{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T16:03:05Z","timestamp":1788624185292,"version":"build-2803163510"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,12,11]],"date-time":"2019-12-11T00:00:00Z","timestamp":1576022400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,12,11]],"date-time":"2019-12-11T00:00:00Z","timestamp":1576022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001702","name":"AO Foundation","doi-asserted-by":"publisher","award":["1406Z"],"award-info":[{"award-number":["1406Z"]}],"id":[{"id":"10.13039\/501100001702","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001702","name":"AO Foundation","doi-asserted-by":"publisher","award":["1406Z"],"award-info":[{"award-number":["1406Z"]}],"id":[{"id":"10.13039\/501100001702","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001702","name":"AO Foundation","doi-asserted-by":"publisher","award":["1406Z"],"award-info":[{"award-number":["1406Z"]}],"id":[{"id":"10.13039\/501100001702","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001702","name":"AO Foundation","doi-asserted-by":"publisher","award":["1406Z"],"award-info":[{"award-number":["1406Z"]}],"id":[{"id":"10.13039\/501100001702","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001702","name":"AO Foundation","doi-asserted-by":"publisher","award":["1406z"],"award-info":[{"award-number":["1406z"]}],"id":[{"id":"10.13039\/501100001702","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001702","name":"AO Foundation","doi-asserted-by":"publisher","award":["1406Z"],"award-info":[{"award-number":["1406Z"]}],"id":[{"id":"10.13039\/501100001702","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001702","name":"AO Foundation","doi-asserted-by":"publisher","award":["1406Z"],"award-info":[{"award-number":["1406Z"]}],"id":[{"id":"10.13039\/501100001702","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive and antiangiogenic therapies. MRONJ is identified by chronic wounds in the oral mucosa associated with exposed necrotic bone. We hypothesized that zoledronic acid (ZOL) impairs keratinocyte and fibroblast function and reduces soft tissue vascularization; therefore, treating MRONJ with proangiogenic cells may benefit MRONJ patients. The effect of ZOL and dexamethasone (DEX) on gingival fibroblasts and keratinocytes was investigated.<jats:italic>In-vitro<\/jats:italic>, ZOL inhibited fibroblast and keratinocyte proliferation, delaying scratch healing.<jats:italic>In-vivo<\/jats:italic>, exposed bone was detected at tooth extraction sites, mainly in ZOL(+)\/DEX(+) rats; and was associated with significantly decreased soft tissue vascularization, serum-VEGF, and tissue-VEGF. Local injection of early and late endothelial progenitor cells (EPCs) healed 13 of 14 MRONJ lesions compared with 2\/7 lesions in the mesenchymal stem cells, and 2\/6, in culture-medium group. The EPCs reduced necrotic bone area, increased serum and tissue VEGF levels. EPCs engraftment was minimal, suggesting their paracrine role in MRONJ healing. The EPC-conditioned medium improved scratch healing of keratinocytes and fibroblasts via VEGF pathway and elevated mRNA of VEGFA and collagen1A1. In conclusion, a novel MRONJ treatment with EPCs, increased vascularization and improved epithelial and fibroblast functions as well as cured the lesion.<\/jats:p>","DOI":"10.1038\/s41598-019-55383-5","type":"journal-article","created":{"date-parts":[[2019,12,11]],"date-time":"2019-12-11T12:44:58Z","timestamp":1576068298000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Endothelial Progenitor Cells inhibit jaw osteonecrosis in a rat model: A major adverse effect of bisphosphonate therapy"],"prefix":"10.1038","volume":"9","author":[{"given":"Tal","family":"Tamari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rina","family":"Elimelech","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gal","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0869-0873","authenticated-orcid":false,"given":"Talia","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ofri","family":"Doppelt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lana","family":"Eskander-Hashoul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4940-6533","authenticated-orcid":false,"given":"Hadar","family":"Zigdon-Giladi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,11]]},"reference":[{"key":"55383_CR1","doi-asserted-by":"publisher","first-page":"1938","DOI":"10.1016\/j.joms.2014.04.031","volume":"72","author":"SL Ruggiero","year":"2014","unstructured":"Ruggiero, S. L. et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw\u20132014 update. J. Oral Maxillofac. Surg. Off. J. Am. Assoc. Oral Maxillofac. Surg. 72, 1938\u20131956 (2014).","journal-title":"J. Oral Maxillofac. Surg. Off. J. Am. Assoc. Oral Maxillofac. Surg."},{"key":"55383_CR2","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.clindermatol.2006.09.007","volume":"25","author":"J Li","year":"2007","unstructured":"Li, J., Chen, J. & Kirsner, R. Pathophysiology of acute wound healing. Clin. Dermatol. 25, 9\u201318 (2007).","journal-title":"Clin. Dermatol."},{"key":"55383_CR3","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1056\/NEJM199909023411006","volume":"341","author":"AJ Singer","year":"1999","unstructured":"Singer, A. J. & Clark, R. A. Cutaneous wound healing. N. Engl. J. Med. 341, 738\u2013746 (1999).","journal-title":"N. Engl. J. Med."},{"key":"55383_CR4","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1016\/S0092-8674(00)81731-6","volume":"94","author":"D Fukumura","year":"1998","unstructured":"Fukumura, D. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 94, 715\u2013725 (1998).","journal-title":"Cell"},{"key":"55383_CR5","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/j.yexcr.2006.10.023","volume":"313","author":"S Kellouche","year":"2007","unstructured":"Kellouche, S. et al. Platelets, thrombospondin-1 and human dermal fibroblasts cooperate for stimulation of endothelial cell tubulogenesis through VEGF and PAI-1 regulation. Exp. Cell Res. 313, 486\u2013499 (2007).","journal-title":"Exp. Cell Res."},{"key":"55383_CR6","doi-asserted-by":"publisher","first-page":"265sr6","DOI":"10.1126\/scitranslmed.3009337","volume":"6","author":"SA Eming","year":"2014","unstructured":"Eming, S. A., Martin, P. & Tomic-Canic, M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci. Transl. Med. 6, 265sr6 (2014).","journal-title":"Sci. Transl. Med."},{"key":"55383_CR7","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/1756-8722-5-56","volume":"5","author":"B Vincenzi","year":"2012","unstructured":"Vincenzi, B. et al. Serum VEGF levels as predictive marker of bisphosphonate-related osteonecrosis of the jaw. J. Hematol. Oncol.J Hematol Oncol 5, 56 (2012).","journal-title":"J. Hematol. Oncol.J Hematol Oncol"},{"key":"55383_CR8","first-page":"2893","volume":"9","author":"D Santini","year":"2003","unstructured":"Santini, D. et al. Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 9, 2893\u20132897 (2003).","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"55383_CR9","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1590\/0103-6440201302229","volume":"24","author":"FG Basso","year":"2013","unstructured":"Basso, F. G. et al. Cytotoxic effects of zoledronic acid on human epithelial cells and gingival fibroblasts. Braz. Dent. J. 24, 551\u2013558 (2013).","journal-title":"Braz. Dent. J."},{"key":"55383_CR10","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1111\/j.1365-2141.2008.07504.x","volume":"144","author":"M Scheper","year":"2009","unstructured":"Scheper, M., Badros, A., Chaisuparat, R., Cullen, K. & Meiller, T. Effect of Zoledronic Acid on Oral Fibroblasts and Epithelial Cells: A Potential Mechanism of Bisphosphonate-Associated Osteonecrosis. Br. J. Haematol. 144, 667\u2013676 (2009).","journal-title":"Br. J. Haematol."},{"key":"55383_CR11","first-page":"711","volume":"43","author":"S Zafar","year":"2014","unstructured":"Zafar, S. et al. Zoledronic acid and geranylgeraniol regulate cellular behaviour and angiogenic gene expression in human gingival fibroblasts. J. Oral Pathol. Med. Off. Publ. Int. Assoc. Oral Pathol. Am. Acad. Oral Pathol. 43, 711\u2013721 (2014).","journal-title":"J. Oral Pathol. Med. Off. Publ. Int. Assoc. Oral Pathol. Am. Acad. Oral Pathol."},{"key":"55383_CR12","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.jtv.2009.11.004","volume":"20","author":"B Li","year":"2011","unstructured":"Li, B. & Wang, J. H.-C. Fibroblasts and myofibroblasts in wound healing: force generation and measurement. J. Tissue Viability 20, 108\u2013120 (2011).","journal-title":"J. Tissue Viability"},{"key":"55383_CR13","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s40902-015-0020-6","volume":"37","author":"H-W Jang","year":"2015","unstructured":"Jang, H.-W., Kim, J.-W. & Cha, I.-H. Development of animal model for Bisphosphonates-related osteonecrosis of the jaw (BRONJ). Maxillofac. Plast. Reconstr. Surg. 37, 18 (2015).","journal-title":"Maxillofac. Plast. Reconstr. Surg."},{"key":"55383_CR14","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.oraloncology.2008.04.013","volume":"45","author":"ST Sonis","year":"2009","unstructured":"Sonis, S. T., Watkins, B. A., Lyng, G. D., Lerman, M. A. & Anderson, K. C. Bony changes in the jaws of rats treated with zoledronic acid and dexamethasone before dental extractions mimic bisphosphonate-related osteonecrosis in cancer patients. Oral Oncol. 45, 164\u2013172 (2009).","journal-title":"Oral Oncol."},{"key":"55383_CR15","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1126\/science.275.5302.964","volume":"275","author":"T Asahara","year":"1997","unstructured":"Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964\u2013967 (1997).","journal-title":"Science"},{"key":"55383_CR16","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/7434","volume":"5","author":"T Takahashi","year":"1999","unstructured":"Takahashi, T. et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat. Med. 5, 434\u2013438 (1999).","journal-title":"Nat. Med."},{"key":"55383_CR17","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1016\/j.bone.2009.07.085","volume":"45","author":"N Rozen","year":"2009","unstructured":"Rozen, N. et al. Transplanted blood-derived endothelial progenitor cells (EPC) enhance bridging of sheep tibia critical size defects. Bone 45, 918\u2013924 (2009).","journal-title":"Bone"},{"key":"55383_CR18","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1111\/cid.12078","volume":"17","author":"H Zigdon-Giladi","year":"2015","unstructured":"Zigdon-Giladi, H., Bick, T., Morgan, E. F., Lewinson, D. & Machtei, E. E. Peripheral blood-derived endothelial progenitor cells enhance vertical bone formation. Clin. Implant Dent. Relat. Res. 17, 83\u201392 (2015).","journal-title":"Clin. Implant Dent. Relat. Res."},{"key":"55383_CR19","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1083\/jcb.106.3.761","volume":"106","author":"P Boukamp","year":"1988","unstructured":"Boukamp, P. et al. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J. Cell Biol. 106, 761\u2013771 (1988).","journal-title":"J. Cell Biol."},{"key":"55383_CR20","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.bone.2015.01.011","volume":"74","author":"K Ogata","year":"2015","unstructured":"Ogata, K. et al. Evaluation of the therapeutic effects of conditioned media from mesenchymal stem cells in a rat bisphosphonate-related osteonecrosis of the jaw-like model. Bone 74, 95\u2013105 (2015).","journal-title":"Bone"},{"key":"55383_CR21","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1016\/j.jcyt.2017.03.079","volume":"19","author":"H Zigdon-Giladi","year":"2017","unstructured":"Zigdon-Giladi, H., Elimelech, R., Michaeli-Geller, G., Rudich, U. & Machtei, E. E. Safety profile and long-term engraftment of human CD31+ blood progenitors in bone tissue engineering. Cytotherapy 19, 895\u2013908 (2017).","journal-title":"Cytotherapy"},{"key":"55383_CR22","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1002\/term.391","volume":"6","author":"AR Costa-Pinto","year":"2012","unstructured":"Costa-Pinto, A. R. et al. Chitosan-poly(butylene succinate) scaffolds and human bone marrow stromal cells induce bone repair in a mouse calvaria model. J. Tissue Eng. Regen. Med. 6, 21\u201328 (2012).","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"55383_CR23","doi-asserted-by":"publisher","first-page":"280","DOI":"10.2353\/ajpath.2010.090592","volume":"177","author":"Y Bi","year":"2010","unstructured":"Bi, Y. et al. Bisphosphonates cause osteonecrosis of the jaw-like disease in mice. Am. J. Pathol. 177, 280\u2013290 (2010).","journal-title":"Am. J. Pathol."},{"key":"55383_CR24","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.actbio.2016.06.022","volume":"42","author":"N Kaibuchi","year":"2016","unstructured":"Kaibuchi, N., Iwata, T., Yamato, M., Okano, T. & Ando, T. Multipotent mesenchymal stromal cell sheet therapy for bisphosphonate-related osteonecrosis of the jaw in a rat model. Acta Biomater. 42, 400\u2013410 (2016).","journal-title":"Acta Biomater."},{"key":"55383_CR25","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/j.tripleo.2009.10.011","volume":"109","author":"FC Senel","year":"2010","unstructured":"Senel, F. C. et al. Jaw bone changes in rats after treatment with zoledronate and pamidronate. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 109, 385\u2013391 (2010).","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod."},{"key":"55383_CR26","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1002\/jemt.22210","volume":"76","author":"FP Yamamoto-Silva","year":"2013","unstructured":"Yamamoto-Silva, F. P., Bradaschia-Correa, V., Lima, L. A. P. A. & Arana-Chavez, V. E. Ultrastructural and immunohistochemical study of early repair of alveolar sockets after the extraction of molars from alendronate-treated rats. Microsc. Res. Tech. 76, 633\u2013640 (2013).","journal-title":"Microsc. Res. Tech."},{"key":"55383_CR27","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1007\/s00520-009-0710-7","volume":"17","author":"MA Scheper","year":"2009","unstructured":"Scheper, M. A. et al. A novel bioassay model to determine clinically significant bisphosphonate levels. Support. Care Cancer 17, 1553 (2009).","journal-title":"Support. Care Cancer"},{"key":"55383_CR28","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1177\/0091270002239824","volume":"43","author":"A Skerjanec","year":"2003","unstructured":"Skerjanec, A. et al. The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with varying degrees of renal function. J. Clin. Pharmacol. 43, 154\u2013162 (2003).","journal-title":"J. Clin. Pharmacol."},{"key":"55383_CR29","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1755-1536-3-6","volume":"3","author":"M Scheper","year":"2010","unstructured":"Scheper, M., Chaisuparat, R., Cullen, K. & Meiller, T. A novel soft-tissue in vitro model for bisphosphonate-associated osteonecrosis. Fibrogenesis Tissue Repair 3, 6 (2010).","journal-title":"Fibrogenesis Tissue Repair"},{"key":"55383_CR30","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/S0015-0282(16)46816-0","volume":"39","author":"M Granat","year":"1983","unstructured":"Granat, M. et al. Effects of dexamethasone on proliferation of autologous fibroblasts and on the immune profile in women undergoing pelvic surgery for infertility. Fertil. Steril. 39, 180\u2013186 (1983).","journal-title":"Fertil. Steril."},{"key":"55383_CR31","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1002\/(SICI)1097-4652(199812)177:3<396::AID-JCP3>3.0.CO;2-K","volume":"177","author":"S Li","year":"1998","unstructured":"Li, S., Mawal-Dewan, M., Cristofalo, V. J. & Sell, C. Enhanced proliferation of human fibroblasts, in the presence of dexamethasone, is accompanied by changes in p21Waf1\/Cip1\/Sdi1 and the insulin-like growth factor type 1 receptor. J. Cell. Physiol. 177, 396\u2013401 (1998).","journal-title":"J. Cell. Physiol."},{"key":"55383_CR32","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/s00784-009-0365-2","volume":"15","author":"T Ziebart","year":"2011","unstructured":"Ziebart, T. et al. Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro. Clin. Oral Investig. 15, 105\u2013111 (2011).","journal-title":"Clin. Oral Investig."},{"key":"55383_CR33","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/8756-3282(95)00445-9","volume":"18","author":"JH Lin","year":"1996","unstructured":"Lin, J. H. Bisphosphonates: a review of their pharmacokinetic properties. Bone 18, 75\u201385 (1996).","journal-title":"Bone"},{"key":"55383_CR34","doi-asserted-by":"crossref","unstructured":"Sharma, D., Hamlet, S. M., Petcu, E. B. & Ivanovski, S. The effect of bisphosphonates on the endothelial differentiation of mesenchymal stem cells. Sci. Rep. 6 (2016).","DOI":"10.1038\/srep20580"},{"key":"55383_CR35","doi-asserted-by":"crossref","unstructured":"Tsai, S.-H. et al. Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells. PLoS ONE 7 (2012).","DOI":"10.1371\/journal.pone.0041065"},{"key":"55383_CR36","doi-asserted-by":"publisher","first-page":"3003","DOI":"10.1158\/1078-0432.CCR-05-2085","volume":"12","author":"A Yano","year":"2006","unstructured":"Yano, A., Fujii, Y., Iwai, A., Kageyama, Y. & Kihara, K. Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 12, 3003\u20133009 (2006).","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"55383_CR37","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1007\/s00280-016-3030-x","volume":"77","author":"F Shang","year":"2016","unstructured":"Shang, F. et al. The anti-angiogenic effect of dexamethasone in a murine hepatocellular carcinoma model by augmentation of gluconeogenesis pathway in malignant cells. Cancer Chemother. Pharmacol. 77, 1087\u20131096 (2016).","journal-title":"Cancer Chemother. Pharmacol."},{"key":"55383_CR38","doi-asserted-by":"publisher","first-page":"e57374","DOI":"10.1371\/journal.pone.0057374","volume":"8","author":"MA Hegeman","year":"2013","unstructured":"Hegeman, M. A. et al. Dexamethasone Attenuates VEGF Expression and Inflammation but Not Barrier Dysfunction in a Murine Model of Ventilator\u2013Induced Lung Injury. PLOS ONE 8, e57374 (2013).","journal-title":"PLOS ONE"},{"key":"55383_CR39","unstructured":"A Novel, Non-Angiogenic, Mechanism of Vegf: Stimulation of Keratinocyte and Fibroblast Migration | Request PDF. ResearchGate Available at, https:\/\/www.researchgate.net\/publication\/284477029_A_Novel_Non-Angiogenic_Mechanism_of_Vegf_Stimulation_of_Keratinocyte_and_Fibroblast_Migration. (Accessed: 20th February 2019)."},{"key":"55383_CR40","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/S0002-9440(10)65282-0","volume":"154","author":"A Rivard","year":"1999","unstructured":"Rivard, A. et al. Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am. J. Pathol. 154, 355\u2013363 (1999).","journal-title":"Am. J. Pathol."},{"key":"55383_CR41","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/jcb.22542","volume":"110","author":"DP Trebec\u2010Reynolds","year":"2010","unstructured":"Trebec\u2010Reynolds, D. P., Voronov, I., Heersche, J. N. M. & Manolson, M. F. VEGF-A expression in osteoclasts is regulated by NF-\u03baB induction of HIF-1\u03b1. J. Cell. Biochem. 110, 343\u2013351 (2010).","journal-title":"J. Cell. Biochem."},{"key":"55383_CR42","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.3727\/096368912X638937","volume":"21","author":"C Seebach","year":"2012","unstructured":"Seebach, C., Henrich, D., Wilhelm, K., Barker, J. H. & Marzi, I. Endothelial progenitor cells improve directly and indirectly early vascularization of mesenchymal stem cell-driven bone regeneration in a critical bone defect in rats. Cell Transplant. 21, 1667\u20131677 (2012).","journal-title":"Cell Transplant."},{"key":"55383_CR43","doi-asserted-by":"publisher","first-page":"1961","DOI":"10.1089\/ten.tea.2009.0715","volume":"16","author":"C Seebach","year":"2010","unstructured":"Seebach, C. et al. Endothelial progenitor cells and mesenchymal stem cells seeded onto beta-TCP granules enhance early vascularization and bone healing in a critical-sized bone defect in rats. Tissue Eng. Part A 16, 1961\u20131970 (2010).","journal-title":"Tissue Eng. Part A"},{"key":"55383_CR44","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1089\/ten.teb.2013.0511","volume":"20","author":"R Kuroda","year":"2014","unstructured":"Kuroda, R. et al. Clinical impact of circulating CD34-positive cells on bone regeneration and healing. Tissue Eng. Part B Rev. 20, 190\u2013199 (2014).","journal-title":"Tissue Eng. Part B Rev."},{"key":"55383_CR45","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1186\/s40425-018-0371-5","volume":"6","author":"AJ Giles","year":"2018","unstructured":"Giles, A. J. et al. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J. Immunother. Cancer 6, 51 (2018).","journal-title":"J. Immunother. Cancer"},{"key":"55383_CR46","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.archoralbio.2016.04.007","volume":"68","author":"Y Liang","year":"2016","unstructured":"Liang, Y. et al. Endothelial progenitors enhanced the osteogenic capacities of mesenchymal stem cells in vitro and in a rat alveolar bone defect model. Arch. Oral Biol. 68, 123\u2013130 (2016).","journal-title":"Arch. Oral Biol."},{"key":"55383_CR47","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1359\/jbmr.2003.18.8.1404","volume":"18","author":"X Yu","year":"2003","unstructured":"Yu, X., Huang, Y., Collin-Osdoby, P. & Osdoby, P. Stromal cell-derived factor-1 (SDF-1) recruits osteoclast precursors by inducing chemotaxis, matrix metalloproteinase-9 (MMP-9) activity, and collagen transmigration. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 18, 1404\u20131418 (2003).","journal-title":"J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res."},{"key":"55383_CR48","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1161\/STROKEAHA.117.019346","volume":"49","author":"Maki Takakuni","year":"2018","unstructured":"Maki Takakuni et al. Endothelial Progenitor Cell Secretome and Oligovascular Repair in a Mouse Model of Prolonged Cerebral Hypoperfusion. Stroke 49, 1003\u20131010 (2018).","journal-title":"Stroke"},{"key":"55383_CR49","doi-asserted-by":"publisher","first-page":"e95731","DOI":"10.1371\/journal.pone.0095731","volume":"9","author":"SD Santo","year":"2014","unstructured":"Santo, S. D., Seiler, S., Fuchs, A.-L., Staudigl, J. & Widmer, H. R. The Secretome of Endothelial Progenitor Cells Promotes Brain Endothelial Cell Activity through PI3-Kinase and MAP-Kinase. PLOS ONE 9, e95731 (2014).","journal-title":"PLOS ONE"},{"key":"55383_CR50","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.3727\/096368910X557164","volume":"20","author":"M Bouchentouf","year":"2011","unstructured":"Bouchentouf, M. et al. A novel and simplified method of culture of human blood-derived early endothelial progenitor cells for the treatment of ischemic vascular disease. Cell Transplant. 20, 1431\u20131443 (2011).","journal-title":"Cell Transplant."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55383-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55383-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55383-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,28]],"date-time":"2024-07-28T12:14:22Z","timestamp":1722168862000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55383-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,11]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["55383"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-55383-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,11]]},"assertion":[{"value":"19 May 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 November 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"18896"}}