{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:20:05Z","timestamp":1790806805625,"version":"4.1.0"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,11,10]],"date-time":"2017-11-10T00:00:00Z","timestamp":1510272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,11,10]],"date-time":"2017-11-10T00:00:00Z","timestamp":1510272000000},"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>\n                  <jats:p>\n                    There is yet no cure for type 1 diabetes (T1DM) so far. A significant body of evidence has demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) showed great potential in controlling T1DM. But there exists much difficulty in using BMSCs as a clinical therapy. We here test whether a new population of mesenchymal stem cells from human gingiva (GMSCs), which has many advantages over BMSCs, can delay or prevent progress of T1DM. GMSCs were adoptively transferred to multiple low-dose streptozotocin (STZ)-induced T1DM. Blood glucose levels and disease severities were analyzed. T cells subsets in blood, spleen and lymph nodes were detected dynamically by flow cytometry. GMSC distribution was dynamically analyzed. We found that infusion of GMSCs but not fibroblast cells significantly controlled blood glucose levels, delayed diabetes onset, ameliorated pathology scores in pancreas, and down-regulated production of IL-17 and IFN-\u03b3 in CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in spleens, pancreatic lymph nodes (pLN) and other lymph nodes. GMSCs also up-regulated the levels of CD4\n                    <jats:sup>+<\/jats:sup>\n                    Treg induced in the periphery. Mechanismly, GMSCs could migrate to pancreas and local lymph node and function through CD39\/CD73 pathway to regulate effector T cells. Thus, GMSCs show a potential promise in treating T1DM in the clinic.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-14979-5","type":"journal-article","created":{"date-parts":[[2017,11,6]],"date-time":"2017-11-06T05:03:02Z","timestamp":1509944582000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Human Gingiva-Derived Mesenchymal Stem Cells Ameliorate Streptozoticin-induced T1DM in mice via Suppression of T effector cells and Up-regulating Treg Subsets"],"prefix":"10.1038","volume":"7","author":[{"given":"Wei","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junlong","family":"Dang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ximei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanming","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jichao","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongqing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Homayoun H.","family":"Zadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Olsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song Guo","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,11,10]]},"reference":[{"key":"14979_CR1","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1002\/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S","volume":"15","author":"KG Alberti","year":"1998","unstructured":"Alberti, K. G. & Zimmet, P. Z. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med \n                           15, 539\u2013553 (1998).","journal-title":"Diabet Med"},{"key":"14979_CR2","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.2337\/dc09-0374","volume":"32","author":"M Rewers","year":"2009","unstructured":"Rewers, M. & Gottlieb, P. Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future. Diabetes care \n                           32, 1769\u20131782 (2009).","journal-title":"Diabetes care"},{"key":"14979_CR3","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\u2013147 (1999).","journal-title":"Science"},{"key":"14979_CR4","doi-asserted-by":"publisher","first-page":"3499","DOI":"10.1182\/blood-2007-02-069716","volume":"110","author":"AJ Nauta","year":"2007","unstructured":"Nauta, A. J. & Fibbe, W. E. Immunomodulatory properties of mesenchymal stromal cells. Blood \n                           110, 3499\u20133506 (2007).","journal-title":"Blood"},{"key":"14979_CR5","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1634\/stemcells.2007-0554","volume":"26","author":"Z Selmani","year":"2008","unstructured":"Selmani, Z. et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+ CD25high FOXP3+ regulatory T cells. Stem cells (Dayton, Ohio) \n                           26, 212\u2013222 (2008).","journal-title":"Stem cells (Dayton, Ohio)"},{"key":"14979_CR6","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1038\/nri2395","volume":"8","author":"A Uccelli","year":"2008","unstructured":"Uccelli, A., Moretta, L. & Pistoia, V. Mesenchymal stem cells in health and disease. Nature reviews. Immunology \n                           8, 726\u2013736 (2008).","journal-title":"Nature reviews. Immunology"},{"key":"14979_CR7","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1002\/eji.200738129","volume":"38","author":"D Polchert","year":"2008","unstructured":"Polchert, D. et al. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. European journal of immunology \n                           38, 1745\u20131755 (2008).","journal-title":"European journal of immunology"},{"key":"14979_CR8","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1016\/S0140-6736(04)16104-7","volume":"363","author":"K Le Blanc","year":"2004","unstructured":"Le Blanc, K. et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet \n                           363, 1439\u20131441 (2004).","journal-title":"Lancet"},{"key":"14979_CR9","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1002\/art.24405","volume":"60","author":"MA Gonzalez","year":"2009","unstructured":"Gonzalez, M. A., Gonzalez-Rey, E., Rico, L., Buscher, D. & Delgado, M. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis and rheumatism \n                           60, 1006\u20131019 (2009).","journal-title":"Arthritis and rheumatism"},{"key":"14979_CR10","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/cmi.2008.52","volume":"5","author":"K Zhou","year":"2008","unstructured":"Zhou, K. et al. Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in MRL\/lpr mice. Cellular & molecular immunology \n                           5, 417\u2013424 (2008).","journal-title":"Cellular & molecular immunology"},{"key":"14979_CR11","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.bbrc.2010.01.126","volume":"393","author":"GB Tomar","year":"2010","unstructured":"Tomar, G. B. et al. Human gingiva-derived mesenchymal stem cells are superior to bone marrow-derived mesenchymal stem cells for cell therapy in regenerative medicine. Biochemical and biophysical research communications \n                           393, 377\u2013383 (2010).","journal-title":"Biochemical and biophysical research communications"},{"key":"14979_CR12","doi-asserted-by":"crossref","unstructured":"Zhang, Q. Z. et al. Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing. Stem Cells \n                           28, 1856-1868 (2010).","DOI":"10.1002\/stem.503"},{"key":"14979_CR13","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.1002\/stem.738","volume":"29","author":"WR Su","year":"2011","unstructured":"Su, W. R., Zhang, Q. Z., Shi, S. H., Nguyen, A. L. & Le, A. D. Human gingiva-derived mesenchymal stromal cells attenuate contact hypersensitivity via prostaglandin E2-dependent mechanisms. 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Journal of immunology (Baltimore, Md. : 1950) \n                           183, 7787\u20137798 (2009)."},{"key":"14979_CR16","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1002\/art.37894","volume":"65","author":"M Chen","year":"2013","unstructured":"Chen, M. et al. Adoptive transfer of human gingiva-derived mesenchymal stem cells ameliorates collagen-induced arthritis via suppression of Th1 and Th17 cells and enhancement of regulatory T cell differentiation. Arthritis Rheum \n                           65, 1181\u20131193 (2013).","journal-title":"Arthritis Rheum"},{"key":"14979_CR17","first-page":"68","volume":"8","author":"F Huang","year":"2017","unstructured":"Huang, F. et al. Human Gingiva-Derived Mesenchymal Stem Cells Inhibit Xeno-Graft-versus-Host Disease via CD39-CD73-Adenosine and IDO Signals. Frontiers in immunology \n                           8, 68 (2017).","journal-title":"Frontiers in immunology"},{"key":"14979_CR18","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/j.humimm.2013.01.024","volume":"74","author":"M Ryba-Stanislawowska","year":"2013","unstructured":"Ryba-Stanislawowska, M. et al. Loss of the balance between CD4(+)Foxp3(+) regulatory T cells and CD4(+)IL17A(+) Th17 cells in patients with type 1 diabetes. Hum Immunol \n                           74, 701 (2013).","journal-title":"Hum Immunol"},{"key":"14979_CR19","doi-asserted-by":"publisher","first-page":"2903","DOI":"10.2337\/db11-0090","volume":"60","author":"A Ferraro","year":"2011","unstructured":"Ferraro, A. et al. Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes. Diabetes \n                           60, 2903 (2011).","journal-title":"Diabetes"},{"key":"14979_CR20","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/j.imbio.2012.05.010","volume":"218","author":"JN Yaochite","year":"2013","unstructured":"Yaochite, J. N. et al. Dynamic changes of the Th17\/Tc17 and regulatory T cell populations interfere in the experimental autoimmune diabetes pathogenesis. Immunobiology \n                           218, 338\u2013352 (2013).","journal-title":"Immunobiology"},{"key":"14979_CR21","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.2337\/db08-1113","volume":"58","author":"JA Emamaullee","year":"2009","unstructured":"Emamaullee, J. A. et al. Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. Diabetes \n                           58, 1302\u20131311 (2009).","journal-title":"Diabetes"},{"key":"14979_CR22","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1002\/eji.200738108","volume":"38","author":"T Brusko","year":"2008","unstructured":"Brusko, T. & Bluestone, J. Clinical application of regulatory T cells for treatment of type 1 diabetes and transplantation. Eur J Immunol \n                           38, 931\u2013934 (2008).","journal-title":"Eur J Immunol"},{"key":"14979_CR23","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.2174\/156652412803833634","volume":"12","author":"SM Cabrera","year":"2012","unstructured":"Cabrera, S. M., Rigby Mr Fau - Mirmira, R. G. & Mirmira, R. G. Targeting regulatory T cells in the treatment of type 1 diabetes mellitus. 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Purinergic signalling \n                           10, 357\u2013365 (2014).","journal-title":"Purinergic signalling"},{"key":"14979_CR26","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.3727\/096368910X546553","volume":"20","author":"C Sattler","year":"2011","unstructured":"Sattler, C. et al. Inhibition of T-cell proliferation by murine multipotent mesenchymal stromal cells is mediated by CD39 expression and adenosine generation. Cell transplantation \n                           20, 1221\u20131230 (2011).","journal-title":"Cell transplantation"},{"key":"14979_CR27","doi-asserted-by":"publisher","first-page":"4619","DOI":"10.1182\/blood-2003-11-3909","volume":"103","author":"R Meisel","year":"2004","unstructured":"Meisel, R. et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood \n                           103, 4619\u20134621 (2004).","journal-title":"Blood"},{"key":"14979_CR28","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.cbi.2015.11.032","volume":"244","author":"SN Goyal","year":"2016","unstructured":"Goyal, S. N. et al. Challenges and issues with streptozotocin-induced diabetes - A clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics. Chemico-biological interactions \n                           244, 49\u201363 (2016).","journal-title":"Chemico-biological interactions"},{"key":"14979_CR29","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.2337\/db10-0044","volume":"59","author":"M Lin","year":"2010","unstructured":"Lin, M. et al. Immune cell-derived c3 is required for autoimmune diabetes induced by multiple low doses of streptozotocin. Diabetes \n                           59, 2247\u20132252 (2010).","journal-title":"Diabetes"},{"key":"14979_CR30","doi-asserted-by":"publisher","first-page":"992","DOI":"10.2337\/diab.43.8.992","volume":"43","author":"D Elias","year":"1994","unstructured":"Elias, D. et al. Autoimmune diabetes induced by the beta-cell toxin STZ. Immunity to the 60-kDa heat shock protein and to insulin. Diabetes \n                           43, 992 (1994).","journal-title":"Diabetes"},{"key":"14979_CR31","first-page":"75","volume":"19","author":"G Kundrotas","year":"2012","unstructured":"Kundrotas, G. Surface markers distinguish MSC from fibroblasts. Acta Med Litu \n                           19, 75\u201379 (2012).","journal-title":"Acta Med Litu"},{"key":"14979_CR32","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1258\/la.2010.010090","volume":"45","author":"MC Deeds","year":"2011","unstructured":"Deeds, M. C. et al. Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models. Laboratory animals \n                           45, 131\u2013140 (2011).","journal-title":"Laboratory animals"},{"key":"14979_CR33","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1126\/science.7761837","volume":"268","author":"JD Katz","year":"1995","unstructured":"Katz, J. D., Benoist C Fau - Mathis, D. & Mathis, D. T helper cell subsets in insulin-dependent diabetes. Science \n                           268, 1185 (1995).","journal-title":"Science"},{"issue":"1713-1722","key":"14979_CR34","first-page":"S1711","volume":"209","author":"M Yadav","year":"2012","unstructured":"Yadav, M. et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. 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