488292
Nie C, Yang D, Xu J et al (2011) Locally administered adipose-derived stem cells accelerate wound healing through differentiation and vasculogenesis. Cell Transplant 20:205–216. https://doi.org/10.3727/096368910X520065
doi: 10.3727/096368910X520065
pubmed: 20719083
Ranganath SH, Levy O, Inamdar MS, Karp JM (2012) Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10:244–258. https://doi.org/10.1016/j.stem.2012.02.005
doi: 10.1016/j.stem.2012.02.005
pubmed: 22385653
pmcid: 3294273
Rodriguez-Menocal L, Salgado M, Ford D, Van Badiavas E (2012) Stimulation of skin and wound fibroblast migration by mesenchymal stem cells derived from normal donors and chronic wound patients. Stem Cells Transl Med 1:221–229. https://doi.org/10.5966/sctm.2011-0029
doi: 10.5966/sctm.2011-0029
pubmed: 23197781
pmcid: 3659842
Rodriguez-Menocal L, Shareef S, Salgado M et al (2015) Role of whole bone marrow, whole bone marrow cultured cells, and mesenchymal stem cells in chronic wound healing. Stem Cell Res Ther 6:24. https://doi.org/10.1186/s13287-015-0001-9
doi: 10.1186/s13287-015-0001-9
pubmed: 25881077
pmcid: 4414366
Schmidt A, Scherer M, Thiermann H, Steinritz D (2013) Mesenchymal stem cells are highly resistant to sulfur mustard. Chem Biol Interact 206:505–511. https://doi.org/10.1016/j.cbi.2013.07.013
doi: 10.1016/j.cbi.2013.07.013
pubmed: 23933411
Schmidt A, Steinritz D, Rothmiller S et al (2018a) Effects of sulfur mustard on mesenchymal stem cells. Toxicol Lett. https://doi.org/10.1016/j.toxlet.2017.08.008
doi: 10.1016/j.toxlet.2017.08.008
pubmed: 29551593
Schmidt A, Steinritz D, Rudolf K-D et al (2018b) Accidental sulfur mustard exposure: a case report. Toxicol Lett 293:62–66. https://doi.org/10.1016/j.toxlet.2017.11.023
doi: 10.1016/j.toxlet.2017.11.023
pubmed: 29191789
Schreier C, Rothmiller S, Scherer MA et al (2018) Mobilization of human mesenchymal stem cells through different cytokines and growth factors after their immobilization by sulfur mustard. Toxicol Lett. https://doi.org/10.1016/j.toxlet.2018.02.011
doi: 10.1016/j.toxlet.2018.02.011
pubmed: 29426001
Sedelnikova OA, Horikawa I, Zimonjic DB et al (2004) Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol 6:168–170. https://doi.org/10.1038/ncb1095
doi: 10.1038/ncb1095
pubmed: 14755273
Severino V, Alessio N, Farina A et al (2013) Insulin-like growth factor binding proteins 4 and 7 released by senescent cells promote premature senescence in mesenchymal stem cells. Cell Death Dis 4:e911. https://doi.org/10.1038/cddis.2013.445
doi: 10.1038/cddis.2013.445
pubmed: 24201810
pmcid: 3847322
Sezigen S, Ivelik K, Ortatatli M et al (2019) Victims of chemical terrorism, a family of four who were exposed to sulfur mustard. Toxicol Lett 303:9–15. https://doi.org/10.1016/j.toxlet.2018.12.006
doi: 10.1016/j.toxlet.2018.12.006
pubmed: 30572106
Sharpless NE, Sherr CJ (2015) Forging a signature of in vivo senescence. Nat Rev Cancer 15:397–408. https://doi.org/10.1038/nrc3960
doi: 10.1038/nrc3960
pubmed: 26105537
Smith WJ, Sanders KM, Ruddle SE, Gross CL (1993) Cytometric analysis of DNA changes induced by sulfur mustard. Cutan Ocul Toxicol 12:337–347. https://doi.org/10.3109/15569529309050150
doi: 10.3109/15569529309050150
Sulzberger MB, Baer RL, Kanof A, Lowenberg C (1947) Skin sensitization to vesicant agents of chemical warfare. J Invest Dermatol 8:365–393
doi: 10.1038/jid.1947.51
Tchkonia T, Zhu Y, van Deursen J et al (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123:966–972. https://doi.org/10.1172/JCI64098
doi: 10.1172/JCI64098
pubmed: 23454759
pmcid: 3582125
Thiruvoth F, Mohapatra D, Sivakumar D et al (2015) Current concepts in the physiology of adult wound healing. Plast Aesthetic Res 2:250. https://doi.org/10.4103/2347-9264.158851
doi: 10.4103/2347-9264.158851
van Deursen JM (2014) The role of senescent cells in ageing. Nature 509:439–446. https://doi.org/10.1038/nature13193
doi: 10.1038/nature13193
pubmed: 4214092
pmcid: 4214092
von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 27:339–344. https://doi.org/10.1016/s0968-0004(02)02110-2
doi: 10.1016/s0968-0004(02)02110-2
Walter MNM, Wright KT, Fuller HR et al (2010) Mesenchymal stem cell-conditioned medium accelerates skin wound healing: an in vitro study of fibroblast and keratinocyte scratch assays. Exp Cell Res 316:1271–1281. https://doi.org/10.1016/j.yexcr.2010.02.026
doi: 10.1016/j.yexcr.2010.02.026
pubmed: 20206158
Wang KX, Denhardt DT (2008) Osteopontin: Role in immune regulation and stress responses. Cytokine Growth Factor Rev 19:333–345
doi: 10.1016/j.cytogfr.2008.08.001
Wang Y, Chen X, Cao W, Shi Y (2014) Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol 15:1009–1016. https://doi.org/10.1038/ni.3002
doi: 10.1038/ni.3002
pubmed: 25329189
Wilkinson HN, Hardman MJ (2020) Senescence in wound repair: emerging strategies to target chronic healing wounds. Front Cell Dev Biol 8:773
doi: 10.3389/fcell.2020.00773
Willyard C (2018) Unlocking the secrets of scar-free skin healing. Nature 563:S86–S88. https://doi.org/10.1038/d41586-018-07430-w
doi: 10.1038/d41586-018-07430-w
pubmed: 30464288
Yosef R, Pilpel N, Tokarsky-Amiel R et al (2016) Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun 7:11190. https://doi.org/10.1038/ncomms11190
doi: 10.1038/ncomms11190
pubmed: 27048913
pmcid: 4823827
Yue L, Zhang Y, Chen J et al (2015) Distribution of DNA adducts and corresponding tissue damage of sprague-dawley rats with percutaneous exposure to sulfur mustard. Chem Res Toxicol 28:532–540. https://doi.org/10.1021/tx5004886
doi: 10.1021/tx5004886
pubmed: 25650027
Zhu Y, Tchkonia T, Pirtskhalava T et al (2015) The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14:644–658. https://doi.org/10.1111/acel.12344
doi: 10.1111/acel.12344
pubmed: 25754370
pmcid: 4531078
Zubel T, Hochgesand S, John H et al (2019) A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure. Arch Toxicol 93:61–79. https://doi.org/10.1007/s00204-018-2324-7
doi: 10.1007/s00204-018-2324-7
pubmed: 30324314