Histological and functional characterization of 3D human skin models mimicking the inflammatory skin diseases psoriasis and atopic dermatitis
Open accessAbstract
Three-dimensional (3D) human skin equivalents have emerged as valuable tools in skin research, replacing animal experimentation and precluding the need for patient biopsies. In this study, we advanced 3D skin equivalents to model the inflammatory skin diseases atopic dermatitis and psoriasis by cytokine stimulation, and were successful in integrating TH1 T cells into skin models to develop an immunocompetent 3D psoriasis model. We performed in-depth histological and functional characterization of 3D skin equivalents and validated them in terms of tissue architecture, pathological changes, expression of antimicrobial peptides and Staphylococcus aureus colonization using 3D reconstruction by multiphoton microscopy and phenotyping by highly multiplexed ‘co-detection by indexing’ (CODEX) microscopy. We show that our skin equivalents have a structural architecture with a well-developed dermis and epidermis, thus resembling human skin. In addition, the skin models of atopic dermatitis and psoriasis show several phenotypic features of inflammatory skin disease, including disturbed epidermal differentiation and alterations in the expression of epidermal barrier genes and antimicrobial peptides, and can be reliably used to test novel treatment strategies. Therefore, these 3D equivalents will be a valuable tool in experimental dermatological research.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
aHSE models offer high customization, facilitating control over organotypic cell populations, genotypes, and culture conditions, thereby enabling controlled studies on tissue-level biology.
“aHSE models offer a high degree of customization, facilitating control over organotypic cell populations, genotypes, and culture conditions, thereby enabling meticulously controlled studies on tissue-level biology [59].”
From Diversity of human skin three-dimensional organotypic cultures (2024) · cites this paper as [59]
The expansion of aHSEs enhances the application of OTC models for investigating therapeutic techniques, particularly in mimicking inflammatory skin diseases like psoriasis and atopic dermatitis, and in studying skin-related bacterial adhesion and infection.
“This expansion enhances the application of OTC models for investigating potential therapeutic techniques [18,60], particularly in mimicking inflammatory skin diseases like psoriasis and atopic dermatitis [59], while also studying skin-related bacterial adhesion and infection [22,45].”
From Diversity of human skin three-dimensional organotypic cultures (2024) · cites this paper as [59]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Human reconstructed skin xenografts on mice to model skin physiology
Salgado, G., Ng, Y. Z., Koh, L. F., Goh, C. S. M., & Common, J. E. (2017) · Differentiation · doi:10.1016/j.diff.2017.09.004 · Cited by 56 · see citing works
Flagged first, then by citations
Research works printed but not linked: 46
- Abeck, D. and Mempel, M. (1998). Staphylococcus aureus colonization in atopic dermatitis and its therapeutic implications. Br. J. Dermatol. 139, 13- 16. 10.1046/j.1365-2133.1998.1390s3013.x 9990408 · DOI
- Ali, N., Hosseini, M., Vainio, S., Taieb, A., Cario-Andre, M. and Rezvani, H. R. (2015). Skin equivalents: skin from reconstructions as models to study skin development and diseases. Br. J. Dermatol. 173, 391- 403. 10.1111/bjd.13886 25939812 · DOI
- Bankhead, P., Loughrey, M. B., Fernández, J. A., Dombrowski, Y., McArt, D. G., Dunne, P. D., McQuaid, S., Gray, R. T., Murray, L. J., Coleman, H. G. et al. (2017). QuPath: Open source software for digital pathology image analysis. Sci. Rep. 7, 16878. 10.1038/s41598-017-17204-5 29203879 PMC5715110 · DOI · Paper page
- Berning, M., Prätzel-Wunder, S., Bickenbach, J. R. and Boukamp, P. (2015). Three-dimensional In Vitro skin and skin cancer models based on human fibroblast-derived matrix. Tissue Eng. Part C Methods 21, 958- 970. 10.1089/ten.tec.2014.0698 25837604 · DOI
- Bissonnette, R., Papp, K. A., Poulin, Y., Gooderham, M., Raman, M., Mallbris, L., Wang, C., Purohit, V., Mamolo, C., Papacharalambous, J. et al. (2016). Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br. J. Dermatol. 175, 902- 911. 10.1111/bjd.14871 27423107 · DOI
- Bitschar, K., Sauer, B., Focken, J., Dehmer, H., Moos, S., Konnerth, M., Schilling, N. A., Grond, S., Kalbacher, H., Kurschus, F. C. et al. (2019). Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors. Nat. Commun. 10, 2730. 10.1038/s41467-019-10646-7 31227691 PMC6588697 · DOI
- Black, S., Phillips, D., Hickey, J. W., Kennedy-Darling, J., Venkataraaman, V. G., Samusik, N., Goltsev, Y., Schurch, C. M. and Nolan, G. P. (2021). CODEX multiplexed tissue imaging with DNA-conjugated antibodies. Nat. Protoc. 16, 3802. 10.1038/s41596-021-00556-8 34215862 PMC8647621 · DOI
- Burian, M., Bitschar, K., Dylus, B., Peschel, A. and Schittek, B. (2017). The protective effect of microbiota on s-aureus skin colonization depends on the integrity of the epithelial barrier. J. Investig. Dermatol. 137, 976- 979. 10.1016/j.jid.2016.11.024 27923738 · DOI
- Chen, W. Y., Chen, S. C., Hsu, S. Y., Lin, Y. A., Shih, C. M., Huang, C. Y., Wang, K. H. and Lee, A. W. (2022). Annoying psoriasis and atopic dermatitis: a narrative review. Int. J. Mol. Sci. 23, 4898. 10.3390/ijms23094898 35563285 PMC9104570 · DOI
- Clarysse, K., Pfaff, C. M., Marquardt, Y., Huth, L., Krohn, I. K., Kluwig, D., Luscher, B., Gutermuth, J. and Baron, J. (2019). JAK1/3 inhibition preserves epidermal morphology in full-thickness 3D skin models of atopic dermatitis and psoriasis. J. Eur. Acad. Dermatol. Venereol. 33, 367- 375. 10.1111/jdv.15301 30357932 · DOI
- Danso, M. O., van Drongelen, V., Mulder, A., van Esch, J., Scott, H., van Smeden, J., El Ghalbzouri, A. and Bouwstra, J. A. (2014). TNF-alpha and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents. J. Investig. Dermatol. 134, 1941- 1950. 10.1038/jid.2014.83 24518171 · DOI
- De Vuyst, E., Giltaire, S., Lambert de Rouvroit, C., Malaisse, J., Mound, A., Bourtembourg, M., Poumay, Y., Nikkels, A. F., Chretien, A. and Salmon, M. (2018). Methyl-beta-cyclodextrin concurs with interleukin (IL)-4, IL-13 and IL-25 to induce alterations reminiscent of atopic dermatitis in reconstructed human epidermis. Exp. Dermatol. 27, 435- 437. 10.1111/exd.13113 27304612 · DOI
- Dickson, M. A., Hahn, W. C., Ino, Y., Ronfard, V., Wu, J. Y., Weinberg, R. A., Louis, D. N., Li, F. P. and Rheinwald, J. G. (2000). Human keratinocytes that express hTERT and also bypass a p16(INK4a)-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics. Mol. Cell. Biol. 20, 1436- 1447. 10.1128/MCB.20.4.1436-1447.2000 10648628 PMC85304 · DOI · Paper page
- Facy, V., Flouret, V., Regnier, M. and Schmidt, R. (2005). Reactivity of Langerhans cells in human reconstructed epidermis to known allergens and UV radiation. Toxicol. In Vitro 19, 787- 795. 10.1016/j.tiv.2005.03.018 15921883 · DOI
- Fiset, P. O., Leung, D. Y. M. and Hamid, Q. (2006). Immunopathology of atopic dermatitis. J. Allergy Clin. Immunol. 118, 287- 290. 10.1016/j.jaci.2006.03.046 16815171 · DOI
- Garzorz-Stark, N., Krause, L., Lauffer, F., Atenhan, A., Thomas, J., Stark, S. P., Franz, R., Weidinger, S., Balato, A., Mueller, N. S. et al. (2016). A novel molecular disease classifier for psoriasis and eczema. Exp. Dermatol. 25, 767- 774. 10.1111/exd.13077 27193975 · DOI
- Gerber, P. A., Buhren, B. A., Schrumpf, H., Homey, B., Zlotnik, A. and Hevezi, P. (2014). The top skin-associated genes: a comparative analysis of human and mouse skin transcriptomes. Biol. Chem. 395, 577- 591. 10.1515/hsz-2013-0279 24497224 · DOI · Paper page
- Guttman-Yassky, E. and Krueger, J. G. (2017). Atopic dermatitis and psoriasis: two different immune diseases or one spectrum? Curr. Opin. Immunol. 48, 68- 73. 10.1016/j.coi.2017.08.008 28869867 · DOI
- Kamsteeg, M., Bergers, M., de Boer, R., Zeeuwen, P. L., Hato, S. V., Schalkwijk, J. and Tjabringa, G. S. (2011). Type 2 helper T-cell cytokines induce morphologic and molecular characteristics of atopic dermatitis in human skin equivalent. Am. J. Pathol. 178, 2091- 2099. 10.1016/j.ajpath.2011.01.037 21514424 PMC3081201 · DOI
- Kennedy-Darling, J., Bhate, S. S., Hickey, J. W., Black, S., Barlow, G. L., Vazquez, G., Venkataraaman, V. G., Samusik, N., Goltsev, Y., Schurch, C. M. et al. (2021). Highly multiplexed tissue imaging using repeated oligonucleotide exchange reaction. Eur. J. Immunol. 51, 1262- 1277. 10.1002/eji.202048891 33548142 PMC8251877 · DOI
- Kryczek, I., Bruce, A. T., Gudjonsson, J. E., Johnston, A., Aphale, A., Vatan, L., Szeliga, W., Wang, Y., Liu, Y., Welling, T. H. et al. (2008). Induction of IL-17(+) T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. J. Immunol. 181, 4733- 4741. 10.4049/jimmunol.181.7.4733 18802076 PMC2677162 · DOI
- Lorthois, I., Asselineau, D., Seyler, N. and Pouliot, R. (2017). Contribution of In Vivo and organotypic 3D models to understanding the role of macrophages and neutrophils in the pathogenesis of psoriasis. Mediat. Inflamm. 2017, 7215072. 10.1155/2017/7215072 PMC5698795 29249871 · DOI
- Lowes, M. A., Kikuchi, T., Fuentes-Duculan, J., Cardinale, I., Zaba, L. C., Haider, A. S., Bowman, E. P. and Krueger, J. G. (2008). Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J. Investig. Dermatol. 128, 1207- 1211. 10.1038/sj.jid.5701213 18200064 · DOI
- Mestas, J. and Hughes, C. C. (2004). Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731- 2738. 10.4049/jimmunol.172.5.2731 14978070 · DOI · Paper page
- Moon, S., Kim, D. H. and Shin, J. U. (2021). In Vitro models mimicking immune response in the skin. Yonsei Med. J. 62, 969- 980. 10.3349/ymj.2021.62.11.969 34672130 PMC8542468 · DOI
- Nestle, F. O., Kaplan, D. and Barker, J. (2009). Psoriasis. N. Engl. J. Med. 361, 496- 509. 10.1056/NEJMra0804595 19641206 · DOI
- Niehues, H. and van den Bogaard, E. H. (2018). Past, present and future of in vitro 3D reconstructed inflammatory skin models to study psoriasis. Exp. Dermatol. 27, 512- 519. 10.1111/exd.13525 29502346 · DOI
- Niehues, H., Bouwstra, J. A., El Ghalbzouri, A., Brandner, J. M., Zeeuwen, P. and van den Bogaard, E. H. (2018). 3D skin models for 3R research: The potential of 3D reconstructed skin models to study skin barrier function. Exp. Dermatol. 27, 501- 511. 10.1111/exd.13531 29518287 · DOI · Paper page
- Nomura, I., Goleva, E., Howell, M. D., Hamid, Q. A., Ong, P. Y., Hall, C. F., Darst, M. A., Gao, B. F., Boguniewicz, M., Travers, J. B. et al. (2003). Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J. Immunol. 171, 3262- 3269. 10.4049/jimmunol.171.6.3262 12960356 · DOI
- O'Shea, J. J. and Murray, P. J. (2008). Cytokine signaling modules in inflammatory responses. Immunity 28, 477- 487. 10.1016/j.immuni.2008.03.002 18400190 PMC2782488 · DOI
- O'Shea, J. J., Schwartz, D. M., Villarino, A. V., Gadina, M., McInnes, I. B. and Laurence, A. (2015). The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu. Rev. Med. 66, 311- 328. 10.1146/annurev-med-051113-024537 25587654 PMC5634336 · DOI
- Ong, P. Y., Ohtake, T., Brandt, C., Strickland, I., Boguniewicz, M., Ganz, T., Gallo, R. L. and Leung, D. Y. M. (2002). Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347, 1151- 1160. 10.1056/NEJMoa021481 12374875 · DOI · Paper page
- Papp, K. A., Krueger, J. G., Feldman, S. R., Langley, R. G., Thaci, D., Torii, H., Tyring, S., Wolk, R., Gardner, A., Mebus, C. et al. (2016). Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study. J. Am. Acad. Dermatol. 74, 841- 850. 10.1016/j.jaad.2016.01.013 26899199 · DOI
- Pasparakis, M., Haase, I. and Nestle, F. O. (2014). Mechanisms regulating skin immunity and inflammation. Nat. Rev. Immunol. 14, 289- 301. 10.1038/nri3646 24722477 · DOI
- Randall, M. J., Jungel, A., Rimann, M. and Wuertz-Kozak, K. (2018). Advances in the biofabrication of 3D skin in vitro: healthy and pathological models. Front. Bioeng. Biotechnol. 6, 154. 10.3389/fbioe.2018.00154 30430109 PMC6220074 · DOI
- Schabitz, A., Eyerich, K. and Garzorz-Stark, N. (2021). So close, and yet so far away: The dichotomy of the specific immune response and inflammation in psoriasis and atopic dermatitis. J. Intern. Med. 290, 27- 39. 10.1111/joim.13235 33428274 · DOI
- Schürch, C. M., Bhate, S. S., Barlow, G. L., Phillips, D. J., Noti, L., Zlobec, I., Chu, P., Black, S., Demeter, J., McIlwain, D. R. et al. (2020). Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. Cell 182, 1341- 1359.e19. 10.1016/j.cell.2020.07.005 32763154 PMC7479520 · DOI
- Shin, J. U., Abaci, H. E., Herron, L., Guo, Z. Y., Sallee, B., Pappalardo, A., Jackow, J., Wang, E. H. C., Doucet, Y. and Christiano, A. M. (2020). Recapitulating T cell infiltration in 3D psoriatic skin models for patient-specific drug testing. Sci. Rep. 10, 4123. 10.1038/s41598-020-60275-0 32139717 PMC7057979 · DOI
- Smits, J. P. H., Niehues, H., Rikken, G., van Vlijmen-Willems, I., van de Zande, G., Zeeuwen, P., Schalkwijk, J. and van den Bogaard, E. H. (2017). Immortalized N/TERT keratinocytes as an alternative cell source in 3D human epidermal models. Sci. Rep. 7, 11838. 10.1038/s41598-017-12041-y 28928444 PMC5605545 · DOI
- Stanton, D. N., Ganguli-Indra, G., Indra, A. K. and Karande, P. (2022). Bioengineered efficacy models of skin disease: advances in the last 10 years. Pharmaceutics 14, 319. 10.3390/pharmaceutics14020319 35214050 PMC8877988 · DOI · Paper page
- Takahashi, T. and Yamasaki, K. (2020). Psoriasis and antimicrobial peptides. Int. J. Mol. Sci. 21, 6791. 10.3390/ijms21186791 32947991 PMC7555190 · DOI
- Todorovic, V., McDonald, H. A., Hoover, P., Wetter, J. B., Marinopoulos, A. E., Woody, C. L., Miller, L., Finkielsztein, A., Dunstan, R. W., Paller, A. S. et al. (2022). Cytokine induced 3-D organotypic psoriasis skin model demonstrates distinct roles for NF-kappa B and JAK pathways in disease pathophysiology. Exp. Dermatol. 31, 1036- 1047. 10.1111/exd.14551 35213752 PMC9283227 · DOI
- van den Bogaard, E. H., Tjabringa, G. S., Joosten, I., Vonk-Bergers, M., van Rijssen, E., Tijssen, H. J., Erkens, M., Schalkwijk, J. and Koenen, H. (2014). Crosstalk between keratinocytes and T cells in a 3D microenvironment: a model to study inflammatory skin diseases. J. Invest. Dermatol. 134, 719- 727. 10.1038/jid.2013.417 24121402 · DOI
- van den Broek, L. J., Bergers, L., Reijnders, C. M. A. and Gibbs, S. (2017). Progress and future prospectives in skin-on-chip development with emphasis on the use of different cell types and technical challenges. Stem Cell Rev. 13, 418- 429. 10.1007/s12015-017-9737-1 PMC5486511 28536890 · DOI
- Weng, W. H., Liao, Y. H., Tsai, M. R., Wei, M. L., Huang, H. Y. and Sun, C. K. (2016). Differentiating intratumoral melanocytes from Langerhans cells in nonmelanocytic pigmented skin tumors in vivo by label-free third-harmonic generation microscopy. J. Biomed. Opt. 21, 76009. 10.1117/1.JBO.21.7.076009 27424606 · DOI
- Zhou, X., Chen, Y., Cui, L., Shi, Y. and Guo, C. (2022). Advances in the pathogenesis of psoriasis: from keratinocyte perspective. Cell Death Dis. 13, 81. 10.1038/s41419-022-04523-3 35075118 PMC8786887 · DOI
Cited by
Sorted by citations
Diversity of human skin three-dimensional organotypic cultures
Jia, Y. Y., & Atwood, S. X. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102275 · Cited by 12 · see citing works
- Authors
- Scheurer, J., Sauer, B., Focken, J., Giampetraglia, M., Jäger, A., Schürch, C. M., Weigelin, B., & Schittek, B.
- Affiliations
- Universitätsklinikum Tübingen (DE)
- University of Tübingen (DE)
- Corresponding author
- Schittek, Birgit
- ORCID
- Venue
- Disease Models & Mechanisms
- Publisher
- The Company of Biologists
- Published
- 2024-01-01
- Volume
- 17
- Issue
- 1
- ISSN
- 1754-8403 (ISSN-L)
- 1754-8411
- PMC
- PMC10846593
- OpenAlex
- W4391109243
- Cited by
- 21
- References
- 1
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 5
- FWCI
- 8.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Disease Models & Mechanisms (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Deutsche Forschungsgemeinschaft (SCHI510-12/1, EXC 2180e390900677, TR156)
- Medizinischen Fakultät, Eberhard Karls Universität Tübingen (2022-1-22)
- Topics
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Keywords
- 3D skin equivalents, psoriasis, atopic dermatitis, inflammatory skin diseases, Th1 cells, antimicrobial peptides, Staphylococcus aureus colonization, epidermal differentiation, multiphoton microscopy, alternatives to animal testing
- MeSH terms
- Antimicrobial Peptides, Animals, Dermatitis, Atopic, Epidermis, Humans, Psoriasis, Skin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review