Collier DA, Ferreira IATM, Kotagiri P, Datir RP, Lim EY, Touizer E, et al. Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2. Nature. 2021;596:417–22.
Iuliano AD, Roguski KM, Chang HH, Muscatello DJ, Palekar R, Tempia S, et al. Estimates of global seasonal influenza-associated respiratory mortality: a modeling study. Lancet. 2018;391:1285–1300.
Krammer F, Smith GJD, Fouchier RAM, Peiris M, Kedzierska K, Doherty PC, et al. Influenza. Nat Rev Dis Prim. 2018;4:3.
Bulloch MN. Treatment and prevention of influenza in geriatric patients. Expert Rev Clin Pharm. 2023;16:825–41.
Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of randomized controlled trials. Lancet. 2015;385:1729–37.
Li J, Hui A, Zhang X, Yang Y, Tang R, Ye H, et al. Safety and immunogenicity of the SARS-CoV-2 BNT162b1 mRNA vaccine in younger and older Chinese adults: a randomized, placebo-controlled, double-blind phase 1 study. Nat Med. 2021;27:1062–70.
Van Heer C, Majumdar SS, Parta I, Martinie M, Dawson R, West D, et al. Effectiveness of community-based oral antiviral treatments against severe COVID-19 outcomes in people 70 years and over in Victoria, Australia, 2022: an observational study. Lancet Regional Health West Pac. 2023;41:100917.
Yousefzadeh MJ, Flores RR, Zhu Y, Schmiechen ZC, Brooks RW, Trussoni CE, et al. An aged immune system drives senescence and aging of solid organs. Nature. 2021;594:100–5.
Turner VM, Mabbott NA. Influence of aging on the microarchitecture of the spleen and lymph nodes. Biogerontology. 2017;18:723–38.
Silva-Cayetano A, Linterman MA. Stromal cell control of conventional and ectopic germinal center reactions. Curr Opin Immunol. 2020;64:26–33.
Mesin L, Ersching J, Victora GD. Germinal center B-cell dynamics. Immunity. 2016;45:471–82.
Lee JL, Fra-Bido SC, Burton AR, Innocentin S, Hill DL, Linterman MA. B-cell-intrinsic changes with age do not impact antibody-secreting cell formation but delay B-cell participation in the germinal center reaction. Aging Cell. 2022;21:e13692.
Lee, JL, Innocentin S, Silva-Cayetano A, Guillaume SM, Linterman, MA. B cells from aged mice do not have intrinsic defects in affinity maturation in response to immunization. J Immunol. 2023;211:1506–15.
Alexandre YO, Schienstock D, Lee HJ, Gandolfo LC, Williams CG, Devi S, et al. A diverse fibroblastic stromal cell landscape in the spleen directs tissue homeostasis and immunity. Sci Immunol. 2022;7:eabj0641.
Krishnamurty AT, Turley SJ. Lymph node stromal cells: cartographers of the immune system. Nat Immunol. 2020;21:369–80.
Pezoldt J, Wiechers C, Erhard F, Rand U, Bulat T, Beckstette M, et al. Single-cell transcriptional profiling of splenic fibroblasts reveals subset-specific innate immune signatures in homeostasis and during viral infection. Commun Biol. 2021;4:1355.
Alexandre YO, Mueller SN. Splenic stromal niches in homeostasis and immunity. Nat Rev Immunol. 2023;23:705–19.
Mueller SN, Matloubian M, Clemens DM, Sharpe AH, Freeman GJ, Gangappa S, et al. Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc Natl Acad Sci USA. 2007;104:15430–5.
Aydar Y, Balogh P, Tew JG, Szakal AK. Follicular dendritic cells in aging, a “bottle-neck” in the humoral immune response. Aging Res Rev. 2004;3:15–29.
Turner VM, Mabbott NA. Structural and functional changes to lymph nodes in aging mice. Immunology. 2017;151:239–47.
Burton AR, Guillaume SM, Foster WS, Wheatley AK, Hill DL, Carr EJ, et al. The memory B-cell response to influenza vaccination is impaired in older persons. Cell Rep. 2022;41:111613.
Allen CDC, Cyster JG. Follicular dendritic cell networks of primary follicles and germinal centers: phenotype and function. Semin Immunol. 2008;20:14–25.
Pikor NB, Mörbe U, Lütge M, Gil-Cruz C, Perez-Shibayama C, Novkovic M, et al. Remodeling of light and dark zone follicular dendritic cells governs germinal center responses. Nat Immunol. 2020;21:649–59.
Cremasco V, Woodruff MC, Onder L, Cupovic J, Nieves-Bonilla JM, Schildberg FA, et al. B-cell homeostasis and follicle confines are governed by fibroblastic reticular cells. Nat Immunol. 2014;15:973–81.
Denton AE, Dooley J, Cinti I, Silva-Cayetano A, Fra-Bido S, Innocentin S, et al. Targeting TLR4 during vaccination boosts MAdCAM-1 + lymphoid stromal cell activation and promotes the aged germinal center response. Sci Immunol. 2022;7:eabk0018.
Zhou J. Mesenchymal stem/stromal cells (MSCs): origin, immune regulation, and clinical applications. Cell Mol Immunol. 2023;20:555–7.
Soliman H, Theret M, Scott W, Hill L, Underhill TM, Hinz B, et al. Multipotent stromal cells: one name, multiple identities. Cell Stem Cell. 2021;28:1690–707.
Song N, Scholtemeijer M, Shah K. Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential. Trends Pharmacol Sci. 2020;41:653–64.
Copp G, Robb KP, Viswanathan S. Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success. Cell Mol Immunol. 2023;20:626–50.
Lei J, Xin Z, Liu N, Ning T, Jing Y, Qiao Y, et al. Senescence-resistant human mesenchymal progenitor cells counter aging in primates. Cell. 2025;188:5039–61.e35. https://doi.org/10.1016/j.cell.2025.05.021.
Yang X, Li Q, Liu W, Zong C, Wei L, Shi Y, et al. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment. Cell Mol Immunol. 2023;20:583–99.
Xia C, Wang T, Cheng H, Dong Y, Weng Q, Sun G, et al. Mesenchymal stem cells suppress leukemia via macrophage-mediated functional restoration of bone marrow microenvironment. Leukemia. 2020;34:2375–83.
Pittenger MF, Discher DE, Péault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. npj Regen Med. 2019;4:22.
Krampera M, Le Blanc K. Mesenchymal stromal cells: putative microenvironmental modulators become cell therapy. Cell Stem Cell. 2021;28:1708–25.
Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol. 2014;15:1009–16.
Zhang X, He J, Zhao K, Liu S, Xuan L, Chen S, et al. Mesenchymal stromal cells ameliorate chronic GVHD by boosting thymic regeneration in a CCR9-dependent manner in mice. Blood Adv. 2023;7:5359–73.
Wang Y, Fang J, Liu B, Shao C, Shi Y. Reciprocal regulation of mesenchymal stem cells and immune responses. Cell Stem Cell. 2022;29:1515–30.
Kadri N, Amu S, Iacobaeus E, Boberg E, Le Blanc K. Current perspectives on mesenchymal stromal cell therapy for graft versus host disease. Cell Mol Immunol. 2023;20:613–25.
NMPA.gov. https://www.nmpa.gov.cn/zhuanti/cxylqx/cxypxx/20250102192741146.html.
Jiang G, Zou Y, Zhao D, Yu J. Optimizing vaccine immunogenicity in aging populations: key strategies. Lancet Infect Dis. 2025;25:e23–33.
Gustafsson K, Isaev S, Mirsanaye K, Hofmann J, Kooshesh KA, Baryawno N, et al. Mesenchymal thymic niche cells enable regeneration of the adult thymus and T cell immunity. Nat Biotechnol. 2025; https://doi.org/10.1038/s41587-025-02864-w.
Huang Y, Wang J, Lai X, Qiu Y, Cai J, Ma Y, et al. Mesenchymal stromal cells attenuate poststroke infection by preventing caspase-1-dependent splenic marginal zone B-cell death. Sig Transduct Target Ther. 2021;6:60.
El-naseery NI, Mousa HSE, Noreldin AE, El-Far AH, Elewa YHA. Aging-associated immunosenescence via alterations in splenic immune cell populations in rats. Life Sci. 2020;241:117168.
Cappellesso-Fleury S, Puissant-Lubrano B, Apoil PA, Titeux M, Winterton P, Casteilla L, et al. Human fibroblasts share immunosuppressive properties with bone marrow mesenchymal stem cells. J Clin Immunol. 2010;30:607–19.
Blasi A, Martino C, Balducci L, Saldarelli M, Soleti A, Navone SE, et al. Dermal fibroblasts display similar phenotypic and differentiation capacity to fat-derived mesenchymal stem cells, but differ in anti-inflammatory and angiogenic potential. Vasc Cell. 2011;3:5.
Sukegawa M, Miyagawa Y, Kuroda S, Yamazaki Y, Yamamoto M, Adachi K, et al. Mesenchymal stem cell origin contributes to the antitumor effect of oncolytic virus carriers. Mol Ther Oncol. 2024;32:200896.
Galipeau J, Sensébé L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell. 2018;22:824–33.
Viswanathan S, Galipeau J. Hallmarks of MSCs: key quality attributes for pharmacology and clinical use. Cell Stem Cell. 2025;32:878–94.
Lee JH, Sutton HJ, Cottrell CA, Phung I, Ozorowski G, Sewall LM, et al. Long-primed germinal centers with enduring affinity maturation and clonal migration. Nature. 2022;609:998–1004.
The unique biology of germinal center B cells: immunity. https://www.cell.com/immunity/fulltext/S1074-7613(21)00301-0.
Kasmani MY, Topchyan P, Brown AK, Brown RJ, Wu X, Chen Y, et al. A spatial sequencing atlas of age-induced changes in the lung during influenza infection. Nat Commun. 2023;14:6597.
Dugan HL, Henry C, Wilson PC. Aging and influenza vaccine-induced immunity. Cell Immunol. 2020;348:103998.
Zhao Y, Liu J, Peng C, Guo S, Wang B, Chen L, et al. Cross-protection against homo and heterologous influenza viruses via intranasal administration of an HA chimeric multiepitope nanoparticle vaccine. J Nanobiotechnol. 2025;23:77.
Boyoglu-Barnum S, Ellis D, Gillespie RA, Hutchinson GB, Park YJ, Moin SM, et al. Quadrivalent influenza nanoparticle vaccines induce broad protection. Nature. 2021;592:623–8.
Cao J, Hou S, Ding H, Liu Z, Song M, Qin X, et al. In vivo tracking of systemically administered allogeneic bone marrow mesenchymal stem cells in normal rats through bioluminescence imaging. Stem Cells Int. 2016;2016:3970942.
Xue J, Gao J, Gu Y, Wang A, Yu S, Li B, et al. Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes. Stem Cell Res Ther. 2022;13:109.
Wuttisarnwattana P, Eid S, Gargesha M, Cooke KR, Wilson DL. Cryo-imaging of stem cell biodistribution in mouse model of graft-versus-host-disease. Ann Biomed Eng. 2020;48:1702–11.
Mebius RE, Kraal G. Structure and function of the spleen. Nat Rev Immunol. 2005;5:606–16.
Castagnaro L, Lenti E, Maruzzelli S, Spinardi L, Migliori E, Farinello D, et al. Nkx2-5+Islet1+ mesenchymal precursors generate distinct spleen stromal cell subsets and participate in restoring stromal network integrity. Immunity. 2013;38:782–91.
Grunewald M, Kumar S, Sharife H, Volinsky E, Gileles-Hillel A, Licht T, et al. Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span. Science. 2021;373:eabc8479.
Zhao G, Xue L, Weiner AI, Gong N, Adams-Tzivelekidis S, Wong J, et al. TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue. Sci Transl Med. 2024;16:eadg6229.
Gerber H-P, Malik AK, Solar GP, Sherman D, Liang XH, Meng G, et al. VEGF regulates hematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417:954–8.
Favier B, Alam A, Barron P, Bonnin J, Laboudie P, Fons P, et al. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood. 2006;108:1243–50.
Alam A, Herault JP, Barron P, Favier B, Fons P, Delesque-Touchard N, et al. Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity. Biochem Biophys Res Commun. 2004;324:909–15.
Monaghan RM, Page DJ, Ostergaard P, Keavney BD. The physiological and pathological functions of VEGFR3 in cardiac and lymphatic development and related diseases. Cardiovas Res. 2021;117:1877–90.
Lee H-K, Lee S-M, Lee D-I. Corneal lymphangiogenesis: current pathophysiological understandings and its functional role in ocular surface disease. IJMS. 2021;22:11628.
Wang X, Bove AM, Simone G, Ma B. Molecular bases of VEGFR-2-mediated physiological function and pathological role. Front Cell Dev Biol. 2020;8:599281.
Lee C, Kim MJ, Kumar A, Lee HW, Yang Y, Kim Y. Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives. Sig Transduct Target Ther. 2025;10:170.
Qu J, Yang F, Zhu T, Wang Y, Fang W, Ding Y, et al. A reference single-cell regulomic and transcriptomic map of cynomolgus monkeys. Nat Commun. 2022;13:4069.
Krammer F. The human antibody response to influenza A virus infection and vaccination. Nat Rev Immunol. 2019;19:383–97.
Aiello A, Farzaneh F, Candore G, Caruso C, Davinelli S, Gambino CM, et al. Immunosenescence and its hallmarks: How to oppose aging strategically? a review of potential options for therapeutic intervention. Front Immunol. 2019;10:2247.
Bajaj V, Gadi N, Spihlman AP, Wu SC, Choi CH, Moulton VR. Aging, immunity, and COVID-19: How age influences the host immune response to coronavirus infections?. Front Physiol. 2021;11:571416.
Hou Y, Chen M, Bian Y, Hu Y, Chuan J, Zhong L, et al. Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies. npj Vaccines. 2024;9:77.
Chen J, Deng JC, Goldstein DR. How aging impacts vaccine efficacy: known molecular and cellular mechanisms and future directions. Trends Mol Med. 2022;28:1100–11.
Lee JL, Linterman MA. Mechanisms underpinning poor antibody responses to vaccines in aging. Immunol Lett. 2022;241:1–14.
Mueller SN, Germain RN. Stromal cell contributions to the homeostasis and functionality of the immune system. Nat Rev Immunol. 2009;9:618–29.
Silva-Cayetano A, Fra-Bido S, Robert PA, Innocentin S, Burton AR, Watson EM, et al. Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging. Nat Immunol. 2023;24:1124–37.
Golub R, Tan J, Watanabe T, Brendolan A. Origin and immunological functions of spleen stromal cells. Trends Immunol. 2018;39:503–14.
Cheng H-W, Onder L, Novkovic M, Soneson C, Lütge M, Pikor N, et al. Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp. Nat Commun. 2019;10:1739.
Heesters BA. Follicular dendritic cells: dynamic antigen libraries. Nat Rev Immunol. 2014;14:495–504.
Keren A, Bertolini M, Keren Y, Ullmann Y, Paus R, Gilhar A. Human organ rejuvenation by VEGF-A: lessons from the skin. Sci Adv. 2022;8:eabm6756.
Huang M, Ji Y, Chen J, Li D, Zhou T, Qi P, et al. Targeted VEGFA therapy in regulating early acute kidney injury and late fibrosis. Acta Pharm Sin. 2023;44:1815–25.
Bao Y, Liu J, Li Z, Sun Y, Chen J, Ma Y, et al. Ex vivo-generated human CD1c+ regulatory B cells by a chemically defined system suppress immune responses and alleviate graft-versus-host disease. Mol Ther. 2024;32:4372–82.
Huang J, Huang W, Yi J, Deng Y, Li R, Chen J, et al. Mesenchymal stromal cells alleviate depressive and anxiety-like behaviors via a lung vagal-to-brain axis in male mice. Nat Commun. 2023;14:7406.
Zhang X, Wei X, Deng Y, Yuan X, Shi J, Huang W, et al. Mesenchymal stromal cells alleviate acute respiratory distress syndrome through the cholinergic anti-inflammatory pathway. Signal Transduct Target Ther. 2022;7:307.
Zhang X, Huang W, Chen X, Lian Y, Wang J, Cai C, et al. CXCR5-overexpressing mesenchymal stromal cells exhibit enhanced homing and can decrease contact hypersensitivity. Mol Ther. 2017;25:1434–47.
Dervovic D, Malik AA, Chen ELY, Narimatsu M, Adler N, Afiuni-Zadeh S, et al. In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer. Nat Commun. 2023;14:3150.
Empey KM, Peebles RS, Janssen WJ. Mouse models of viral infection. Lung Innate Immun Inflamm. 2018;1809:395–414.
Barman TK, Huber VC, Bonin JL, Califano D, Salmon SL, McKenzie ANJ, et al. Viral PB1-F2 and host IFN-γ guide ILC2 and T-cell activity during influenza virus infection. Proc Natl Acad Sci USA. 2022;119:e2118535119.
Wang T, Sharma AK, Wu C, Maushart CI, Ghosh A, Yang W, et al. Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes. Cell Metab. 2024;36:2130–45.e7.
Denton AE, Roberts EW, Linterman MA, Fearon DT. Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells. Proc Natl Acad Sci USA. 2014;111:12139–44.
Bauer SA, Arndt TP, Leslie KE, Pearl DL, Turner PV. Obesity in rhesus and cynomolgus macaques: a comparative review of the condition and its implications for research. Compar Med. 2011;61:514–26.