{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T09:40:04Z","timestamp":1792662004931,"version":"4.5.0"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2016,8,22]],"date-time":"2016-08-22T00:00:00Z","timestamp":1471824000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2016,9]]},"DOI":"10.1038\/nm.4154","type":"journal-article","created":{"date-parts":[[2016,8,22]],"date-time":"2016-08-22T16:55:24Z","timestamp":1471884924000},"page":"1050-1055","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":104,"title":["3K3A\u2013activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice"],"prefix":"10.1038","volume":"22","author":[{"given":"Yaoming","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanket V","family":"Rege","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Si","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H","family":"Griffin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5498-4303","authenticated-orcid":false,"given":"Steven A","family":"Goldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6802-8232","authenticated-orcid":false,"given":"Berislav V","family":"Zlokovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,8,22]]},"reference":[{"key":"BFnm4154_CR1","doi-asserted-by":"publisher","first-page":"2898","DOI":"10.1182\/blood-2015-02-355974","volume":"125","author":"JH Griffin","year":"2015","unstructured":"Griffin, J.H., Zlokovic, B.V. & Mosnier, L.O. Activated protein C: biased for translation. Blood 125, 2898\u20132907 (2015).","journal-title":"Blood"},{"key":"BFnm4154_CR2","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/nm826","volume":"9","author":"T Cheng","year":"2003","unstructured":"Cheng, T. et al. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat. Med. 9, 338\u2013342 (2003).","journal-title":"Nat. Med."},{"key":"BFnm4154_CR3","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1038\/nm1498","volume":"12","author":"T Cheng","year":"2006","unstructured":"Cheng, T. et al. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat. Med. 12, 1278\u20131285 (2006).","journal-title":"Nat. Med."},{"key":"BFnm4154_CR4","doi-asserted-by":"publisher","first-page":"12788","DOI":"10.1523\/JNEUROSCI.3485-08.2008","volume":"28","author":"M Thiyagarajan","year":"2008","unstructured":"Thiyagarajan, M., Fern\u00e1ndez, J.A., Lane, S.M., Griffin, J.H. & Zlokovic, B.V. Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. J. Neurosci. 28, 12788\u201312797 (2008).","journal-title":"J. Neurosci."},{"key":"BFnm4154_CR5","doi-asserted-by":"publisher","first-page":"2444","DOI":"10.1161\/STROKEAHA.112.658997","volume":"43","author":"Y Wang","year":"2012","unstructured":"Wang, Y. et al. An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents. Stroke 43, 2444\u20132449 (2012).","journal-title":"Stroke"},{"key":"BFnm4154_CR6","doi-asserted-by":"publisher","first-page":"3529","DOI":"10.1161\/STROKEAHA.113.003350","volume":"44","author":"Y Wang","year":"2013","unstructured":"Wang, Y. et al. Activated protein C analog protects from ischemic stroke and extends the therapeutic window of tissue-type plasminogen activator in aged female mice and hypertensive rats. Stroke 44, 3529\u20133536 (2013).","journal-title":"Stroke"},{"key":"BFnm4154_CR7","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.brainres.2010.05.075","volume":"1347","author":"CT Walker","year":"2010","unstructured":"Walker, C.T. et al. Activated protein C analog with reduced anticoagulant activity improves functional recovery and reduces bleeding risk following controlled cortical impact. Brain Res. 1347, 125\u2013131 (2010).","journal-title":"Brain Res."},{"key":"BFnm4154_CR8","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1038\/nature06559","volume":"451","author":"MH Han","year":"2008","unstructured":"Han, M.H. et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451, 1076\u20131081 (2008).","journal-title":"Nature"},{"key":"BFnm4154_CR9","doi-asserted-by":"publisher","first-page":"E1035","DOI":"10.1073\/pnas.1401595111","volume":"111","author":"EA Winkler","year":"2014","unstructured":"Winkler, E.A. et al. Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc. Natl. Acad. Sci. USA 111, E1035\u2013E1042 (2014).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFnm4154_CR10","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1172\/JCI112902","volume":"79","author":"FB Taylor Jr.","year":"1987","unstructured":"Taylor, F.B. Jr. et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J. Clin. Invest. 79, 918\u2013925 (1987).","journal-title":"J. Clin. Invest."},{"key":"BFnm4154_CR11","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/s00281-011-0284-6","volume":"34","author":"CT Esmon","year":"2012","unstructured":"Esmon, C.T. Protein C anticoagulant system\u2014anti-inflammatory effects. Semin. Immunopathol. 34, 127\u2013132 (2012).","journal-title":"Semin. Immunopathol."},{"key":"BFnm4154_CR12","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1161\/ATVBAHA.109.188656","volume":"29","author":"STBG Loubele","year":"2009","unstructured":"Loubele, S.T.B.G. et al. Activated protein C protects against myocardial ischemia\/reperfusion injury via inhibition of apoptosis and inflammation. Arterioscler. Thromb. Vasc. Biol. 29, 1087\u20131092 (2009).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"BFnm4154_CR13","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1038\/ki.2009.255","volume":"76","author":"SW Park","year":"2009","unstructured":"Park, S.W., Chen, S.W.C., Kim, M., D'Agati, V.D. & Lee, H.T. Human activated protein C attenuates both hepatic and renal injury caused by hepatic ischemia and reperfusion injury in mice. Kidney Int. 76, 739\u2013750 (2009).","journal-title":"Kidney Int."},{"key":"BFnm4154_CR14","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1038\/nm1667","volume":"13","author":"B Isermann","year":"2007","unstructured":"Isermann, B. et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat. Med. 13, 1349\u20131358 (2007).","journal-title":"Nat. Med."},{"key":"BFnm4154_CR15","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1038\/nm.2813","volume":"18","author":"H Geiger","year":"2012","unstructured":"Geiger, H. et al. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat. Med. 18, 1123\u20131129 (2012).","journal-title":"Nat. Med."},{"key":"BFnm4154_CR16","doi-asserted-by":"publisher","first-page":"7479","DOI":"10.2174\/1381612819666131230131454","volume":"19","author":"P Lyden","year":"2013","unstructured":"Lyden, P. et al. Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. Curr. Pharm. Des. 19, 7479\u20137485 (2013).","journal-title":"Curr. Pharm. Des."},{"key":"BFnm4154_CR17","unstructured":"Safety evaluation of 3K3A-APC in ischemic stroke (RHAPSODY); 2014 August 18; \n                    https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02222714\n                    \n                  ."},{"key":"BFnm4154_CR18","doi-asserted-by":"publisher","first-page":"14635","DOI":"10.1523\/JNEUROSCI.1729-10.2010","volume":"30","author":"S Wang","year":"2010","unstructured":"Wang, S. et al. Prospective identification, isolation, and profiling of a telomerase-expressing subpopulation of human neural stem cells, using sox2 enhancer-directed fluorescence-activated cell sorting. J. Neurosci. 30, 14635\u201314648 (2010).","journal-title":"J. Neurosci."},{"key":"BFnm4154_CR19","doi-asserted-by":"publisher","first-page":"6181","DOI":"10.1523\/JNEUROSCI.4491-12.2013","volume":"33","author":"H Guo","year":"2013","unstructured":"Guo, H. et al. An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway. J. Neurosci. 33, 6181\u20136190 (2013).","journal-title":"J. Neurosci."},{"issue":"Suppl. 1","key":"BFnm4154_CR20","doi-asserted-by":"publisher","first-page":"S107","DOI":"10.1161\/STROKEAHA.112.679605","volume":"44","author":"SI Savitz","year":"2013","unstructured":"Savitz, S.I. Cell therapies: careful translation from animals to patients. Stroke 44 (Suppl. 1), S107\u2013S109 (2013).","journal-title":"Stroke"},{"key":"BFnm4154_CR21","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1038\/nbt0901-843","volume":"19","author":"HM Keyoung","year":"2001","unstructured":"Keyoung, H.M. et al. High-yield selection and extraction of two promoter-defined phenotypes of neural stem cells from the fetal human brain. Nat. Biotechnol. 19, 843\u2013850 (2001).","journal-title":"Nat. Biotechnol."},{"key":"BFnm4154_CR22","doi-asserted-by":"publisher","first-page":"2645","DOI":"10.1161\/STROKEAHA.111.618850","volume":"42","author":"GW Albers","year":"2011","unstructured":"Albers, G.W. et al. Stroke Treatment Academic Industry Roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies. Stroke 42, 2645\u20132650 (2011).","journal-title":"Stroke"},{"key":"BFnm4154_CR23","doi-asserted-by":"publisher","first-page":"11839","DOI":"10.1073\/pnas.0404474101","volume":"101","author":"S Kelly","year":"2004","unstructured":"Kelly, S. et al. Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proc. Natl. Acad. Sci. USA 101, 11839\u201311844 (2004).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFnm4154_CR24","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1172\/JCI200420622","volume":"114","author":"A Taguchi","year":"2004","unstructured":"Taguchi, A. et al. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J. Clin. Invest. 114, 330\u2013338 (2004).","journal-title":"J. Clin. Invest."},{"key":"BFnm4154_CR25","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1038\/nm1387","volume":"12","author":"B-Q Zhao","year":"2006","unstructured":"Zhao, B.-Q. et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat. Med. 12, 441\u2013445 (2006).","journal-title":"Nat. Med."},{"key":"BFnm4154_CR26","first-page":"578","volume":"7","author":"Z Wen","year":"2012","unstructured":"Wen, Z. & Wang, P. Recombinant human erythropoietin increases cerebral cortical width index and neurogenesis following ischemic stroke. Neural Regen. Res. 7, 578\u2013582 (2012).","journal-title":"Neural Regen. Res."},{"key":"BFnm4154_CR27","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.brainres.2013.02.023","volume":"1507","author":"Y Wang","year":"2013","unstructured":"Wang, Y. et al. Activated protein C analog promotes neurogenesis and improves neurological outcome after focal ischemic stroke in mice via protease activated receptor 1. Brain Res. 1507, 97\u2013104 (2013).","journal-title":"Brain Res."},{"key":"BFnm4154_CR28","doi-asserted-by":"publisher","first-page":"3255","DOI":"10.1172\/JCI42957","volume":"120","author":"M Abematsu","year":"2010","unstructured":"Abematsu, M. et al. Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury. J. Clin. Invest. 120, 3255\u20133266 (2010).","journal-title":"J. Clin. Invest."},{"key":"BFnm4154_CR29","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1038\/nmeth.1398","volume":"6","author":"L Tian","year":"2009","unstructured":"Tian, L. et al. Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators. Nat. Methods 6, 875\u2013881 (2009).","journal-title":"Nat. Methods"},{"key":"BFnm4154_CR30","doi-asserted-by":"publisher","first-page":"15931","DOI":"10.1523\/JNEUROSCI.1818-14.2014","volume":"34","author":"MP Vanni","year":"2014","unstructured":"Vanni, M.P. & Murphy, T.H. Mesoscale transcranial spontaneous activity mapping in GCaMP3 transgenic mice reveals extensive reciprocal connections between areas of somatomotor cortex. J. Neurosci. 34, 15931\u201315946 (2014).","journal-title":"J. Neurosci."},{"key":"BFnm4154_CR31","doi-asserted-by":"publisher","first-page":"3131","DOI":"10.1523\/JNEUROSCI.4469-11.2012","volume":"32","author":"HA Zariwala","year":"2012","unstructured":"Zariwala, H.A. et al. A Cre-dependent GCaMP3 reporter mouse for neuronal imaging in vivo. J. Neurosci. 32, 3131\u20133141 (2012).","journal-title":"J. Neurosci."},{"key":"BFnm4154_CR32","first-page":"193","volume":"7","author":"D Li","year":"2013","unstructured":"Li, D., Agulhon, C., Schmidt, E., Oheim, M. & Ropert, N. New tools for investigating astrocyte-to-neuron communication. Front. Cell. Neurosci. 7, 193 (2013).","journal-title":"Front. Cell. Neurosci."},{"key":"BFnm4154_CR33","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1002\/stem.584","volume":"29","author":"N Horie","year":"2011","unstructured":"Horie, N. et al. Transplanted stem cell-secreted vascular endothelial growth factor effects poststroke recovery, inflammation, and vascular repair. Stem Cells 29, 274\u2013285 (2011).","journal-title":"Stem Cells"},{"key":"BFnm4154_CR34","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/nature02604","volume":"430","author":"AE Wurmser","year":"2004","unstructured":"Wurmser, A.E. et al. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature 430, 350\u2013356 (2004).","journal-title":"Nature"},{"key":"BFnm4154_CR35","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.stem.2016.01.012","volume":"18","author":"SA Goldman","year":"2016","unstructured":"Goldman, S.A. Stem and progenitor cell-based therapy of the central nervous system: hopes, hype, and wishful thinking. Cell Stem Cell 18, 174\u2013188 (2016).","journal-title":"Cell Stem Cell"},{"key":"BFnm4154_CR36","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1111\/imr.12154","volume":"258","author":"EJ Fuchs","year":"2014","unstructured":"Fuchs, E.J. Transplantation tolerance: from theory to clinic. Immunol. Rev. 258, 64\u201379 (2014).","journal-title":"Immunol. Rev."},{"key":"BFnm4154_CR37","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1161\/01.STR.25.1.153","volume":"25","author":"CG Markgraf","year":"1994","unstructured":"Markgraf, C.G. et al. Recovery of sensorimotor function after distal middle cerebral artery photothrombotic occlusion in rats. Stroke 25, 153\u2013159 (1994).","journal-title":"Stroke"},{"key":"BFnm4154_CR38","doi-asserted-by":"publisher","first-page":"4215","DOI":"10.2174\/138161212802430413","volume":"18","author":"PD Williams","year":"2012","unstructured":"Williams, P.D. et al. Preclinical safety and pharmacokinetic profile of 3K3A-APC, a novel, modified activated Protein C for ischemic stroke. Curr. Pharm. Des. 18, 4215\u20134222 (2012).","journal-title":"Curr. Pharm. Des."},{"key":"BFnm4154_CR39","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1038\/nprot.2009.125","volume":"4","author":"V Bouet","year":"2009","unstructured":"Bouet, V. et al. The adhesive removal test: a sensitive method to assess sensorimotor deficits in mice. Nat. Protoc. 4, 1560\u20131564 (2009).","journal-title":"Nat. Protoc."},{"key":"BFnm4154_CR40","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1037\/a0014157","volume":"123","author":"T Freret","year":"2009","unstructured":"Freret, T. et al. Behavioral deficits after distal focal cerebral ischemia in mice: Usefulness of adhesive removal test. Behav. Neurosci. 123, 224\u2013230 (2009).","journal-title":"Behav. Neurosci."},{"key":"BFnm4154_CR41","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1093\/jb\/mvj216","volume":"140","author":"N Furukawa","year":"2006","unstructured":"Furukawa, N., Saito, M., Hakoshima, T. & Kohno, K. A diphtheria toxin receptor deficient in epidermal growth factor-like biological activity. J. Biochem. 140, 831\u2013841 (2006).","journal-title":"J. Biochem."},{"key":"BFnm4154_CR42","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1038\/90795","volume":"19","author":"M Saito","year":"2001","unstructured":"Saito, M. et al. Diphtheria toxin receptor-mediated conditional and targeted cell ablation in transgenic mice. Nat. Biotechnol. 19, 746\u2013750 (2001).","journal-title":"Nat. Biotechnol."},{"key":"BFnm4154_CR43","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1126\/science.291.5504.657","volume":"291","author":"EM Ullian","year":"2001","unstructured":"Ullian, E.M., Sapperstein, S.K., Christopherson, K.S. & Barres, B.A. Control of synapse number by glia. Science 291, 657\u2013661 (2001).","journal-title":"Science"}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/nm.4154.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/nm.4154","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/nm.4154.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T22:58:20Z","timestamp":1684450700000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/nm.4154"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,22]]},"references-count":43,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2016,9]]}},"alternative-id":["BFnm4154"],"URL":"https:\/\/doi.org\/10.1038\/nm.4154","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,22]]},"assertion":[{"value":"31 August 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 August 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"B.V.Z. is a founder of ZZ Biotech LLC, a biotechnology company with a mission to develop APC and its functional mutants for the treatment of stroke and other neurological disorders. J.H.G. is a consultant for ZZ Biotech LLC and an inventor for some uses of 3K3A-APC.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}