{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T07:12:29Z","timestamp":1780989149833,"version":"3.54.1"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T00:00:00Z","timestamp":1602806400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T00:00:00Z","timestamp":1602806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["Project E_04\/2013"],"award-info":[{"award-number":["Project E_04\/2013"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Stem Cell Rev and Rep"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mesenchymal stromal cells (MSCs) were first used as a source for cell therapy in 1995; however, despite their versatility and unambiguous demonstration of efficacy and safety in preclinical\/phase I studies, the positive effect of MSCs in human phase III studies did not resemble the success obtained in mouse models of disease. This dissonance highlights the need to more thoroughly study the immunobiology of MSCs to make better use of these cells. Thus, we aimed to study the immunobiology of MSCs by using chip array analysis as a method for general screening to obtain a global picture in our model study and found IFNy and IL-17 signaling as the first two \u201ctop canonical pathways\u201d involved in MSCs immunomodulation. The role of IFNy in triggering the immunosuppressive properties of MSCs is well recognized by many groups; however, the role of IL-17 in this process remains uncertain. Interestingly, in contrast to IFNy, which actively improved the MSCs-mediated immunosuppression, IL-17 did not improve directly the MSCs-mediated immunosuppression. Instead, IL-17 signaling induced the migration of MSCs and inflammatory cells, bringing these cell types together and increasing the likelihood of the lymphocytes sensing the immunosuppressive molecules produced by the MSCs. These effects also correlated with high levels of cytokine\/chemokine production and metalloprotease activation by MSCs. Importantly, this treatment maintained the MSCs safety profile by not inducing the expression of molecules related to antigen presentation. In this way, our findings highlight the possibility of using IL-17, in combination with IFNy, to prime MSCs for cell therapy to improve their biological properties and thus their therapeutic efficacy. Finally, the use of preactivated MSCs may also minimize variations among MSCs to produce more uniform therapeutic products. In the not-so-distant future, we envisage a portfolio of MSCs activated by different cocktails specifically designed to target and treat specific diseases.<\/jats:p>","DOI":"10.1007\/s12015-020-10051-4","type":"journal-article","created":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T16:02:38Z","timestamp":1602864158000},"page":"1266-1279","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["IL-17 Triggers Invasive and Migratory Properties in Human MSCs, while IFNy Favors their Immunosuppressive Capabilities: Implications for the \u201cLicensing\u201d Process"],"prefix":"10.1007","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1020-8038","authenticated-orcid":false,"given":"B\u00e1rbara","family":"Du-Rocher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Binato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio Cesar Madureira","family":"de-Freitas-Junior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephany","family":"Corr\u00eaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 Luiz","family":"Mencalha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Andr\u00e9s","family":"Morgado-D\u00edaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana","family":"Abdelhay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,16]]},"reference":[{"key":"10051_CR1","doi-asserted-by":"publisher","unstructured":"Mastrolia, I., et al. (2019). Concise review: challenges in clinical development of mesenchymal stromal\/stem cells. Stem Cells Translational Medicine. https:\/\/doi.org\/10.1002\/sctm.19-0044.","DOI":"10.1002\/sctm.19-0044"},{"issue":"1","key":"10051_CR2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1111\/cpr.12002","volume":"46","author":"R Binato","year":"2013","unstructured":"Binato, R., de Souza Fernandez, T., Lazzarotto-Silva, C., du Rocher, B., Mencalha, A., Pizzatti, L., Bouzas, L. F., & Abdelhay, E. (2013). Stability of human mesenchymal stem cells during in vitro culture: considerations for cell therapy. Cell Proliferation, 46(1), 10\u201322. https:\/\/doi.org\/10.1111\/cpr.12002.","journal-title":"Cell Proliferation"},{"issue":"10","key":"10051_CR3","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1002\/sctm.16-0485","volume":"6","author":"AJ Guess","year":"2017","unstructured":"Guess, A. J., Daneault, B., Wang, R., Bradbury, H., la Perle, K. M. D., Fitch, J., Hedrick, S. L., Hamelberg, E., Astbury, C., White, P., Overolt, K., Rangarajan, H., Abu-Arja, R., Devine, S. M., Otsuru, S., Dominici, M., O'Donnell, L., & Horwitz, E. M. (2017). Safety profile of good manufacturing practice manufactured interferon \u03b3-primed mesenchymal stem\/stromal cells for clinical trials. Stem Cells Translational Medicine, 6(10), 1868\u20131879. https:\/\/doi.org\/10.1002\/sctm.16-0485.","journal-title":"Stem Cells Translational Medicine"},{"issue":"6","key":"10051_CR4","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., & Sens\u00e9b\u00e9, L. (2018). Mesenchymal stromal cells: Clinical challenges and therapeutic opportunities. Cell Stem Cell, 22(6), 824\u2013833. https:\/\/doi.org\/10.1016\/j.stem.2018.05.004.","journal-title":"Cell Stem Cell"},{"key":"10051_CR5","doi-asserted-by":"publisher","unstructured":"Hoogduijn, M. J., & Lombardo, E. Concise review: mesenchymal stromal cells Anno 2019: dawn of the therapeutic era? Stem Cells Translational Medicine, 2019, 1126\u20131134. https:\/\/doi.org\/10.1002\/sctm.19-0073.","DOI":"10.1002\/sctm.19-0073"},{"issue":"4","key":"10051_CR6","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1080\/14653240600855905","volume":"8","author":"M Dominici","year":"2006","unstructured":"Dominici, M., le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F. C., Krause, D. S., Deans, R. J., Keating, A., Prockop, D. J., & Horwitz, E. M. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8(4), 315\u2013317. https:\/\/doi.org\/10.1080\/14653240600855905.","journal-title":"Cytotherapy"},{"issue":"1","key":"10051_CR7","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3109\/14653249.2011.594792","volume":"14","author":"B Du Rocher","year":"2012","unstructured":"Du Rocher, B., Mencalha, A. L., Gomes, B. E., & Abdelhay, E. (2012). Mesenchymal stromal cells impair the differentiation of CD14++ CD16- CD64+ classical monocytes into CD14++ CD16+ CD64++ activate monocytes. Cytotherapy, 14(1), 12\u201325. https:\/\/doi.org\/10.3109\/14653249.2011.594792.","journal-title":"Cytotherapy"},{"issue":"12","key":"10051_CR8","doi-asserted-by":"publisher","first-page":"4817","DOI":"10.1182\/blood-2006-01-0057","volume":"107","author":"JL Chan","year":"2006","unstructured":"Chan, J. L., Tang, K. C., Patel, A. P., Bonilla, L. M., Pierobon, N., Ponzio, N. M., & Rameshwar, P. (2006). Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-\u03b3. Blood, 107(12), 4817\u20134824. https:\/\/doi.org\/10.1182\/blood-2006-01-0057.","journal-title":"Blood"},{"issue":"13","key":"10051_CR9","doi-asserted-by":"publisher","first-page":"2632","DOI":"10.1182\/blood-2009-02-207795","volume":"114","author":"M Fran\u00e7ois","year":"2009","unstructured":"Fran\u00e7ois, M., Romieu-Mourez, R., Stock-Martineau, S., Boivin, M. N., Bramson, J. L., & Galipeau, J. (2009). Mesenchymal stromal cells cross-present soluble exogenous antigens as part of their antigen-presenting cell properties. Blood, 114(13), 2632\u20132638. https:\/\/doi.org\/10.1182\/blood-2009-02-207795.","journal-title":"Blood"},{"issue":"3","key":"10051_CR10","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.4049\/jimmunol.180.3.1826","volume":"180","author":"KC Tang","year":"2008","unstructured":"Tang, K. C., Trzaska, K. A., Smirnov, S. V., Kotenko, S. V., Schwander, S. K., Ellner, J. J., & Rameshwar, P. (2008). Down-regulation of MHC II in Mesenchymal stem cells at high IFN-\u03b3 can be partly explained by cytoplasmic retention of CIITA. Journal of Immunology, 180(3), 1826\u20131833. https:\/\/doi.org\/10.4049\/jimmunol.180.3.1826.","journal-title":"Journal of Immunology"},{"issue":"8","key":"10051_CR11","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1038\/nri2586","volume":"9","author":"SL Gaffen","year":"2009","unstructured":"Gaffen, S. L. (2009). Structure and signalling in the IL-17 receptor family. Nature Reviews. Immunology, 9(8), 556\u2013567. https:\/\/doi.org\/10.1038\/nri2586.","journal-title":"Nature Reviews. Immunology"},{"issue":"3","key":"10051_CR12","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1111\/j.1600-0897.2007.00467.x","volume":"57","author":"S Pongcharoen","year":"2007","unstructured":"Pongcharoen, S., Niumsup, P. R., & Sanguansermsri, D. (2007). JEG-3 cell culture supernatants cause reduced interferon-\u03b3 and interleukin-17 production in mixed-lymphocyte reactions. American Journal of Reproductive Immunology, 57(3), 227\u2013231. https:\/\/doi.org\/10.1111\/j.1600-0897.2007.00467.x.","journal-title":"American Journal of Reproductive Immunology"},{"issue":"9","key":"10051_CR13","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1038\/ni.2080","volume":"12","author":"K Bulek","year":"2011","unstructured":"Bulek, K., Liu, C., Swaidani, S., Wang, L., Page, R. C., Gulen, M. F., Herjan, T., Abbadi, A., Qian, W., Sun, D., Lauer, M., Hascall, V., Misra, S., Chance, M. R., Aronica, M., Hamilton, T., & Li, X. (2011). The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation. Nature Immunology, 12(9), 844\u2013852. https:\/\/doi.org\/10.1038\/ni.2080.","journal-title":"Nature Immunology"},{"issue":"10","key":"10051_CR14","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1161\/CIRCULATIONAHA.108.827618","volume":"119","author":"RE Eid","year":"2009","unstructured":"Eid, R. E., Rao, D. A., Zhou, J., Lo, S. F. L., Ranjbaran, H., Gallo, A., Sokol, S. I., Pfau, S., Pober, J. S., & Tellides, G. (2009). Interleukin-17 and interferon-\u03b3 are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation, 119(10), 1424\u20131432. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.108.827618.","journal-title":"Circulation"},{"issue":"1","key":"10051_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/jor.21206","volume":"29","author":"MA Gabr","year":"2011","unstructured":"Gabr, M. A., Jing, L., Helbling, A. R., Sinclair, S. M., Allen, K. D., Shamji, M. F., Richardson, W. J., Fitch, R. D., Setton, L. A., & Chen, J. (Jan. 2011). Interleukin-17 synergizes with IFN\u03b3 or TNF\u03b1 to promote inflammatory mediator release and intercellular adhesion molecule-1 (ICAM-1) expression in human intervertebral disc cells. Journal of Orthopaedic Research, 29(1), 1\u20137. https:\/\/doi.org\/10.1002\/jor.21206.","journal-title":"Journal of Orthopaedic Research"},{"key":"10051_CR16","doi-asserted-by":"crossref","unstructured":"Albanesi, C., Cavani, A., & Girolomoni, G. (1999). IL-17 is produced by nickel-specific T lymphocytes and regulates ICAM-1 expression and chemokine production in human keratinocytes: synergistic or antagonist effects with IFN-gamma and TNF-alpha. Journal of Immunology, 162(1), 494\u2013502. [Online]. Available: https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/9886425.","DOI":"10.1016\/S0923-1811(98)84061-9"},{"issue":"6","key":"10051_CR17","doi-asserted-by":"publisher","first-page":"4135","DOI":"10.4049\/jimmunol.179.6.4135","volume":"179","author":"J Hartupee","year":"2007","unstructured":"Hartupee, J., Liu, C., Novotny, M., Li, X., & Hamilton, T. (2007). IL-17 enhances chemokine gene expression through mRNA stabilization. Journal of Immunology, 179(6), 4135\u20134141. https:\/\/doi.org\/10.4049\/jimmunol.179.6.4135.","journal-title":"Journal of Immunology"},{"issue":"10","key":"10051_CR18","doi-asserted-by":"publisher","first-page":"6676","DOI":"10.4049\/jimmunol.175.10.6676","volume":"175","author":"C-Y Kao","year":"2005","unstructured":"Kao, C.-Y., Huang, F., Chen, Y., Thai, P., Wachi, S., Kim, C., Tam, L., & Wu, R. (2005). Up-regulation of CC chemokine ligand 20 expression in human airway epithelium by IL-17 through a JAK-independent but MEK\/NF-\u03baB-dependent signaling pathway. Journal of Immunology, 175(10), 6676\u20136685. https:\/\/doi.org\/10.4049\/jimmunol.175.10.6676.","journal-title":"Journal of Immunology"},{"issue":"1","key":"10051_CR19","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1634\/stemcells.2007-0416","volume":"26","author":"L Raffaghello","year":"2008","unstructured":"Raffaghello, L., Bianchi, G., Bertolotto, M., Montecucco, F., Busca, A., Dallegri, F., Ottonello, L., & Pistoia, V. (2008). Human Mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells, 26(1), 151\u2013162. https:\/\/doi.org\/10.1634\/stemcells.2007-0416.","journal-title":"Stem Cells"},{"issue":"9","key":"10051_CR20","doi-asserted-by":"publisher","first-page":"2393","DOI":"10.1002\/stem.2417","volume":"34","author":"D Jiang","year":"2016","unstructured":"Jiang, D., Muschhammer, J., Qi, Y., K\u00fcgler, A., de Vries, J. C., Saffarzadeh, M., Sindrilaru, A., Beken, S. V., Wlaschek, M., Kluth, M. A., Ganss, C., Frank, N. Y., Frank, M. H., Preissner, K. T., & Scharffetter-Kochanek, K. (Sep. 2016). Suppression of neutrophil-mediated tissue damage-a novel skill of mesenchymal stem cells. Stem Cells, 34(9), 2393\u20132406. https:\/\/doi.org\/10.1002\/stem.2417.","journal-title":"Stem Cells"},{"key":"10051_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/cdd.2014.85","volume":"21","author":"X Han","year":"2014","unstructured":"Han, X., Yang, Q., Lin, L., Xu, C., Zheng, C., Chen, X., Han, Y., Li, M., Cao, W., Cao, K., Chen, Q., Xu, G., Zhang, Y., Zhang, J., Schneider, R. J., Qian, Y., Wang, Y., Brewer, G., & Shi, Y. (2014). Interleukin-17 enhances immunosuppression by mesenchymal stem cells. Cell Death and Differentiation, 21, 1\u201311. https:\/\/doi.org\/10.1038\/cdd.2014.85.","journal-title":"Cell Death and Differentiation"},{"issue":"28","key":"10051_CR22","doi-asserted-by":"publisher","first-page":"42953","DOI":"10.18632\/oncotarget.10261","volume":"7","author":"J Tian","year":"2016","unstructured":"Tian, J., et al. (2016). IL-17 down-regulates the immunosuppressive capacity of olfactory ecto-mesenchymal stem cells in murine collagen-induced arthritis. Oncotarget, 7(28), 42953\u201342962. https:\/\/doi.org\/10.18632\/oncotarget.10261.","journal-title":"Oncotarget"},{"issue":"9","key":"10051_CR23","doi-asserted-by":"publisher","first-page":"2850","DOI":"10.1002\/stem.2075","volume":"33","author":"KN Sivanathan","year":"2015","unstructured":"Sivanathan, K. N., Rojas-Canales, D. M., Hope, C. M., Krishnan, R., Carroll, R. P., Gronthos, S., Grey, S. T., & Coates, P. T. (2015). Interleukin-17A-induced human mesenchymal stem cells are superior modulators of immunological function. Stem Cells, 33(9), 2850\u20132863. https:\/\/doi.org\/10.1002\/stem.2075.","journal-title":"Stem Cells"},{"issue":"2","key":"10051_CR24","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.bbamcr.2014.11.025","volume":"1853","author":"J Krsti\u0107","year":"2015","unstructured":"Krsti\u0107, J., Obradovi\u0107, H., Jaukovi\u0107, A., Oki\u0107-\u0110or\u0111evi\u0107, I., Trivanovi\u0107, D., Kukolj, T., Mojsilovi\u0107, S., Ili\u0107, V., Santiba\u00f1ez, J. F., & Bugarski, D. (2015). Urokinase type plasminogen activator mediates interleukin-17-induced peripheral blood mesenchymal stem cell motility and transendothelial migration. Biochimica et Biophysica Acta Molecular Cell Research, 1853(2), 431\u2013444. https:\/\/doi.org\/10.1016\/j.bbamcr.2014.11.025.","journal-title":"Biochimica et Biophysica Acta Molecular Cell Research"},{"issue":"2","key":"10051_CR25","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1007\/s00424-011-1039-x","volume":"463","author":"B Pang","year":"2012","unstructured":"Pang, B., Shin, D. H., Park, K. S., Huh, Y. J., Woo, J., Zhang, Y. H., Kang, T. M., Lee, K. Y., & Kim, S. J. (2012). Differential pathways for calcium influx activated by concanavalin A and CD3 stimulation in Jurkat T cells. Pflugers Archiv: European Journal of Physiology, 463(2), 309\u2013318. https:\/\/doi.org\/10.1007\/s00424-011-1039-x.","journal-title":"Pflugers Archiv: European Journal of Physiology"},{"issue":"2","key":"10051_CR26","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1634\/stemcells.2005-0008","volume":"24","author":"M Krampera","year":"2006","unstructured":"Krampera, M., Cosmi, L., Angeli, R., Pasini, A., Liotta, F., Andreini, A., Santarlasci, V., Mazzinghi, B., Pizzolo, G., Vinante, F., Romagnani, P., Maggi, E., Romagnani, S., & Annunziato, F. (2006). Role for interferon-\u03b3 in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells, 24(2), 386\u2013398. https:\/\/doi.org\/10.1634\/stemcells.2005-0008.","journal-title":"Stem Cells"},{"key":"10051_CR27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2019\/7219297","volume":"2019","author":"BS Guerrouahen","year":"2019","unstructured":"Guerrouahen, B. S., Sidahmed, H., Al Sulaiti, A., Al Khulaifi, M., & Cugno, C. (2019). Enhancing mesenchymal stromal cell immunomodulation for treating conditions influenced by the immune system. Stem Cells International, 2019, 1\u201311. https:\/\/doi.org\/10.1155\/2019\/7219297.","journal-title":"Stem Cells International"},{"key":"10051_CR28","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.ebiom.2018.01.002","volume":"28","author":"DS Kim","year":"2018","unstructured":"Kim, D. S., Jang, I. K., Lee, M. W., Ko, Y. J., Lee, D. H., Lee, J. W., Sung, K. W., Koo, H. H., & Yoo, K. H. (2018). Enhanced immunosuppressive properties of human mesenchymal stem cells primed by interferon-\u03b3. EBioMedicine, 28, 261\u2013273. https:\/\/doi.org\/10.1016\/j.ebiom.2018.01.002.","journal-title":"EBioMedicine"},{"issue":"1","key":"10051_CR29","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1080\/21645515.2015.1030549","volume":"12","author":"Q Wang","year":"2016","unstructured":"Wang, Q., Yang, Q., Wang, Z., Tong, H., Ma, L., Zhang, Y., Shan, F., Meng, Y., & Yuan, Z. (2016). Comparative analysis of human mesenchymal stem cells from fetal-bone marrow, adipose tissue, and Warton\u2019s jelly as sources of cell immunomodulatory therapy. Human Vaccines and Immunotherapeutics, 12(1), 85\u201396. https:\/\/doi.org\/10.1080\/21645515.2015.1030549.","journal-title":"Human Vaccines and Immunotherapeutics"}],"container-title":["Stem Cell Reviews and Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12015-020-10051-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12015-020-10051-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12015-020-10051-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,16]],"date-time":"2021-10-16T04:30:26Z","timestamp":1634358626000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12015-020-10051-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,16]]},"references-count":29,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["10051"],"URL":"https:\/\/doi.org\/10.1007\/s12015-020-10051-4","relation":{},"ISSN":["2629-3269","2629-3277"],"issn-type":[{"value":"2629-3269","type":"print"},{"value":"2629-3277","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,16]]},"assertion":[{"value":"28 September 2020","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 October 2020","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"The authors declare that they have no financial or commercial conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declaration of Interest"}}]}}