{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:06:07Z","timestamp":1792109167846,"version":"4.4.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T00:00:00Z","timestamp":1598486400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T00:00:00Z","timestamp":1598486400000},"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":["Sig Transduct Target Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20099 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3\u2009\u00d7\u200910\n                    <jats:sup>7<\/jats:sup>\n                    cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO\n                    <jats:sub>2<\/jats:sub>\n                    \/FiO\n                    <jats:sub>2<\/jats:sub>\n                    ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12\u2009h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2\/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.\n                  <\/jats:p>","DOI":"10.1038\/s41392-020-00286-5","type":"journal-article","created":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T03:03:59Z","timestamp":1598497439000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":265,"title":["Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial"],"prefix":"10.1038","volume":"5","author":[{"given":"Fanping","family":"Meng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruonan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8126-8145","authenticated-orcid":false,"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junliang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianjun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Yuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8582-8012","authenticated-orcid":false,"given":"Jinwen","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmei","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunbao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Maeurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alimuddin","family":"Zumla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8043-6685","authenticated-orcid":false,"given":"Fu-Sheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,27]]},"reference":[{"key":"286_CR1","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1016\/S0140-6736(20)30920-X","volume":"395","author":"H Li","year":"2020","unstructured":"Li, H. et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet 395, 1517\u20131520 (2020).","journal-title":"Lancet"},{"key":"286_CR2","unstructured":"WHO. 2020. Coronavirus disease (COVID-19) Situation Reports https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/situation-reports. Accessed 7 July 2020."},{"key":"286_CR3","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1111\/jth.14768","volume":"18","author":"N Tang","year":"2020","unstructured":"Tang, N., Li, D., Wang, X. & Sun, Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J. Thromb. Haemost. 18, 844\u2013847 (2020).","journal-title":"J. Thromb. Haemost."},{"key":"286_CR4","doi-asserted-by":"publisher","unstructured":"Bian, X. & the COVID-19 Pathology Team. Autopsy of COVID-19 victims in China. Natl Sci. Rev. https:\/\/doi.org\/10.1093\/nsr\/nwaa123 (2020).","DOI":"10.1093\/nsr\/nwaa123"},{"key":"286_CR5","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1016\/S2213-2600(20)30076-X","volume":"8","author":"Z Xu","year":"2020","unstructured":"Xu, Z. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 8, 420\u2013422 (2020).","journal-title":"Lancet Respir. Med."},{"key":"286_CR6","doi-asserted-by":"publisher","first-page":"e35","DOI":"10.1016\/S0140-6736(20)30305-6","volume":"395","author":"A Zumla","year":"2020","unstructured":"Zumla, A. et al. Reducing mortality from 2019-nCoV: host-directed therapies should be an option. Lancet 395, e35\u2013e36 (2020).","journal-title":"Lancet"},{"key":"286_CR7","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1016\/j.stem.2018.05.004","volume":"22","author":"J Galipeau","year":"2018","unstructured":"Galipeau, J. & Sensebe, L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 22, 824\u2013833 (2018).","journal-title":"Cell Stem Cell"},{"key":"286_CR8","doi-asserted-by":"publisher","first-page":"682","DOI":"10.3390\/jcm9030682","volume":"3","author":"J Behnke","year":"2020","unstructured":"Behnke, J. et al. MSC based therapies-new perspectives for the injured lung. J. Clin. Med. 3, 682\u2013727 (2020).","journal-title":"J. Clin. Med."},{"key":"286_CR9","first-page":"557","volume":"16","author":"HM Lazarus","year":"1995","unstructured":"Lazarus, H. M. et al. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 16, 557\u2013564 (1995).","journal-title":"Bone Marrow Transplant."},{"key":"286_CR10","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1177\/0963689718787501","volume":"27","author":"HM Chuang","year":"2018","unstructured":"Chuang, H. M. et al. Mesenchymal stem cell therapy of pulmonary fibrosis: improvement with target combination. Cell Transplant. 27, 1581\u20131587 (2018).","journal-title":"Cell Transplant."},{"key":"286_CR11","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1111\/bjh.12545","volume":"163","author":"LM Ball","year":"2013","unstructured":"Ball, L. M. et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III-IV acute graft-versus-host disease. Br. J. Haematol. 163, 501\u2013509 (2013).","journal-title":"Br. J. Haematol."},{"key":"286_CR12","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/S2213-2600(14)70291-7","volume":"3","author":"JG Wilson","year":"2015","unstructured":"Wilson, J. G. et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir. Med. 3, 24\u201332 (2015).","journal-title":"Lancet Respir. Med."},{"key":"286_CR13","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/S2213-2600(18)30418-1","volume":"7","author":"MA Matthay","year":"2019","unstructured":"Matthay, M. A. et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir. Med. 7, 154\u2013162 (2019).","journal-title":"Lancet Respir. Med."},{"key":"286_CR14","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.ijid.2020.05.040","volume":"17","author":"A Zumla","year":"2020","unstructured":"Zumla, A. et al. Reducing mortality and morbidity in patients with severe COVID-19 disease by advancing ongoing trials of mesenchymal stromal (stem) cell (MSC) therapy -achieving global consensus and visibility for cellular host-directed therapies. Int. J. Infect. Dis. 17, 431\u2013439 (2020).","journal-title":"Int. J. Infect. Dis."},{"key":"286_CR15","doi-asserted-by":"publisher","first-page":"4410","DOI":"10.1128\/IAI.72.8.4410-4415.2004","volume":"72","author":"Y Zhang","year":"2004","unstructured":"Zhang, Y. et al. Analysis of serum cytokines in patients with severe acute respiratory syndrome. Infect. Immun. 72, 4410\u20134415 (2004).","journal-title":"Infect. Immun."},{"key":"286_CR16","first-page":"30272","volume":"28","author":"N Mangalmurti","year":"2020","unstructured":"Mangalmurti, N. & Hunter, C. A. Cytokine storms: understanding COVID-19. Immunity 28, 30272\u201330277 (2020).","journal-title":"Immunity"},{"key":"286_CR17","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/s41392-020-0190-2","volume":"5","author":"B Chen","year":"2020","unstructured":"Chen, B. et al. Overview of lethal human coronaviruses. Signal. Transduct. Target. Ther. 5, 89 (2020).","journal-title":"Signal. Transduct. Target. Ther."},{"key":"286_CR18","doi-asserted-by":"publisher","first-page":"1626","DOI":"10.3389\/fimmu.2017.01626","volume":"8","author":"P Lohan","year":"2017","unstructured":"Lohan, P. et al. Anti-donor immune responses elicited by allogeneic mesenchymal stem cells and their extracellular vesicles: are we still learning? Front. Immunol. 8, 1626 (2017).","journal-title":"Front. Immunol."},{"key":"286_CR19","doi-asserted-by":"publisher","first-page":"100249","DOI":"10.1016\/j.eclinm.2019.100249","volume":"19","author":"M Thompson","year":"2020","unstructured":"Thompson, M. et al. Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: an updated systematic review and meta-analysis. EClinicalMedicine 19, 100249 (2020).","journal-title":"EClinicalMedicine"},{"key":"286_CR20","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/1465-9921-15-39","volume":"15","author":"G Zheng","year":"2014","unstructured":"Zheng, G. et al. Treatment of aute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir. Res. 15, 39 (2014).","journal-title":"Respir. Res."},{"key":"286_CR21","doi-asserted-by":"publisher","first-page":"216","DOI":"10.14336\/AD.2020.0228","volume":"11","author":"Z Leng","year":"2020","unstructured":"Leng, Z. et al. Transplantation of ACE2 mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis. 11, 216\u2013228 (2020).","journal-title":"Aging Dis."},{"key":"286_CR22","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1097\/QAD.0b013e32835fab77","volume":"27","author":"Z Zhang","year":"2013","unstructured":"Zhang, Z. et al. Safety and immunological responses to human mesenchymal stem cell therapy in difficult-to-treat HIV-1-infected patients. AIDS 27, 1283\u20131293 (2013).","journal-title":"AIDS"},{"key":"286_CR23","doi-asserted-by":"publisher","first-page":"725","DOI":"10.5966\/sctm.2012-0034","volume":"1","author":"M Shi","year":"2012","unstructured":"Shi, M. et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl. Med. 1, 725\u2013731 (2012).","journal-title":"Stem Cells Transl. Med."},{"key":"286_CR24","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1038\/mi.2012.2","volume":"5","author":"O Dienz","year":"2012","unstructured":"Dienz, O. et al. Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung. Mucosal Immunol. 5, 258\u2013266 (2012).","journal-title":"Mucosal Immunol."},{"key":"286_CR25","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","volume":"395","author":"C Huang","year":"2020","unstructured":"Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497\u2013506 (2020).","journal-title":"Lancet"},{"key":"286_CR26","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/cmi.2012.40","volume":"9","author":"H Fan","year":"2012","unstructured":"Fan, H. et al. Pre-treatment with IL-1\u03b2 enhances the efficacy of MSC transplantation in DSS-induced colitis. Cell. Mol. Immunol. 9, 473\u2013481 (2012).","journal-title":"Cell. Mol. Immunol."},{"key":"286_CR27","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1016\/j.chom.2020.04.009","volume":"27","author":"EJ Giamarellos-Bourboulis","year":"2020","unstructured":"Giamarellos-Bourboulis, E. J. et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe 27, 992\u20131000 (2020).","journal-title":"Cell Host Microbe"},{"key":"286_CR28","doi-asserted-by":"crossref","first-page":"9165267","DOI":"10.1155\/2016\/9165267","volume":"2016","author":"L Wang","year":"2016","unstructured":"Wang, L. et al. Clinical observation of employment of umbilical cord derived mesenchymal stem cell for juvenile idiopathic arthritis therapy. Stem Cells Int. 2016, 9165267 (2016).","journal-title":"Stem Cells Int."},{"key":"286_CR29","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1080\/14653240600855905","volume":"8","author":"M Dominici","year":"2006","unstructured":"Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy 8, 315\u2013317 (2006).","journal-title":"Cytotherapy"},{"key":"286_CR30","doi-asserted-by":"publisher","unstructured":"Song J. W. et al. Immunological and inflammatory profiles in mild and severe cases of COVID-19. Nat. Commun. https:\/\/doi.org\/10.1038\/s41467-020-17240-2 (2020).","DOI":"10.1038\/s41467-020-17240-2"}],"container-title":["Signal Transduction and Targeted Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41392-020-00286-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-020-00286-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-020-00286-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T13:16:11Z","timestamp":1723468571000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41392-020-00286-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,27]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["286"],"URL":"https:\/\/doi.org\/10.1038\/s41392-020-00286-5","relation":{},"ISSN":["2059-3635"],"issn-type":[{"value":"2059-3635","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,27]]},"assertion":[{"value":"8 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 July 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 July 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2020","order":4,"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":"172"}}