References
-
Liao, S. & Padera, T. P. Lymphatic function and immune regulation in health and disease. Lymphat Res. Biol. 11, 136–143. https://doi.org/10.1089/lrb.2013.0012 (2013).
-
Li, L., Wu, J., Abdi, R., Jewell, C. M. & Bromberg, J. S. Lymph node fibroblastic reticular cells steer immune responses. Trends Immunol. 42, 723–734. https://doi.org/10.1016/j.it.2021.06.006 (2021).
-
Saxena, V. et al. Role of lymph node stroma and microenvironment in T cell tolerance. Immunol. Rev. 292, 9–23. https://doi.org/10.1111/imr.12799 (2019).
-
Knoblich, K. et al. The human lymph node microenvironment unilaterally regulates T-cell activation and differentiation. Plos Biol. 16, e2005046. https://doi.org/10.1371/journal.pbio.2005046 (2018).
-
Li, L. et al. The lymph node stromal laminin alpha5 shapes alloimmunity. J. Clin. Invest. 130, 2602–2619. https://doi.org/10.1172/JCI135099 (2020).
-
Panocha, D., Roet, J. E. G., Kuipers, J. E., de Winde, C. M. & Mebius, R. E. Lymph node fibroblast-produced extracellular matrix shapes immune function. Trends Immunol. 46, 229–243. https://doi.org/10.1016/j.it.2025.02.002 (2025).
-
Berdiaki, A. et al. Extracellular matrix components and mechanosensing pathways in health and disease. Biomolecules https://doi.org/10.3390/biom14091186 (2024).
-
Sixt, M. et al. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity 22, 19–29. https://doi.org/10.1016/j.immuni.2004.11.013 (2005).
-
Longstreth, J. H. & Wang, K. The role of fibronectin in mediating cell migration. Am. J. Physiol. Cell. Physiol. 326, C1212–C1225. https://doi.org/10.1152/ajpcell.00633.2023 (2024).
-
Tremmel, D. M. et al. A human pancreatic ECM hydrogel optimized for 3-D modeling of the islet microenvironment. Sci. Rep. 12, 7188. https://doi.org/10.1038/s41598-022-11085-z (2022).
-
Bogdani, M. et al. Extracellular matrix components in the pathogenesis of type 1 diabetes. Curr. Diab. Rep. 14, 552. https://doi.org/10.1007/s11892-014-0552-7 (2014).
-
Brown, T. J., Kimpton, W. G. & Fraser, J. R. Biosynthesis of glycosaminoglycans and proteoglycans by the lymph node. Glycoconj J. 17, 795–805. https://doi.org/10.1023/a:1010940826602 (2000).
-
Kaldjian, E. P., Gretz, J. E., Anderson, A. O., Shi, Y. & Shaw, S. Spatial and molecular organization of lymph node T cell cortex: A labyrinthine cavity bounded by an epithelium-like monolayer of fibroblastic reticular cells anchored to basement membrane-like extracellular matrix. Int. Immunol. 13, 1243–1253. https://doi.org/10.1093/intimm/13.10.1243 (2001).
-
Sleeboom, J. J. F. et al. The extracellular matrix as hallmark of cancer and metastasis: From biomechanics to therapeutic targets. Sci. Transl. Med. 16, eadg3840. https://doi.org/10.1126/scitranslmed.adg3840 (2024).
-
Karsdal, M. et al. Advances in extracellular matrix-associated diagnostics and therapeutics. J. Clin. Med. https://doi.org/10.3390/jcm14061856 (2025).
-
Pickup, M. W., Mouw, J. K. & Weaver, V. M. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 15, 1243–1253. https://doi.org/10.15252/embr.201439246 (2014).
-
Willcox, A. et al. Germinal centre frequency is decreased in pancreatic lymph nodes from individuals with recent-onset type 1 diabetes. Diabetologia 60, 1294–1303. https://doi.org/10.1007/s00125-017-4221-7 (2017).
-
Sun, F. et al. Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes. Cell. Biosci. 13, 156. https://doi.org/10.1186/s13578-023-01110-7 (2023).
-
Gonzalez Badillo, F. et al. Tissue-engineered stromal reticula to study lymph node fibroblastic reticular cells in type I diabetes. Cell. Mol. Bioeng. 13, 419–434. https://doi.org/10.1007/s12195-020-00627-y (2020).
-
Hahnlein, J. S. et al. Impaired lymph node stromal cell function during the earliest phases of rheumatoid arthritis. Arthritis Res. Ther. 20, 35. https://doi.org/10.1186/s13075-018-1529-8 (2018).
-
Crapo, P. M., Gilbert, T. W. & Badylak, S. F. An overview of tissue and whole organ decellularization processes. Biomaterials 32, 3233–3243. https://doi.org/10.1016/j.biomaterials.2011.01.057 (2011).
-
Citro, A. et al. Directed self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes. Nat. Commun. 14, 878. https://doi.org/10.1038/s41467-023-36582-1 (2023).
-
Petrou, C. L. et al. Clickable decellularized extracellular matrix as a new tool for building hybrid-hydrogels to model chronic fibrotic diseases in vitro. J. Mater. Chem. B 8, 6814–6826. https://doi.org/10.1039/d0tb00613k (2020).
-
da Palma, R. K. et al. Equine lung decellularization: A potential approach for in vitro modeling the role of the extracellular matrix in asthma. J. Tissue Eng. 9, 2041731418810164. https://doi.org/10.1177/2041731418810164 (2018).
-
Dosh, R. H., Jordan-Mahy, N., Sammon, C. & Le Maitre, C. L. Long-term in vitro 3D hydrogel co-culture model of inflammatory bowel disease. Sci. Rep. 9, 1812. https://doi.org/10.1038/s41598-019-38524-8 (2019).
-
Zhang, R. et al. Analysis of structural components of decellularized scaffolds in renal fibrosis. Bioact. Mater. 6, 2187–2197. https://doi.org/10.1016/j.bioactmat.2020.12.028 (2021).
-
Zhang, X. et al. Decellularized extracellular matrix scaffolds: Recent trends and emerging strategies in tissue engineering. Bioact. Mater. 10, 15–31. https://doi.org/10.1016/j.bioactmat.2021.09.014 (2022).
-
Lin, H. J. et al. Decellularized lymph node scaffolding as a carrier for dendritic cells to induce anti-tumor immunity. Pharmaceutics https://doi.org/10.3390/pharmaceutics11110553 (2019).
-
Kang, H. J. et al. Recellularized lymph node scaffolds with human adipose-derived stem cells enhance lymph node regeneration to improve lymphedema. Sci. Rep. 13, 5397. https://doi.org/10.1038/s41598-023-32473-z (2023).
-
Liu, J. et al. Bioactive scaffolds for tissue engineering: A review of decellularized extracellular matrix applications and innovations. Exploration 5, 20230078. https://doi.org/10.1002/EXP.20230078 (2025).
-
Shevchuk, O. I. et al. Application of decellularization methods for scaffold production: Advantages, disadvantages, biosafety and modifications. Front. Bioeng. Biotechnol. 13, 1621641. https://doi.org/10.3389/fbioe.2025.1621641 (2025).
-
Cuzzone, D. A., Albano, N. J., Aschen, S. Z., Ghanta, S. & Mehrara, B. J. Decellularized lymph nodes as scaffolds for tissue engineered lymph nodes. Lymphat. Res. Biol. 13, 186–194. https://doi.org/10.1089/lrb.2013.0054 (2015).
-
Choi, Y. S. et al. Immunomodulatory scaffolds derived from lymph node extracellular matrices. ACS Appl. Mater. Interfaces 13, 14037–14049. https://doi.org/10.1021/acsami.1c02542 (2021).
-
Liu, S. et al. Vibratome sectioning of tumors to evaluate the interactions between nanoparticles and the tumor microenvironment ex-vivo. Front. Bioeng. Biotechnol. 10, 1007151. https://doi.org/10.3389/fbioe.2022.1007151 (2022).
-
Li, Y. et al. Precision vibratome for high-speed ultrathin biotissue cutting and organ-wide imaging. iScience 24, 103016. https://doi.org/10.1016/j.isci.2021.103016 (2021).
-
Siwczak, F., Hiller, C., Pfannkuche, H. & Schneider, M. R. Culture of vibrating microtome tissue slices as a 3D model in biomedical research. J. Biol. Eng. 17, 36. https://doi.org/10.1186/s13036-023-00357-5 (2023).
-
Wang, Q., Bechet, N. B. & Lindstedt, S. Automated vibratome sectioning of agarose-embedded lung tissue for multiplex fluorescence imaging. J. Vis. Exp. https://doi.org/10.3791/65943 (2023).
-
Doke, M. et al. Dynamic scRNA-seq of live human pancreatic slices reveals functional endocrine cell neogenesis through an intermediate ducto-acinar stage. Cell Metab. 35, 1944–1960. https://doi.org/10.1016/j.cmet.2023.10.001 (2023).
-
Panzer, J. K. et al. Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesis. JCI Insight https://doi.org/10.1172/jci.insight.134525 (2020).
-
He, L. & Deng, C. Recent advances in organotypic tissue slice cultures for anticancer drug development. Int. J. Biol. Sci. 18, 5885–5896. https://doi.org/10.7150/ijbs.78997 (2022).
-
Katakai, T., Hara, T., Sugai, M., Gonda, H. & Shimizu, A. Lymph node fibroblastic reticular cells construct the stromal reticulum via contact with lymphocytes. J. Exp. Med. 200, 783–795. https://doi.org/10.1084/jem.20040254 (2004).
-
Teles, L. N. et al. Engineered macroporous gelatin scaffolds enhance lymph node fibroblastic reticular cell identity and enable diabetogenic T cell immunomodulation. Biomaterials 324, 123460. https://doi.org/10.1016/j.biomaterials.2025.123460 (2025).
-
Philips, C., Terrie, L., Muylle, E. & Thorrez, L. Determination of DNA content as quality control in decellularized tissues: Challenges and pitfalls. Regen Biomater. 11, 123. https://doi.org/10.1093/rb/rbae123 (2024).
-
Ban, E. & Kim, A. PicoGreen assay for nucleic acid quantification—Applications, challenges, and solutions. Anal. Biochem. 692, 115577. https://doi.org/10.1016/j.ab.2024.115577 (2024).
-
Cho, D. H., Aguayo, S. & Cartagena-Rivera, A. X. Atomic force microscopy-mediated mechanobiological profiling of complex human tissues. Biomaterials 303, 122389. https://doi.org/10.1016/j.biomaterials.2023.122389 (2023).
-
Ziebarth, N. M., Wojcikiewicz, E. P., Manns, F., Moy, V. T. & Parel, J. M. Atomic force microscopy measurements of lens elasticity in monkey eyes. Mol. Vis. 13, 504–510 (2007).
-
Fletcher, A. L. et al. Reproducible isolation of lymph node stromal cells reveals site-dependent differences in fibroblastic reticular cells. Front. Immunol. 2, 35. https://doi.org/10.3389/fimmu.2011.00035 (2011).
-
Krishnamurthy, B. et al. Autoimmunity to both proinsulin and IGRP is required for diabetes in nonobese diabetic 8.3 TCR transgenic mice. J. Immunol. 180, 4458–4464. https://doi.org/10.4049/jimmunol.180.7.4458 (2008).
-
Gilpin, A. & Yang, Y. Decellularization strategies for regenerative medicine: From processing techniques to applications. Biomed. Res. Int. 2017, 9831534. https://doi.org/10.1155/2017/9831534 (2017).
-
Faulk, D. M. et al. The effect of detergents on the basement membrane complex of a biologic scaffold material. Acta Biomater. 10, 183–193. https://doi.org/10.1016/j.actbio.2013.09.006 (2014).
-
White, L. J. et al. The impact of detergents on the tissue decellularization process: A ToF-SIMS study. Acta Biomater. 50, 207–219. https://doi.org/10.1016/j.actbio.2016.12.033 (2017).
-
Yue, B. Biology of the extracellular matrix: An overview. J Glaucoma 23, S20-23. https://doi.org/10.1097/IJG.0000000000000108 (2014).
-
Roet, J. E. G. et al. Human lymph node fibroblastic reticular cells maintain heterogeneous characteristics in culture. iScience 27, 110179. https://doi.org/10.1016/j.isci.2024.110179 (2024).
-
Horikawa, S. et al. PDGFRalpha plays a crucial role in connective tissue remodeling. Sci. Rep. 5, 17948. https://doi.org/10.1038/srep17948 (2015).
-
Kang, X. et al. Pdgfralpha(+) stromal cells, a key regulator for tissue homeostasis and dysfunction in distinct organs. Genes. Dis. 12, 101264. https://doi.org/10.1016/j.gendis.2024.101264 (2025).
-
Yao, L. et al. Temporal control of PDGFRalpha regulates the fibroblast-to-myofibroblast transition in wound healing. Cell Rep. 40, 111192. https://doi.org/10.1016/j.celrep.2022.111192 (2022).
-
Huang, J. et al. Extracellular matrix and its therapeutic potential for cancer treatment. Signal Transduct. Target Ther. 6, 153. https://doi.org/10.1038/s41392-021-00544-0 (2021).
-
Yuan, Z. et al. Extracellular matrix remodeling in tumor progression and immune escape: From mechanisms to treatments. Mol. Cancer 22, 48. https://doi.org/10.1186/s12943-023-01744-8 (2023).
-
Marangio, A. et al. The study of the extracellular matrix in chronic inflammation: A way to prevent cancer initiation?. Cancers https://doi.org/10.3390/cancers14235903 (2022).
-
Liao, Z. et al. Lymph node-biomimetic scaffold boosts CAR-T therapy against solid tumor. Natl. Sci. Rev. 11, nwae018. https://doi.org/10.1093/nsr/nwae018 (2024).
-
Liu, B. et al. An engineered lymph node comprising porous collagen scaffold with hybridized biological signals embedded in B cell membrane coatings. Biomaterials 304, 122420. https://doi.org/10.1016/j.biomaterials.2023.122420 (2024).
-
Ozulumba, T., Montalbine, A. N., Ortiz-Cardenas, J. E. & Pompano, R. R. New tools for immunologists: Models of lymph node function from cells to tissues. Front. Immunol. 14, 1183286. https://doi.org/10.3389/fimmu.2023.1183286 (2023).
-
Shou, Y., Johnson, S. C., Quek, Y. J., Li, X. & Tay, A. Integrative lymph node-mimicking models created with biomaterials and computational tools to study the immune system. Mater. Today Bio. 14, 100269. https://doi.org/10.1016/j.mtbio.2022.100269 (2022).
-
Wang, Q. et al. Lymph node-on-chip technology: Cutting-edge advances in immune microenvironment simulation. Pharmaceutics https://doi.org/10.3390/pharmaceutics16050666 (2024).
-
Neishabouri, A., Soltani Khaboushan, A., Daghigh, F., Kajbafzadeh, A. M. & Majidi Zolbin, M. Decellularization in tissue engineering and regenerative medicine: Evaluation, modification, and application methods. Front. Bioeng. Biotechnol. 10, 805299. https://doi.org/10.3389/fbioe.2022.805299 (2022).
-
Fernandez-Perez, J. & Ahearne, M. The impact of decellularization methods on extracellular matrix derived hydrogels. Sci. Rep. 9, 14933. https://doi.org/10.1038/s41598-019-49575-2 (2019).
-
Moffat, D., Ye, K. & Jin, S. Decellularization for the retention of tissue niches. J. Tissue Eng. 13, 20417314221101150. https://doi.org/10.1177/20417314221101151 (2022).
-
Kalli, M., Poskus, M. D., Stylianopoulos, T. & Zervantonakis, I. K. Beyond matrix stiffness: Targeting force-induced cancer drug resistance. Trends Cancer 9, 937–954. https://doi.org/10.1016/j.trecan.2023.07.006 (2023).
-
Willard-Mack, C. L. Normal structure, function, and histology of lymph nodes. Toxicol Pathol. 34, 409–424. https://doi.org/10.1080/01926230600867727 (2006).
-
Wang, B. et al. Ultrasound elastography for the evaluation of lymph nodes. Front. Oncol. 11, 714660. https://doi.org/10.3389/fonc.2021.714660 (2021).
-
Qin, Q., Wang, D., Xu, L., Lan, Y. & Tong, M. Evaluating lymph node stiffness to differentiate bacterial cervical lymphadenitis and lymph node-first presentation of Kawasaki disease by shear wave elastography. J. Ultrasound Med. 40, 1371–1380. https://doi.org/10.1002/jum.15518 (2021).
-
Herman, J. et al. The role of ultrasound and shear-wave elastography in evaluation of cervical lymph nodes. Biomed. Res. Int. 2019, 4318251. https://doi.org/10.1155/2019/4318251 (2019).
-
Assen, F. P. et al. Multitier mechanics control stromal adaptations in the swelling lymph node. Nat. Immunol. 23, 1246–1255. https://doi.org/10.1038/s41590-022-01257-4 (2022).
-
Hwang, J. et al. Molecular assessment of collagen denaturation in decellularized tissues using a collagen hybridizing peptide. Acta Biomater. 53, 268–278. https://doi.org/10.1016/j.actbio.2017.01.079 (2017).
-
Jarde, T. et al. Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids. Nat. Commun. 7, 13207. https://doi.org/10.1038/ncomms13207 (2016).
-
Li, X., Ootani, A. & Kuo, C. An air-liquid interface culture system for 3D organoid culture of diverse primary gastrointestinal tissues. Methods Mol. Biol 1422, 33–40. https://doi.org/10.1007/978-1-4939-3603-8_4 (2016).
-
Valdoz, J. C. et al. Soluble ECM promotes organotypic formation in lung alveolar model. Biomaterials 283, 121464. https://doi.org/10.1016/j.biomaterials.2022.121464 (2022).
