{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T19:18:14Z","timestamp":1777058294211,"version":"3.51.4"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,6,27]],"date-time":"2017-06-27T00:00:00Z","timestamp":1498521600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,6,27]],"date-time":"2017-06-27T00:00:00Z","timestamp":1498521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic skin ulcers and burns require advanced treatments. Mesenchymal Stromal Cells (MSCs) are effective in treating these pathologies. Bone Morphogenic Protein-2 (BMP-2) is known to enhance angiogenesis. We investigated whether recombinant human hBMP-2 potentiates the effect of MSCs on wound healing. Severe ulceration was induced in rats by irradiation and treated by co-infusion of MSCs with hBMP-2 into the ulcerated area which accelerated wound healing. Potentiation of the effect of MSCs by hBMP-2 on endothelial repair improved skin healing. HBMP-2 and MSCs synergistically, in a supra additive or enhanced manner, renewed tissue structures, resulting in normalization of the epidermis, hair follicles, sebaceous glands, collagen fibre density, and blood vessels. Co-localization of MSCs with CD31\u2009+\u2009cells suggests recruitment of endothelial cells at the site of injection. HBMP-2 and MSCs enhanced angiogenesis and induced micro-vessel formation in the dermis where hair follicles were regenerated. HBMP-2 acts by causing hypoxia-inducible factor-1 \u03b1 (HIF-1\u03b1) expression which impacts endothelial tube formation and skin repair. This effect is abolished by siRNA. These results propose that new strategies adding cytokines to MSCs should be evaluated for treating radiation-induced dermatitis, burns, and chronic ulcers in humans.<\/jats:p>","DOI":"10.1038\/s41598-017-04496-w","type":"journal-article","created":{"date-parts":[[2017,6,21]],"date-time":"2017-06-21T10:01:10Z","timestamp":1498039270000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Synergistic effect of human Bone Morphogenic Protein-2 and Mesenchymal Stromal Cells on chronic wounds through hypoxia-inducible factor-1 \u03b1 induction"],"prefix":"10.1038","volume":"7","author":[{"given":"Sabine","family":"Fran\u00e7ois","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V\u00e9ronique","family":"Eder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karim","family":"Belmokhtar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie-Christine","family":"Machet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc","family":"Douay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert-Claude","family":"Gorin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Benderitter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4687-4120","authenticated-orcid":false,"given":"Alain","family":"Chapel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,6,27]]},"reference":[{"key":"4496_CR1","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.ijpharm.2016.05.035","volume":"509","author":"M Tenci","year":"2016","unstructured":"Tenci, M. et al. Particulate systems based on pectin\/chitosan association for the delivery of manuka honey components and platelet lysate in chronic skin ulcers. Int J Pharm. 509, 59\u201370 (2016).","journal-title":"Int J Pharm."},{"key":"4496_CR2","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1016\/j.xphs.2015.11.047","volume":"5","author":"M Mori","year":"2016","unstructured":"Mori, M. et al. Sponge-Like Dressings Based on the Association of Chitosan and Sericin for the Treatment of Chronic Skin Ulcers. I. Design of Experiments-Assisted Development. J Pharm Sci. 5, 1180\u20137 (2016).","journal-title":"J Pharm Sci."},{"key":"4496_CR3","doi-asserted-by":"publisher","first-page":"e007733","DOI":"10.1136\/bmjopen-2015-007733","volume":"5","author":"N Morimoto","year":"2015","unstructured":"Morimoto, N. et al. Exploratory clinical trial of combination wound therapy with a gelatin sheet and platelet-rich plasma in patients with chronic skin ulcers: study protocol. BMJ Open. 5, e007733 (2015).","journal-title":"BMJ Open."},{"key":"4496_CR4","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1097\/HP.0b013e318240595b","volume":"103","author":"D Riccobono","year":"2012","unstructured":"Riccobono, D. et al. Application of adipocyte-derived stem cells in treatment of cutaneous radiation syndrome. Health Phys. 103, 120\u20136 (2012).","journal-title":"Health Phys."},{"key":"4496_CR5","doi-asserted-by":"publisher","first-page":"68","DOI":"10.2353\/ajpath.2008.070937","volume":"173","author":"KC Flanders","year":"2008","unstructured":"Flanders, K. C. et al. Absence of Smad3 induces neutrophil migration after cutaneous irradiation: possible contribution to subsequent radioprotection. Am J Pathol. 173, 68\u201376 (2008).","journal-title":"Am J Pathol."},{"key":"4496_CR6","doi-asserted-by":"publisher","first-page":"e31694","DOI":"10.1371\/journal.pone.0031694","volume":"7","author":"F Forcheron","year":"2012","unstructured":"Forcheron, F. et al. Autologous adipocyte derived stem cells favour healing in a minipig model of cutaneous radiation syndrome. PLoS One. 7, e31694 (2012).","journal-title":"PLoS One."},{"key":"4496_CR7","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.ancard.2008.02.015","volume":"57","author":"F Milliat","year":"2008","unstructured":"Milliat, F. et al. Role of endothelium in radiation-induced normal tissue damages. Ann Cardiol Angeiol (Paris). 57, 139\u201348 (2008).","journal-title":"Ann Cardiol Angeiol (Paris)."},{"key":"4496_CR8","doi-asserted-by":"publisher","first-page":"1799","DOI":"10.1515\/cclm-2015-0079","volume":"53","author":"N Leg\u00e1ny","year":"2015","unstructured":"Leg\u00e1ny, N. et al. Increased plasma soluble urokinase plasminogen activator receptor levels in systemic sclerosis: possible association with microvascular abnormalities and extent of fibrosis. Clin Chem Lab Med. 53, 1799\u2013805 (2015).","journal-title":"Clin Chem Lab Med."},{"key":"4496_CR9","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.msec.2016.11.038","volume":"72","author":"S Yasasvini","year":"2017","unstructured":"Yasasvini, S. et al. Topical hydrogel matrix loaded with Simvastatin microparticles for enhanced wound healing activity. Mater Sci Eng C Mater Biol Appl. 72, 160\u2013167 (2017).","journal-title":"Mater Sci Eng C Mater Biol Appl."},{"key":"4496_CR10","doi-asserted-by":"crossref","unstructured":"Nicholas, M. N., Yeung, J. Current Status and Future of Skin Substitutes for Chronic Wound Healing. J Cutan Med Surg. pii: 1203475416664037 (2016).","DOI":"10.1177\/1203475416664037"},{"key":"4496_CR11","doi-asserted-by":"publisher","first-page":"25476","DOI":"10.3390\/ijms161025476","volume":"16","author":"N Ojeh","year":"2015","unstructured":"Ojeh, N., Pastar, I., Tomic-Canic, M. & Stojadinovic, O. Stem Cells in Skin Regeneration, Wound Healing, and Their Clinical Applications. Int J Mol Sci. 16, 25476\u2013501 (2015).","journal-title":"Int J Mol Sci."},{"key":"4496_CR12","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.semradonc.2008.11.005","volume":"19","author":"RP Coppes","year":"2009","unstructured":"Coppes, R. P., van der Goot, A. & Lombaert, I. M. Stem cell therapy to reduce radiation-induced normal tissue damage. Semin Radiat Oncol. 19, 112\u201321 (2009).","journal-title":"Semin Radiat Oncol."},{"key":"4496_CR13","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1080\/15476278.2015.1126018","volume":"11","author":"G Marfia","year":"2015","unstructured":"Marfia, G. et al. Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds. Organogenesis. 11, 183\u2013206 (2015).","journal-title":"Organogenesis."},{"key":"4496_CR14","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s13287-016-0303-6","volume":"7","author":"DE Lee","year":"2016","unstructured":"Lee, D. E., Ayoub, N. & Agrawal, D. K. Mesenchymal stem cells and cutaneous wound healing: novel methods to increase cell delivery and therapeutic efficacy. Stem Cell Res Ther. 7, 37 (2016).","journal-title":"Stem Cell Res Ther."},{"key":"4496_CR15","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1016\/j.exphem.2010.06.008","volume":"38","author":"D Agay","year":"2010","unstructured":"Agay, D. et al. Multipotent mesenchymal stem cell grafting to treat cutaneous radiation syndrome: development of a new minipig model. Exp Hematol. 38, 945\u201356 (2010).","journal-title":"Exp Hematol."},{"key":"4496_CR16","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1089\/wound.2015.0627","volume":"5","author":"M Otero-Vi\u00f1as","year":"2016","unstructured":"Otero-Vi\u00f1as, M. & Falanga, V. Mesenchymal Stem Cells in Chronic Wounds: The Spectrum from Basic to Advanced Therapy. Adv Wound Care (New Rochelle). 5, 149\u2013163 (2016).","journal-title":"Adv Wound Care (New Rochelle)."},{"key":"4496_CR17","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1111\/j.1743-6109.2006.00153.x","volume":"14","author":"K McFarlin","year":"2006","unstructured":"McFarlin, K. et al. Bone marrow-derived mesenchymal stromal cells accelerate wound healing in the rat. Wound Repair Regen. 14, 471\u20138 (2006).","journal-title":"Wound Repair Regen."},{"key":"4496_CR18","unstructured":"Motegi, S.I., Ishikawa, O. Mesenchymal stem cells: The roles and functions in cutaneous wound healing and tumor growth. J Dermatol Sci. pii: S0923, 30721\u20136 (2016)."},{"key":"4496_CR19","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1016\/j.jcyt.2015.04.001","volume":"17","author":"D Ma","year":"2015","unstructured":"Ma, D., Kua, J. E., Lim, W. K., Lee, S. T. & Chua, A. W. In vitro characterization of human hair follicle dermal sheath mesenchymal stromal cells and their potential in enhancing diabetic wound healing. Cytotherapy. 17, 1036\u201351 (2015).","journal-title":"Cytotherapy."},{"key":"4496_CR20","doi-asserted-by":"publisher","first-page":"785","DOI":"10.2217\/17460751.2.5.785","volume":"2","author":"J Lataillade","year":"2007","unstructured":"Lataillade, J. et al. A new approach of radiation-burn treatment by dosimetry-guides surgery combined with autologous mesenchymal stem cells therapy. Regen Med. 2, 785 (2007).","journal-title":"Regen Med."},{"key":"4496_CR21","doi-asserted-by":"publisher","first-page":"1684","DOI":"10.1038\/sj.jcbfm.9600475","volume":"27","author":"A Zacharek","year":"2007","unstructured":"Zacharek, A. et al. Angiopoietin1\/Tie2 and VEGF\/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J Cereb Blood Flow Metab. 27, 1684\u201391 (2007).","journal-title":"J Cereb Blood Flow Metab."},{"key":"4496_CR22","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1007\/s12015-011-9254-6","volume":"7","author":"K Belmokhtar","year":"2011","unstructured":"Belmokhtar, K. et al. Regeneration of Three Layers Vascular Wall by using BMP2-Treated MSC Involving HIF-1alpha and Id1 Expressions Through JAK\/STAT Pathways. Stem Cell Rev. 7, 847\u201359 (2011).","journal-title":"Stem Cell Rev."},{"key":"4496_CR23","first-page":"735","volume":"18","author":"M Raida","year":"2006","unstructured":"Raida, M., Heymann, A. C., Gunther, C. & Niederwieser, D. Role of bone morphogenetic protein 2 in the crosstalk between endothelial progenitor cells and mesenchymal stem cells. Int J Mol Med. 18, 735\u20139 (2006).","journal-title":"Int J Mol Med."},{"key":"4496_CR24","first-page":"1528","volume":"242","author":"JM Wozney","year":"1988","unstructured":"Wozney, J. M. et al. Novel regulators of bone formation: molecular clones and activities. EA. Science. 242, 1528\u201334 (1988).","journal-title":"EA. Science."},{"key":"4496_CR25","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1016\/j.orthres.2004.12.005","volume":"23","author":"G Li","year":"2005","unstructured":"Li, G. et al. rhBMP-2, rhVEGF(165), rhPTN and thrombin-related peptide, TP508 induce chemotaxis of human osteoblasts and microvascular endothelial cells. J Orthop Res. 23, 680\u20135 (2005).","journal-title":"J Orthop Res."},{"key":"4496_CR26","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1007\/s00403-013-1381-2","volume":"305","author":"J Moura","year":"2013","unstructured":"Moura, J., da Silva, L., Cruz, M. T. & Carvalho, E. Molecular and cellular mechanisms of bone morphogenetic proteins and activins in the skin: potential benefits for wound healing. Arch Dermatol Res. 305, 557\u201369 (2013).","journal-title":"Arch Dermatol Res."},{"key":"4496_CR27","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.2353\/ajpath.2010.090048","volume":"176","author":"C Yan","year":"2010","unstructured":"Yan, C. et al. Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol. 176, 2247\u20132258 (2010).","journal-title":"Am J Pathol."},{"key":"4496_CR28","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1038\/jid.2011.141","volume":"131","author":"HR Rezvani","year":"2011","unstructured":"Rezvani, H. R. et al. HIF-1alpha in epidermis: oxygen sensing, cutaneous angiogenesis, cancer, and non-cancer disorders. J. Invest. Dermatol. 131, 1793\u20131805 (2011).","journal-title":"J. Invest. Dermatol."},{"key":"4496_CR29","doi-asserted-by":"crossref","unstructured":"Xia, X. et al. Growth Hormone-Releasing Hormone and Its Analogues: Significance for MSCs-Mediated Angiogenesis. Stem Cells Int.8737589 (2016).","DOI":"10.1155\/2016\/8737589"},{"key":"4496_CR30","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1111\/cpr.12209","volume":"48","author":"M Mehrabani","year":"2015","unstructured":"Mehrabani, M. et al. Deferoxamine preconditioning to restore impaired HIF-1\u03b1-mediated angiogenic mechanisms in adipose-derived stem cells from STZ-induced type 1 diabetic rats. Cel. Prolif. 48, 532\u201349 (2015).","journal-title":"Cel. Prolif."},{"key":"4496_CR31","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/S1053-4296(03)00031-6","volume":"13","author":"A Trotti","year":"2003","unstructured":"Trotti, A. et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol. 13, 176\u201381 (2003).","journal-title":"Semin Radiat Oncol."},{"key":"4496_CR32","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1667\/RR3352","volume":"163","author":"JM Bertho","year":"2005","unstructured":"Bertho, J. M. et al. Application of autologous hematopoietic cell therapy to a nonhuman primate model of heterogeneous high-dose irradiation. Radiat. Res. 163, 557\u201370 (2005).","journal-title":"Radiat. Res."},{"key":"4496_CR33","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1111\/j.1365-2133.2005.06554.x","volume":"153","author":"H Nakagawa","year":"2005","unstructured":"Nakagawa, H. et al. Human mesenchymal stem cells successfully improve skin-substitute wound healing. Br J Dermatol. 153, 29\u201336 (2005).","journal-title":"Br J Dermatol."},{"key":"4496_CR34","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1111\/j.1600-0560.2009.01477.x","volume":"37","author":"K Sellheyer","year":"2010","unstructured":"Sellheyer, K. & Krahl, D. J. Cutaneous mesenchymal stem cells: status of current knowledge, implications for dermatopathology. Cutan. Pathol. 37, 624\u201334 (2010).","journal-title":"Cutan. Pathol."},{"key":"4496_CR35","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1387\/ijdb.072564mp","volume":"53","author":"MV Plikus","year":"2009","unstructured":"Plikus, M. V. et al. Analyses of regenerative wave patterns in adult hair follicle populations reveal macro-environmental regulation of stem cell activity. Int. J. Dev.s Biol. 53, 857\u201368 (2009).","journal-title":"Int. J. Dev.s Biol."},{"key":"4496_CR36","doi-asserted-by":"crossref","unstructured":"Klein, D. et al. Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression. Antioxid Redox Signal. [Epub ahead of print] (2016)","DOI":"10.1089\/ars.2016.6748"},{"key":"4496_CR37","doi-asserted-by":"publisher","first-page":"H858","DOI":"10.1152\/ajpheart.00308.2014","volume":"307","author":"NM Ashpole","year":"2014","unstructured":"Ashpole, N. M. et al. Am, J. Systemic influences contribute to prolonged microvascular rarefaction after brain irradiation: a role for endothelial progenitor cells. Physio Heart Circ Physiol. 307, H858\u201368 (2014).","journal-title":"Physio Heart Circ Physiol."},{"key":"4496_CR38","doi-asserted-by":"crossref","unstructured":"Usunier, B., Benderitter, M., Tamarat, R., Chapel, A. Management of fibrosis: the mesenchymal stromal cells breakthrough. Stem Cells Int. 340257 (2014).","DOI":"10.1155\/2014\/340257"},{"key":"4496_CR39","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1161\/01.RES.0000338613.89841.c1","volume":"103","author":"J Krishnan","year":"2008","unstructured":"Krishnan, J. et al. Essential role of developmentally activated hypoxia-inducible factor 1alpha for cardiac morphogenesis and function. Circ. Res. 103, 1139\u201346 (2008).","journal-title":"Circ. Res."},{"key":"4496_CR40","doi-asserted-by":"publisher","first-page":"11142","DOI":"10.1074\/jbc.M808348200","volume":"24","author":"S Amir","year":"2009","unstructured":"Amir, S. et al. SEPT9_v1 up-regulates hypoxia-inducible factor 1 by preventing its RACK1-mediated degradation. J. Biol. Chem. 24, 11142\u201351 (2009).","journal-title":"J. Biol. Chem."},{"key":"4496_CR41","doi-asserted-by":"publisher","first-page":"3669","DOI":"10.1182\/blood-2009-03-213629","volume":"116","author":"OZ Lerman","year":"2010","unstructured":"Lerman, O. Z. et al. Low-dose radiation augments vasculogenesis signaling through HIF-1-dependent and -independent SDF-1 induction. Blood. 116, 3669\u201376 (2010).","journal-title":"Blood."},{"key":"4496_CR42","doi-asserted-by":"publisher","first-page":"401","DOI":"10.2307\/3574407","volume":"66","author":"BG Douglas","year":"1976","unstructured":"Douglas, B. G. & Fowler, J. F. The effect of multiple small doses of x rays on skin reactions in the mouse and a basic interpretation. Radiat. Res. 66, 401\u201326 (1976).","journal-title":"Radiat. Res."},{"key":"4496_CR43","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/S0360-3016(02)04202-5","volume":"55","author":"U Hoeller","year":"2003","unstructured":"Hoeller, U. et al. Increasing the rate of late toxicity by changing the score? A comparison of RTOG\/EORTC and LENT\/SOMA scores. Int. J. Radiat. Oncol. Biol. Phys. 55, 1013\u20138 (2003).","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."}],"updated-by":[{"DOI":"10.1038\/s41598-018-23594-x","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2018,4,11]],"date-time":"2018-04-11T00:00:00Z","timestamp":1523404800000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04496-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04496-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04496-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T05:56:35Z","timestamp":1671774995000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04496-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,27]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["4496"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-04496-w","relation":{"correction":[{"id-type":"doi","id":"10.1038\/s41598-018-23594-x","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,27]]},"assertion":[{"value":"23 January 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 May 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 June 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 April 2018","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"4272"}}