{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T19:32:56Z","timestamp":1780083176369,"version":"3.54.0"},"reference-count":35,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Diabetic nephropathy (DN) is the most common cause of kidney failure worldwide. Mesenchymal stromal cells (MSCs) have demonstrated promise for treating DN by promoting kidney repair and regulating inflammation. Allogeneic (Allo)-MSCs may have similar or superior anti-inflammatory effects to autologous (Auto)-MSCs but also have potential to elicit adverse immune responses due to major histocompatibility complex (MHC) mismatches. To better understand how MSC-delivered allo-antigens influence therapeutic effects of Allo-MSCs compared to Auto-MSCs in DN, lentiviral transduction was used to generate adipose-derived MSCs (ADSCs) from DBA\/2J (H-2d) mice which expressed an allogeneic class I MHC protein (H-2Kb). H-2Kb-ADSCs were injected intravenously into male DBA\/2J mice at 11 and 13 weeks after initiation of diabetes, and their effects on renal functional and structural indices were compared at week 15 with those of diabetic DBA\/2J recipients of vehicle alone or of empty vector-transduced DBA\/2J ADSCs (EV-ADSCs). Both EV-ADSCs and H-2Kb-ADSCs resulted in reduced kidney\/total body weight ratio, blood urea nitrogen (BUN), urine albumin creatinine ratio (uACR), mesangial matrix expansion (MME) and renal fibrosis compared to vehicle alone, without influencing glycemia or survival. However, H-2Kb-ADSCs recipients had greater reductions in BUN and uACR, reduced intra-renal myeloid cell infiltration, increased splenic regulatory T cell (Treg) proportions and increased intra-renal Treg infiltration and FOXP3 and IL-10 mRNA. Nonetheless, recipients of H-2Kb-ADSCs also had decreased splenic CD4\/CD8 T cell ratios, increased circulating anti-H-2Kb IgG antibodies and histological and biochemical evidence of inflammatory liver injury. These novel findings demonstrated that ADSCs expressing an MHC-I allo-antigen had superior beneficial effects on DN than fully autologous ADSCs. Improved DN severity was associated with immune modulation, including Treg enhancement, but also had potentially detrimental immunological effects in mice with established diabetes. The results highlight the need for further investigation of the immune modulatory effects of Allo-MSCs in diabetes and its organ-specific complications.<\/jats:p>","DOI":"10.3390\/cells15020196","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T17:20:42Z","timestamp":1768929642000},"page":"196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Effects of Repeated Intravenous Injections of Autologous Adipose-Derived Mesenchymal Stromal Cells Expressing an Allogeneic MHC Protein in a Mouse Model of Diabetic Nephropathy"],"prefix":"10.3390","volume":"15","author":[{"given":"Fuxuan","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengkun","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6268-2134","authenticated-orcid":false,"given":"Ruixue","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiqi","family":"Meng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Fu","sequence":"additional","affiliation":[{"name":"Core Facilities 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Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2843-0769","authenticated-orcid":false,"given":"Jun","family":"Ma","sequence":"additional","affiliation":[{"name":"Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8701-8056","authenticated-orcid":false,"given":"Matthew D.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Research Ireland Centre for Medical Devices, School of Medicine, University of Galway, H91 TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9021-7040","authenticated-orcid":false,"given":"Cuiqing","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","unstructured":"Magliano, D.J., and Boyko, E.J. (2021). IDF Diabetes Atlas, International Diabetes Federation. [10th ed.]. Available online: https:\/\/diabetesatlas.org\/media\/uploads\/sites\/3\/2025\/02\/IDF_Atlas_10th_Edition_2021.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/s00125-015-3785-3","article-title":"Death, End-Stage Renal Disease and Renal Function Decline in Patients with Diabetic Nephropathy in French Cohorts of Type 1 and Type 2 Diabetes","volume":"59","author":"Hadjadj","year":"2016","journal-title":"Diabetologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"A8","DOI":"10.1053\/j.ajkd.2024.01.001","article-title":"US Renal Data System 2023 Annual Data Report: Epidemiology of Kidney Disease in the United States","volume":"83","author":"Johansen","year":"2024","journal-title":"Am. J. Kidney Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.3390\/jcm4061207","article-title":"The Concept and the Epidemiology of Diabetic Nephropathy Have Changed in Recent Years","volume":"4","year":"2015","journal-title":"J. Clin. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Prattichizzo, F., Candia, P., and Ceriello, A. (2021). Diabetes and Kidney Disease: Emphasis on Treatment with SGLT-2 Inhibitors and GLP-1 Receptor Agonists. Metabolism, 120.","DOI":"10.1016\/j.metabol.2021.154799"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s11892-016-0734-6","article-title":"The Promise of Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease","volume":"16","author":"Griffin","year":"2016","journal-title":"Curr. Diabetes Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1182\/blood-2003-09-3070","article-title":"Adult Stem Cells from Bone Marrow (MSCs) Isolated from Different Strains of Inbred Mice Vary in Surface Epitopes, Rates of Proliferation, and Differentiation Potential","volume":"103","author":"Peister","year":"2004","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/ni.3002","article-title":"Plasticity of Mesenchymal Stem Cells in Immunomodulation: Pathological and Therapeutic Implications","volume":"15","author":"Wang","year":"2014","journal-title":"Nat. Immunol."},{"key":"ref_9","first-page":"1","article-title":"Mesenchymal Stem Cells Prevent the Progression of Diabetic Nephropathy by Improving Mitochondrial Function in Tubular Epithelial Cells","volume":"51","author":"Lee","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41581-018-0023-5","article-title":"Immunoregulatory Mechanisms of Mesenchymal Stem and Stromal Cells in Inflammatory Diseases","volume":"14","author":"Shi","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s13287-019-1177-1","article-title":"Exosome Secreted from Adipose-Derived Stem Cells Attenuates Diabetic Nephropathy by Promoting Autophagy Flux and Inhibiting Apoptosis in Podocyte","volume":"10","author":"Jin","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.2337\/db11-1141","article-title":"Infusion of Mesenchymal Stem Cells Ameliorates Hyperglycemia in Type 2 Diabetic Rats: Identification of a Novel Role in Improving Insulin Sensitivity","volume":"61","author":"Si","year":"2012","journal-title":"Diabetes"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1681\/ASN.0000000000000189","article-title":"Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM)","volume":"34","author":"Perico","year":"2023","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Paulini, J., Higuti, E., Bastos, R.M.C., Gomes, S.A., and Rangel, \u00c9.B. (2016). Mesenchymal Stem Cells as Therapeutic Candidates for Halting the Progression of Diabetic Nephropathy. Stem Cells Int., 2016.","DOI":"10.1155\/2016\/9521629"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s13287-017-0555-9","article-title":"Differential Expression of Cell Cycle and WNT Pathway-Related Genes Accounts for Differences in the Growth and Differentiation Potential of Wharton\u2019s Jelly and Bone Marrow-Derived Mesenchymal Stem Cells","volume":"8","author":"Batsali","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lohan, P., Treacy, O., Griffin, M.D., Ritter, T., and Ryan, A.E. (2017). Anti-Donor Immune Responses Elicited by Allogeneic Mesenchymal Stem Cells and Their Extracellular Vesicles: Are We Still Learning?. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01626"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1002\/jcb.23119","article-title":"Allogeneic Mesenchymal Stem Cells: Agents of Immune Modulation","volume":"112","author":"English","year":"2011","journal-title":"J. Cell. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"F214","DOI":"10.1152\/ajprenal.00204.2005","article-title":"Impact of Genetic Background on Nephropathy in Diabetic Mice","volume":"290","author":"Gurley","year":"2006","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.2337\/diabetes.54.9.2628","article-title":"Characterization of Susceptibility of Inbred Mouse Strains to Diabetic Nephropathy","volume":"54","author":"Qi","year":"2005","journal-title":"Diabetes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal Criteria for Defining Multipotent Mesenchymal Stromal Cells. The International Society for Cellular Therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s13287-024-03647-x","article-title":"Amelioration of Diabetic Nephropathy in Mice by a Single Intravenous Injection of Human Mesenchymal Stromal Cells at Early and Later Disease Stages Is Associated with Restoration of Autophagy","volume":"15","author":"He","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1007\/s12015-021-10323-7","article-title":"Comparison of Single and Repeated Dosing of Anti-Inflammatory Human Umbilical Cord Mesenchymal Stromal Cells in a Mouse Model of Polymicrobial Sepsis","volume":"18","author":"Fazekas","year":"2022","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Torres Crigna, A., Daniele, C., Gamez, C., Medina Balbuena, S., Pastene, D.O., Nardozi, D., Brenna, C., Yard, B., Gretz, N., and Bieback, K. (2018). Stem\/Stromal Cells for Treatment of Kidney Injuries with Focus on Preclinical Models. Front. Med., 5.","DOI":"10.3389\/fmed.2018.00179"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Galleu, A., Riffo-Vasquez, Y., Trento, C., Lomas, C., Dolcetti, L., Cheung, T.S., Von Bonin, M., Barbieri, L., Halai, K., and Ward, S. (2017). Apoptosis in Mesenchymal Stromal Cells Induces in Vivo Recipient-Mediated Immunomodulation. Sci. Transl. Med., 9.","DOI":"10.1126\/scitranslmed.aam7828"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Atkinson, M.A. (2012). The Pathogenesis and Natural History of Type 1 Diabetes. Cold Spring Harb. Perspect. Med., 2.","DOI":"10.1101\/cshperspect.a007641"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Liu, Y., Lv, Y., and Zhang, T. (2023). T Cells and Their Products in Diabetic Kidney Disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1084448"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.1002\/stem.217","article-title":"Direct Imaging of Immune Rejection and Memory Induction by Allogeneic Mesenchymal Stromal Cells","volume":"27","author":"Zangi","year":"2009","journal-title":"Stem Cells"},{"key":"ref_28","first-page":"2147","article-title":"Biodistribution of Mesenchymal Stem Cells (MSCs) in Animal Models and Implied Role of Exosomes Following Systemic Delivery of MSCs: A Systematic Review","volume":"14","author":"Chan","year":"2022","journal-title":"Am. J. Transl. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1186\/s13287-017-0742-8","article-title":"Immunoprivileged No More: Measuring the Immunogenicity of Allogeneic Adult Mesenchymal Stem Cells","volume":"8","author":"Berglund","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Torre, R., Qui\u00f1ones-Vico, M.I., Fern\u00e1ndez-Gonz\u00e1lez, A., S\u00e1nchez-D\u00edaz, M., Montero-V\u00edlchez, T., Sierra-S\u00e1nchez, \u00c1., and Arias-Santiago, S. (2021). Alloreactive Immune Response Associated to Human Mesenchymal Stromal Cells Treatment: A Systematic Review. J. Clin. Med., 10.","DOI":"10.3390\/jcm10132991"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Habiba, U.E., Khan, N., Greene, D.L., Ahmad, K., Shamim, S., and Umer, A. (2024). Meta-Analysis Shows That Mesenchymal Stem Cell Therapy Can Be a Possible Treatment for Diabetes. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1380443"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhang, J., Zheng, Y., Huang, L., and He, J. (2023). Research Progress on Mesenchymal Stem Cells for the Treatment of Diabetes and Its Complications. Int. J. Endocrinol., 2023.","DOI":"10.1155\/2023\/9324270"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.jval.2021.09.012","article-title":"Key Considerations in the Health Technology Assessment of Advanced Therapy Medicinal Products in Scotland, The Netherlands, and England","volume":"25","author":"Ham","year":"2022","journal-title":"Value Health"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1017\/S0266462320000781","article-title":"Value of Mesenchymal Stem Cell Therapy for Patients with Septic Shock: An Early Health Economic Evaluation","volume":"36","author":"Thavorn","year":"2020","journal-title":"Int. J. Technol. Assess. Health Care"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.4049\/jimmunol.172.5.2731","article-title":"Of Mice and Not Men: Differences between Mouse and Human Immunology","volume":"172","author":"Mestas","year":"2004","journal-title":"J. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/196\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T05:24:51Z","timestamp":1769145891000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/196"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,20]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cells15020196"],"URL":"https:\/\/doi.org\/10.3390\/cells15020196","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,20]]}}}