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An Organotypic Human Lymph Node Model Reveals the Importance of Fibroblastic Reticular Cells for Dendritic Cell Function

  • Original Article
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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

Human lymph node (HuLN) models have emerged with invaluable potential for immunological research and therapeutic application given their fundamental role in human health and disease. While fibroblastic reticular cells (FRCs) are instrumental to HuLN functioning, their inclusion and recognition of importance for organotypic in vitro lymphoid models remain limited.

Methods:

Here, we established an in vitro three-dimensional (3D) model in a collagen-fibrin hydrogel with primary FRCs and a dendritic cell (DC) cell line (MUTZ-3 DC). To study and characterise the cellular interactions seen in this 3D FRC-DC organotypic model compared to the native HuLN; flow cytometry, immunohistochemistry, immunofluorescence and cytokine/chemokine analysis were performed.

Results:

FRCs were pivotal for survival, proliferation and localisation of MUTZ-3 DCs. Additionally, we found that CD1a expression was absent on MUTZ-3 DCs that developed in the presence of FRCs during cytokine-induced MUTZ-3 DC differentiation, which was also seen with primary monocyte-derived DCs (moDCs). This phenotype resembled HuLN-resident DCs, which we detected in primary HuLNs, and these CD1a− MUTZ-3 DCs induced T cell proliferation within a mixed leukocyte reaction (MLR), indicating a functional DC status. FRCs expressed podoplanin (PDPN), CD90 (Thy-1), CD146 (MCAM) and Gremlin-1, thereby resembling the DC supporting stromal cell subset identified in HuLNs.

Conclusion:

This 3D FRC-DC organotypic model highlights the influence and importance of FRCs for DC functioning in a more realistic HuLN microenvironment. As such, this work provides a starting point for the development of an in vitro HuLN.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The presented work was funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No. 847551 ARCAID. AM is supported by NWO ZonMw TOP Grant (91217014). AJA is supported by NWO Veni ZonMw (09150162010163). JJK is supported by NWO LymphChip (1292.19.019). CMdW is supported by Cancer Center Amsterdam (Grant No. CCA2019-9-57 and CCA2020-9-73). LJWvdL is supported by funding from the Convergence Health Technology Flagship grant (Organ Transplantation) and Medical Delta program grant (Regenerative Medicine 4D). The authors would like to thank and acknowledge the expert help of the Microscopy & Cytometry Core Facility at Amsterdam UMC (location Vrije Universiteit Amsterdam). We thank Kim Ober and Dr. Monique Verstegen from the Erasmus MC, Rotterdam for sample logistics.

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Authors and Affiliations

  1. Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands

    Andrew I. Morrison, Aleksandra M. Mikula, Sander W. Spiekstra, Michael de Kok, Alsya J. Affandi, Charlotte M. de Winde, Jasper J. Koning, Susan Gibbs & Reina E. Mebius

  2. Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands

    Andrew I. Morrison, Aleksandra M. Mikula, Sander W. Spiekstra, Michael de Kok, Alsya J. Affandi, Charlotte M. de Winde, Jasper J. Koning, Susan Gibbs & Reina E. Mebius

  3. Cancer Center Amsterdam, Amsterdam, The Netherlands

    Alsya J. Affandi & Charlotte M. de Winde

  4. Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015GD, Rotterdam, The Netherlands

    Henk P. Roest & Luc J. W. van der Laan

  5. Department Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Amsterdam, The Netherlands

    Susan Gibbs

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Contributions

Conceptualization: AIM, JJK, CMdW, SG and REM; Methodology: AIM, SWS, JJK, CMdW, SG and REM; Investigation: AIM; Validation: AIM, SWS, AJA, JJK and CMdW; Software: AM and MdK; Data curation: AIM; Writing-original draft preparation: AIM; Writing-review and editing: AIM, JJK, CMdW, SG and REM; Supervision: JJK, CMdW, SG and REM; Funding acquisition: SG and REM; Ethical approval and donor information: LJWvdL and HPR. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Reina E. Mebius.

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HuLNs were obtained from donors during liver transplant procedures performed at the Erasmus MC, Rotterdam, The Netherlands, in accordance to the Medical Ethical Committee (Medisch Ethische Toetsings Commissie; METC) of Erasmus MC (MEC-2014-060). All patients (liver transplant recipients) gave written informed consent to use their donor tissue.

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Morrison, A.I., Mikula, A.M., Spiekstra, S.W. et al. An Organotypic Human Lymph Node Model Reveals the Importance of Fibroblastic Reticular Cells for Dendritic Cell Function. Tissue Eng Regen Med 21, 455–471 (2024). https://doi.org/10.1007/s13770-023-00609-x

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