{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T02:44:31Z","timestamp":1779331471638,"version":"3.51.4"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,10,2]],"date-time":"2017-10-02T00:00:00Z","timestamp":1506902400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,10,2]],"date-time":"2017-10-02T00:00:00Z","timestamp":1506902400000},"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>MRC-5 represents the most frequent human diploid cells (HDCs)-type cell substrate in the production of human viral vaccines. However, early-passage MRC-5 is diminishing and, due to both technical and ethical issues, it is extremely difficult to derive novel HDCs from fetal lung tissues, which are the common sources of HDCs. Our previous studies suggested that human umbilical cord may represent an alternative but convenient source of new HDCs. Here, we established a three-tiered cell banking system of a hUC-MSC line, designated previously as Cell Collection and Research Center-1 (CCRC-1). The full characterization indicated that the banked CCRC-1 cells were free from adventitious agents and remained non-tumorigenic. The CCRC-1 cells sustained its rapid proliferation even at passage 30 and were susceptible to the infection of a wide spectrum of viruses. Interestingly, the CCRC-1 cells showed much higher production of EV71 or Rubella viruses than MRC-5 and Vero cells when growing in serum-free medium. More importantly, the EV71 vaccine produced from CCRC-1 cells induced immunogenicity while eliciting no detectable toxicities in the tested mice. Collectively, these studies further supported that CCRC-1, and likely other hUC-MSCs as well, may serve as novel, safe and high-yielding HDCs for the production of human viral vaccines.<\/jats:p>","DOI":"10.1038\/s41598-017-11997-1","type":"journal-article","created":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T08:49:32Z","timestamp":1506415772000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The hUC-MSCs cell line CCRC-1 represents a novel, safe and high-yielding HDCs for the production of human viral vaccines"],"prefix":"10.1038","volume":"7","author":[{"given":"Ping","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke-Hua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Na","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Dong","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bao-Zhu","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-Zhi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,10,2]]},"reference":[{"key":"11997_CR1","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.biologicals.2007.11.005","volume":"36","author":"I Knezevic","year":"2008","unstructured":"Knezevic, I., Stacey, G. & Petricciani, J. WHO Study Group on cell substrates. WHO Study Group on cell substrates for production of biologicals, Geneva, Switzerland, 11\u201312 June 2007. Biologicals. \n                           36, 203\u201311 (2008).","journal-title":"Biologicals."},{"key":"11997_CR2","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.biologicals.2009.08.019","volume":"38","author":"I Knezevic","year":"2010","unstructured":"Knezevic, I., Stacey, G., Petricciani, J. & Sheets, R. WHO Study Group on Cell Substrates. Evaluation of cell substrates for the production of biologicals: Revision of WHO recommendations. Report of the WHO Study Group on Cell Substrates for the Production of Biologicals, 22\u201323 April 2009, Bethesda, USA. Biologicals. \n                           38, 162\u20139 (2010).","journal-title":"Biologicals."},{"key":"11997_CR3","doi-asserted-by":"publisher","first-page":"1672","DOI":"10.3390\/v6041672","volume":"6","author":"I Jordan","year":"2014","unstructured":"Jordan, I. & Sandig, V. Matrix and backstage: cellular substrates for viral vaccines. Viruses. \n                           6, 1672\u2013700 (2014).","journal-title":"Viruses."},{"key":"11997_CR4","doi-asserted-by":"publisher","first-page":"5905","DOI":"10.1016\/j.vaccine.2015.06.110","volume":"33","author":"F Aubrit","year":"2015","unstructured":"Aubrit, F. et al. Cell substrates for the production of viral vaccines. Vaccine. \n                           33, 5905\u201312 (2015).","journal-title":"Vaccine."},{"key":"11997_CR5","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1002\/biot.201400387","volume":"10","author":"AF Rodrigues","year":"2015","unstructured":"Rodrigues, A. F., Soares, H. R., Guerreiro, M. R., Alves, P. M. & Coroadinha, A. S. Viral vaccines and their manufacturing cell substrates: New trends and designs in modern vaccinology. Biotechnol J. \n                           10, 1329\u201344 (2015).","journal-title":"Biotechnol J."},{"key":"11997_CR6","doi-asserted-by":"publisher","first-page":"2715","DOI":"10.1016\/j.vaccine.2012.02.015","volume":"30","author":"RD Hess","year":"2012","unstructured":"Hess, R. D., Weber, F., Watson, K. & Schmitt, S. Regulatory, biosafety and safety challenges for novel cells as substrates for human vaccines. Vaccine. \n                           30, 2715\u201327 (2012).","journal-title":"Vaccine."},{"key":"11997_CR7","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1006\/biol.1998.0153","volume":"26","author":"V Grachev","year":"1998","unstructured":"Grachev, V., Magrath, D. & Griffiths, E. WHO requirements for the use of animal cells as in vitro substrates for the production of biologicals (Requirements for biological susbstances no. 50). Biologicals. \n                           26, 175\u201393 (1998).","journal-title":"Biologicals."},{"key":"11997_CR8","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1016\/j.biologicals.2010.04.003","volume":"38","author":"D Onions","year":"2010","unstructured":"Onions, D., Egan, W., Jarrett, R., Novicki, D. & Gregersen, J. P. Validation of the safety of MDCK cells as a substrate for the production of a cell-derived influenza vaccine. Biologicals. \n                           38, 544\u201351 (2010).","journal-title":"Biologicals."},{"key":"11997_CR9","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1586\/erv.12.55","volume":"11","author":"CY Chan","year":"2012","unstructured":"Chan, C. Y. & Tambyah, P. A. Preflucel\u00ae: a Vero-cell culture-derived trivalent influenza vaccine. Expert Rev Vaccines. \n                           11, 759\u201373 (2012).","journal-title":"Expert Rev Vaccines."},{"key":"11997_CR10","first-page":"97","volume":"93","author":"MA Fletcher","year":"1998","unstructured":"Fletcher, M. A., Hessel, L. & Plotkin, S. A. Human diploid cell strains (HDCS) viral vaccines. Dev Biol Stand. \n                           93, 97\u2013107 (1998).","journal-title":"Dev Biol Stand."},{"key":"11997_CR11","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1080\/21645515.2015.1009811","volume":"11","author":"B Ma","year":"2015","unstructured":"Ma, B. et al. Characteristics and viral propagation properties of a new human diploid cell line, Walvax-2, and its suitability as a candidate cell substrate for vaccine production. Hum Vaccin Immunother. \n                           11, 998\u20131009 (2015).","journal-title":"Hum Vaccin Immunother."},{"key":"11997_CR12","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1126\/science.284.5411.143","volume":"284","author":"MF Pittenger","year":"1999","unstructured":"Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science. \n                           284, 143\u20137 (1999).","journal-title":"Science."},{"key":"11997_CR13","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1002\/stem.269","volume":"28","author":"HK Salem","year":"2010","unstructured":"Salem, H. K. & Thiemermann, C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells. \n                           28, 585\u201396 (2010).","journal-title":"Stem Cells."},{"key":"11997_CR14","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.stem.2007.11.014","volume":"2","author":"G Ren","year":"2008","unstructured":"Ren, G. et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. \n                           2, 141\u201350 (2008).","journal-title":"Cell Stem Cell."},{"key":"11997_CR15","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.stem.2013.09.006","volume":"13","author":"ME Bernardo","year":"2013","unstructured":"Bernardo, M. E. & Fibbe, W. E. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. \n                           13, 392\u2013402 (2013).","journal-title":"Cell Stem Cell."},{"key":"11997_CR16","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1089\/scd.2012.0594","volume":"22","author":"C Menard","year":"2013","unstructured":"Menard, C. et al. Clinical-grade mesenchymal stromal cells produced under various good manufacturing practice processes differ in their immunomodulatory properties: standardization of immune quality controls. Stem Cells Dev. \n                           22, 1789\u2013801 (2013).","journal-title":"Stem Cells Dev."},{"key":"11997_CR17","doi-asserted-by":"publisher","first-page":"6820","DOI":"10.1016\/j.vaccine.2014.07.071","volume":"32","author":"K Zhang","year":"2014","unstructured":"Zhang, K. et al. Human diploid MRC-5 cells exhibit several critical properties of human umbilical cord-derived mesenchymal stem cells. Vaccine. \n                           32, 6820\u20137 (2014).","journal-title":"Vaccine."},{"key":"11997_CR18","unstructured":"WHO. Recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological medicinal products and for the characterization of cell banks. WHO Expert Committee on Biological Standardization Geneva, World Health Organization, In press. (Drafted in 2010 and implemented in 2013)."},{"key":"11997_CR19","unstructured":"National Pharmacopoeia Committee. Pharmacopoeia of People\u2019s Republic of China. Part 3. Beijing: China Medical Science Press (2015)."},{"key":"11997_CR20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0046043","volume":"7","author":"Q Mao","year":"2012","unstructured":"Mao, Q. et al. Comparative analysis of the immunogenicity and protective effects of inactivated EV71 vaccines in mice. PLoS One. \n                           7, e46043 (2012).","journal-title":"PLoS One."},{"key":"11997_CR21","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/S0264-410X(02)00623-0","volume":"21","author":"J Ehreth","year":"2003","unstructured":"Ehreth, J. The global value of vaccination. Vaccine. \n                           21, 596\u2013600 (2003).","journal-title":"Vaccine."},{"key":"11997_CR22","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1016\/j.vaccine.2013.02.026","volume":"31","author":"JD Grabenstein","year":"2013","unstructured":"Grabenstein, J. D. What the world\u2019s religions teach, applied to vaccines and immune globulins. Vaccine. \n                           31, 2011\u201323 (2013).","journal-title":"Vaccine."},{"key":"11997_CR23","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.biologicals.2010.01.003","volume":"38","author":"D Onions","year":"2010","unstructured":"Onions, D. & Kolman, J. Massively parallel sequencing, a new method for detecting adventitious agents. Biologicals. \n                           38, 377\u201380 (2010).","journal-title":"Biologicals."},{"key":"11997_CR24","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.biologicals.2007.06.002","volume":"36","author":"M Manohar","year":"2008","unstructured":"Manohar, M., Orrison, B., Peden, K. & Lewis, A. M. Jr. Assessing the tumorigenic phenotype of VERO cells in adult and newborn nude mice. Biologicals. \n                           36, 65\u201372 (2008).","journal-title":"Biologicals."},{"key":"11997_CR25","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1016\/j.vaccine.2009.11.023","volume":"28","author":"J Liu","year":"2010","unstructured":"Liu, J., Mani, S., Schwartz, R., Richman, L. & Tabor, D. E. Cloning and assessment of tumorigenicity and oncogenicity of a Madin-Darby canine kidney (MDCK) cell line for influenza vaccine production. Vaccine. \n                           28, 1285\u201393 (2010).","journal-title":"Vaccine."},{"key":"11997_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.480","volume":"4","author":"Y Wang","year":"2013","unstructured":"Wang, Y. et al. Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation. Cell Death Dis. \n                           4, e950 (2013).","journal-title":"Cell Death Dis."},{"key":"11997_CR27","doi-asserted-by":"publisher","first-page":"9142","DOI":"10.1158\/0008-5472.CAN-06-4690","volume":"67","author":"ME Bernardo","year":"2007","unstructured":"Bernardo, M. E. et al. Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. \n                           67, 9142\u20139 (2007).","journal-title":"Cancer Res."},{"key":"11997_CR28","doi-asserted-by":"publisher","first-page":"4975","DOI":"10.1016\/j.vaccine.2009.05.083","volume":"27","author":"V Lohr","year":"2009","unstructured":"Lohr, V. et al. New avian suspension cell lines provide production of influenza virus and MVA in serum-free media: studies on growth, metabolism and virus propagation. Vaccine. \n                           27, 4975\u201382 (2009).","journal-title":"Vaccine."},{"key":"11997_CR29","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1007\/s00441-008-0696-3","volume":"334","author":"CH Jo","year":"2008","unstructured":"Jo, C. H. et al. Fetal mesenchymal stem cells derived from human umbilical cord sustain primitive characteristics during extensive expansion. Cell Tissue Res. \n                           334, 423\u201333 (2008).","journal-title":"Cell Tissue Res."},{"key":"11997_CR30","doi-asserted-by":"publisher","first-page":"6028","DOI":"10.1016\/j.vaccine.2007.05.013","volume":"25","author":"O Kistner","year":"2007","unstructured":"Kistner, O. et al. Cell culture (Vero) derived whole virus (H5N1) vaccine based on wild-type virus strain induces cross-protective immune responses. Vaccine. \n                           25, 6028\u201336 (2007).","journal-title":"Vaccine."},{"key":"11997_CR31","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.3390\/v7072803","volume":"7","author":"J Li","year":"2015","unstructured":"Li, J. et al. Optimization and Characterization of Candidate Strain for Coxsackievirus A16 Inactivated Vaccine. Viruses. \n                           7, 3891\u2013909 (2015).","journal-title":"Viruses."},{"key":"11997_CR32","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1002\/jmv.21804","volume":"83","author":"B Alirezaie","year":"2011","unstructured":"Alirezaie, B., Taqavian, M., Aghaiypour, K., Esna-Ashari, F. & Shafyi, A. Phenotypic and genomic analysis of serotype 3 Sabin poliovirus vaccine produced in MRC-5 cell substrate. J Med Virol. \n                           83, 897\u2013903 (2011).","journal-title":"J Med Virol."},{"key":"11997_CR33","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1007\/s00253-011-3574-y","volume":"93","author":"K Trabelsi","year":"2012","unstructured":"Trabelsi, K., Majoul, S., Rourou, S. & Kallel, H. Development of a measles vaccine production process in MRC-5 cells grown on Cytodex1 microcarriers and in a stirred bioreactor. Appl Microbiol Biotechnol. \n                           93, 1031\u201340 (2012).","journal-title":"Appl Microbiol Biotechnol."},{"key":"11997_CR34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0136420","volume":"10","author":"CY Wu","year":"2015","unstructured":"Wu, C. Y. et al. Inactivated Enterovirus 71 Vaccine Produced by 200-L Scale Serum-Free Microcarrier Bioreactor System Provides Cross-Protective Efficacy in Human SCARB2 Transgenic Mouse. PLoS One. \n                           10, e0136420 (2015).","journal-title":"PLoS One."},{"key":"11997_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1099\/vir.0.026187-0","volume":"92","author":"D Jackson","year":"2011","unstructured":"Jackson, D., Elderfield, R. A. & Barclay, W. S. Molecular studies of influenza B virus in the reverse genetics era. J Gen Virol. \n                           92, 1\u201317 (2011).","journal-title":"J Gen Virol."},{"key":"11997_CR36","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.virusres.2015.04.005","volume":"204","author":"D Shin","year":"2015","unstructured":"Shin, D. et al. Comparison of immunogenicity of cell-and egg-passaged viruses for manufacturing MDCK cell culture-based influenza vaccines. Virus Res. \n                           204, 40\u20136 (2015).","journal-title":"Virus Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-11997-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-11997-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-11997-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T11:37:23Z","timestamp":1671795443000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-11997-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,2]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["11997"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-11997-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,2]]},"assertion":[{"value":"14 December 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 August 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 October 2017","order":3,"name":"first_online","label":"First Online","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":"12484"}}