{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T22:20:33Z","timestamp":1789510833591,"version":"build-2803163510"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100010256","name":"Guangzhou Municipal Science and Technology Project","doi-asserted-by":"publisher","award":["2024A03J0690"],"award-info":[{"award-number":["2024A03J0690"]}],"id":[{"id":"10.13039\/501100010256","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010843","name":"Guangzhou Science, Technology and Innovation Commission","doi-asserted-by":"publisher","award":["2023A03J0693"],"award-info":[{"award-number":["2023A03J0693"]}],"id":[{"id":"10.13039\/501100010843","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010256","name":"Guangzhou Municipal Science and Technology Project","doi-asserted-by":"publisher","award":["2024A03J0634"],"award-info":[{"award-number":["2024A03J0634"]}],"id":[{"id":"10.13039\/501100010256","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2022A1515010307"],"award-info":[{"award-number":["2022A1515010307"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2024A1515012050"],"award-info":[{"award-number":["2024A1515012050"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Stem Cell Res Ther"],"DOI":"10.1186\/s13287-025-04449-5","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T13:14:05Z","timestamp":1752671645000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Endothelial cell-secreted bone targeting exosomes promote angiogenesis coupling with osteogenesis via the PERK-ATF4-CRELD2 pathway"],"prefix":"10.1186","volume":"16","author":[{"given":"Zhilong","family":"Pi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingyue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3942-8739","authenticated-orcid":false,"given":"Renkai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"issue":"3","key":"4449_CR1","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/s41419-020-2377-4","volume":"11","author":"R Wang","year":"2020","unstructured":"Wang R, Zhang H, Ding W, Fan Z, Ji B, Ding C, Ji F, Tang H. miR-143 promotes angiogenesis and osteoblast differentiation by targeting HDAC7. Cell Death Dis. 2020;11(3):179.","journal-title":"Cell Death Dis"},{"key":"4449_CR2","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1146\/annurev-cellbio-111315-124936","volume":"32","author":"SK Ramasamy","year":"2016","unstructured":"Ramasamy SK, Kusumbe AP, Itkin T, Gur-Cohen S, Lapidot T, Adams RH. Regulation of hematopoiesis and osteogenesis by blood vessel-derived signals. Annu Rev Cell Dev Biol. 2016;32:649\u201375.","journal-title":"Annu Rev Cell Dev Biol"},{"key":"4449_CR3","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.796227","volume":"10","author":"X Lin","year":"2022","unstructured":"Lin X, Xu F, Zhang KW, Qiu WX, Zhang H, Hao Q, Li M, Deng XN, Tian Y, Chen ZH, et al. Acacetin prevents bone loss by disrupting osteoclast formation and promoting type H vessel formation in ovariectomy-induced osteoporosis. Front Cell Dev Biol. 2022;10: 796227.","journal-title":"Front Cell Dev Biol"},{"issue":"7","key":"4449_CR4","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13403","volume":"56","author":"L Gao","year":"2023","unstructured":"Gao L, Chen W, Li L, Li J, Kongling W, Zhang Y, Yang X, Zhao Y, Bai J, Wang F. Targeting soluble epoxide hydrolase promotes osteogenic-angiogenic coupling via activating SLIT3\/HIF-1alpha signalling pathway. Cell Prolif. 2023;56(7): e13403.","journal-title":"Cell Prolif"},{"issue":"4","key":"4449_CR5","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1007\/s00592-023-02224-7","volume":"61","author":"H Lei","year":"2024","unstructured":"Lei H, Guo W, Pan Y, Lu X, Zhang Q. LOX-1 regulation of H-type vascular endothelial cell regeneration in hyperglycemia. Acta Diabetol. 2024;61(4):515\u201324.","journal-title":"Acta Diabetol"},{"key":"4449_CR6","doi-asserted-by":"publisher","first-page":"6910312","DOI":"10.1155\/2020\/6910312","volume":"2020","author":"M Tobeiha","year":"2020","unstructured":"Tobeiha M, Moghadasian MH, Amin N, Jafarnejad S. RANKL\/RANK\/OPG pathway: a mechanism involved in exercise-induced bone remodeling. Biomed Res Int. 2020;2020:6910312.","journal-title":"Biomed Res Int"},{"issue":"43","key":"4449_CR7","doi-asserted-by":"publisher","first-page":"2310282","DOI":"10.1002\/advs.202310282","volume":"11","author":"C Kan","year":"2024","unstructured":"Kan C, Tan Z, Wang H, Wang W, Yang J, Zhang Y, Zheng H. Spatiotemporal analysis of mesenchymal stem cells fate determination by inflammatory niche following soft tissue injury at a single-cell level. Adv Sci. 2024;11(43):2310282.","journal-title":"Adv Sci"},{"issue":"1","key":"4449_CR8","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1186\/s13287-022-03142-1","volume":"13","author":"Y Bi","year":"2022","unstructured":"Bi Y, Qiao X, Liu Q, Song S, Zhu K, Qiu X, Zhang X, Jia C, Wang H, Yang Z, et al. Systemic proteomics and miRNA profile analysis of exosomes derived from human pluripotent stem cells. Stem Cell Res Ther. 2022;13(1):449.","journal-title":"Stem Cell Res Ther"},{"issue":"9","key":"4449_CR9","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1016\/j.cmet.2021.08.006","volume":"33","author":"R Isaac","year":"2021","unstructured":"Isaac R, Reis FCG, Ying W, Olefsky JM. Exosomes as mediators of intercellular crosstalk in metabolism. Cell Metab. 2021;33(9):1744\u201362.","journal-title":"Cell Metab"},{"issue":"9","key":"4449_CR10","first-page":"2905","volume":"6","author":"Y Hu","year":"2021","unstructured":"Hu Y, Li X, Zhang Q, Gu Z, Luo Y, Guo J, Wang X, Jing Y, Chen X, Su J. Exosome-guided bone targeted delivery of Antagomir-188 as an anabolic therapy for bone loss. Bioact Mater. 2021;6(9):2905\u201313.","journal-title":"Bioact Mater"},{"key":"4449_CR11","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.804049","volume":"9","author":"X Liu","year":"2021","unstructured":"Liu X, Shao Y, Tu J, Sun J, Dong B, Wang Z, Zhou J, Chen L, Tao J, Chen J. TMAO-activated hepatocyte-derived exosomes impair angiogenesis via repressing CXCR4. Front Cell Dev Biol. 2021;9: 804049.","journal-title":"Front Cell Dev Biol"},{"key":"4449_CR12","doi-asserted-by":"publisher","first-page":"1117414","DOI":"10.3389\/fendo.2023.1117414","volume":"14","author":"Q Tang","year":"2023","unstructured":"Tang Q, Liu Q, Li Y, Mo L, He J. CRELD2, endoplasmic reticulum stress, and human diseases. Front Endocrinol (Lausanne). 2023;14:1117414.","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"10","key":"4449_CR13","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202002713RR","volume":"35","author":"P Kern","year":"2021","unstructured":"Kern P, Balzer NR, Blank N, Cygon C, Wunderling K, Bender F, Frolov A, Sowa JP, Bonaguro L, Ulas T, et al. Creld2 function during unfolded protein response is essential for liver metabolism homeostasis. FASEB J. 2021;35(10): e21939.","journal-title":"FASEB J"},{"issue":"2","key":"4449_CR14","doi-asserted-by":"publisher","DOI":"10.1016\/j.acthis.2021.151679","volume":"123","author":"V Lasic","year":"2021","unstructured":"Lasic V, Kosovic I, Juric M, Racetin A, Curcic J, Solic I, Lozic M, Filipovic N, Soljic V, Martinovic V, et al. GREB1L, CRELD2 and ITGA10 expression in the human developmental and postnatal kidneys: an immunohistochemical study. Acta Histochem. 2021;123(2): 151679.","journal-title":"Acta Histochem"},{"issue":"7","key":"4449_CR15","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1038\/s41556-020-0523-y","volume":"22","author":"ST Boyle","year":"2020","unstructured":"Boyle ST, Poltavets V, Kular J, Pyne NT, Sandow JJ, Lewis AC, Murphy KJ, Kolesnikoff N, Moretti PAB, Tea MN, et al. ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism. Nat Cell Biol. 2020;22(7):882\u201395.","journal-title":"Nat Cell Biol"},{"issue":"1","key":"4449_CR16","doi-asserted-by":"publisher","first-page":"13884","DOI":"10.1038\/s41598-022-17347-0","volume":"12","author":"A Duxfield","year":"2022","unstructured":"Duxfield A, Munkley J, Briggs MD, Dennis EP. CRELD2 is a novel modulator of calcium release and calcineurin-NFAT signalling during osteoclast differentiation. Sci Rep. 2022;12(1):13884.","journal-title":"Sci Rep"},{"key":"4449_CR17","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.627718","volume":"12","author":"B Li","year":"2021","unstructured":"Li B, Wang R, Huang X, Ou Y, Jia Z, Lin S, Zhang Y, Xia H, Chen B. Extracorporeal shock wave therapy promotes osteogenic differentiation in a rabbit osteoporosis model. Front Endocrinol (Lausanne). 2021;12: 627718.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"4449_CR18","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.666140","volume":"12","author":"H Zhang","year":"2021","unstructured":"Zhang H, Wang R, Wang G, Zhang B, Wang C, Li D, Ding C, Wei Q, Fan Z, Tang H, et al. Single-cell RNA sequencing reveals b cells are important regulators in fracture healing. Front Endocrinol (Lausanne). 2021;12: 666140.","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"9","key":"4449_CR19","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.7150\/thno.22144","volume":"8","author":"J Huang","year":"2018","unstructured":"Huang J, Yin H, Rao SS, Xie PL, Cao X, Rao T, Liu SY, Wang ZX, Cao J, Hu Y, et al. Harmine enhances type H vessel formation and prevents bone loss in ovariectomized mice. Theranostics. 2018;8(9):2435\u201346.","journal-title":"Theranostics"},{"issue":"1","key":"4449_CR20","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1186\/s13018-023-04166-w","volume":"18","author":"B Chen","year":"2023","unstructured":"Chen B, Luo Y, Zhang Z, Lin S, Wang R, Li B. Extracorporeal shock wave therapy inhibits osteoclast differentiation by targeting NF-kappaB signaling pathway. J Orthop Surg Res. 2023;18(1):805.","journal-title":"J Orthop Surg Res"},{"issue":"25","key":"4449_CR21","doi-asserted-by":"publisher","first-page":"5262","DOI":"10.1093\/hmg\/ddt383","volume":"22","author":"CL Hartley","year":"2013","unstructured":"Hartley CL, Edwards S, Mullan L, Bell PA, Fresquet M, Boot-Handford RP, Briggs MD. Armet\/Manf and Creld2 are components of a specialized ER stress response provoked by inappropriate formation of disulphide bonds: implications for genetic skeletal diseases. Hum Mol Genet. 2013;22(25):5262\u201375.","journal-title":"Hum Mol Genet"},{"issue":"5","key":"4449_CR22","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1016\/S1097-2765(00)00108-8","volume":"6","author":"HP Harding","year":"2000","unstructured":"Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6(5):1099\u2013108.","journal-title":"Mol Cell"},{"issue":"1","key":"4449_CR23","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1007\/s00223-023-01096-x","volume":"113","author":"S Iyer","year":"2023","unstructured":"Iyer S, Adams DJ. Bone and the unfolded protein response: in sickness and in health. Calcif Tissue Int. 2023;113(1):96\u2013109.","journal-title":"Calcif Tissue Int"},{"key":"4449_CR24","doi-asserted-by":"publisher","first-page":"7923","DOI":"10.2147\/IJN.S444582","volume":"18","author":"J Tian","year":"2023","unstructured":"Tian J, Han Z, Song D, Peng Y, Xiong M, Chen Z, Duan S, Zhang L. Engineered exosome for drug delivery: recent development and clinical applications. Int J Nanomed. 2023;18:7923\u201340.","journal-title":"Int J Nanomed"},{"issue":"5","key":"4449_CR25","doi-asserted-by":"publisher","first-page":"499","DOI":"10.4252\/wjsc.v16.i5.499","volume":"16","author":"S Zhang","year":"2024","unstructured":"Zhang S, Lu C, Zheng S, Hong G. Hydrogel loaded with bone marrow stromal cell-derived exosomes promotes bone regeneration by inhibiting inflammatory responses and angiogenesis. World J Stem Cells. 2024;16(5):499\u2013511.","journal-title":"World J Stem Cells"},{"issue":"1","key":"4449_CR26","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s13287-020-1562-9","volume":"11","author":"L Zhang","year":"2020","unstructured":"Zhang L, Jiao G, Ren S, Zhang X, Li C, Wu W, Wang H, Liu H, Zhou H, Chen Y. Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion. Stem Cell Res Ther. 2020;11(1):38.","journal-title":"Stem Cell Res Ther"},{"issue":"5","key":"4449_CR27","first-page":"4463","volume":"17","author":"SL Li","year":"2019","unstructured":"Li SL, An N, Liu B, Wang SY, Wang JJ, Ye Y. Exosomes from LNCaP cells promote osteoblast activity through miR-375 transfer. Oncol Lett. 2019;17(5):4463\u201373.","journal-title":"Oncol Lett"},{"issue":"8","key":"4449_CR28","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1002\/jbmr.4010","volume":"35","author":"EP Dennis","year":"2020","unstructured":"Dennis EP, Edwards SM, Jackson RM, Hartley CL, Tsompani D, Capulli M, Teti A, Boot-Handford RP, Young DA, Pirog KA, et al. CRELD2 is a novel LRP1 chaperone that regulates noncanonical WNT signaling in skeletal development. J Bone Miner Res. 2020;35(8):1452\u201369.","journal-title":"J Bone Miner Res"},{"issue":"5","key":"4449_CR29","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.4049\/jimmunol.1701036","volume":"200","author":"JH Kim","year":"2018","unstructured":"Kim JH, Kim K, Kim I, Seong S, Nam KI, Kim KK, Kim N. Endoplasmic reticulum-bound transcription factor CREBH stimulates RANKL-induced osteoclastogenesis. J Immunol. 2018;200(5):1661\u201370.","journal-title":"J Immunol"},{"key":"4449_CR30","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.biopha.2018.05.030","volume":"104","author":"L Zhang","year":"2018","unstructured":"Zhang L, Bao D, Li P, Lu Z, Pang L, Chen Z, Guo H, Gao Z, Jin Q. Particle-induced SIRT1 downregulation promotes osteoclastogenesis and osteolysis through ER stress regulation. Biomed Pharmacother. 2018;104:300\u20136.","journal-title":"Biomed Pharmacother"},{"issue":"4","key":"4449_CR31","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1111\/jre.12232","volume":"50","author":"H Yamada","year":"2015","unstructured":"Yamada H, Nakajima T, Domon H, Honda T, Yamazaki K. Endoplasmic reticulum stress response and bone loss in experimental periodontitis in mice. J Periodontal Res. 2015;50(4):500\u20138.","journal-title":"J Periodontal Res"},{"issue":"4","key":"4449_CR32","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/nbt.1807","volume":"29","author":"L Alvarez-Erviti","year":"2011","unstructured":"Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341\u20135.","journal-title":"Nat Biotechnol"},{"issue":"1","key":"4449_CR33","doi-asserted-by":"publisher","first-page":"1440131","DOI":"10.1080\/20013078.2018.1440131","volume":"7","author":"Y Yang","year":"2018","unstructured":"Yang Y, Hong Y, Cho E, Kim GB, Kim IS. Extracellular vesicles as a platform for membrane-associated therapeutic protein delivery. J Extracell Vesicles. 2018;7(1):1440131.","journal-title":"J Extracell Vesicles"}],"container-title":["Stem Cell Research & Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-025-04449-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13287-025-04449-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-025-04449-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T12:22:03Z","timestamp":1757247723000},"score":1,"resource":{"primary":{"URL":"https:\/\/stemcellres.biomedcentral.com\/articles\/10.1186\/s13287-025-04449-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,16]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["4449"],"URL":"https:\/\/doi.org\/10.1186\/s13287-025-04449-5","relation":{},"ISSN":["1757-6512"],"issn-type":[{"value":"1757-6512","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,16]]},"assertion":[{"value":"1 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Medical Research Ethics Board of the General Hospital of Southern Theater Command of PLA (title: exosomal CRELD2 promotes angiogenesis and osteogenesis via the PERK-ATF4-CRELD2 pathway. Approval number: No. 2023110101. Date of approval: 20231101). All methods were carried out in accordance with relevant guidelines and regulations. HUVECs were purchased from a commercial vendor (Procell, China), which information and ethics can be found on its official website (Information and ethics can be found on its official website ().","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no conflicts of interest. The authors declare that they have not use AI-generated work in this manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"382"}}