Journal of Molecular Medicine

, Volume 98, Issue 1, pp 111–122 | Cite as

Increased presence and differential molecular imprinting of transit amplifying cells in psoriasis

  • Katrin Witte
  • Karsten Jürchott
  • Demetrios Christou
  • Jochen Hecht
  • Gabriela Salinas
  • Ulrike Krüger
  • Oliver Klein
  • Georgios Kokolakis
  • Ellen Witte-Händel
  • Rotraut Mössner
  • Hans-Dieter Volk
  • Kerstin Wolk
  • Robert SabatEmail author
Original Article


Psoriasis is a very common chronic inflammatory skin disease characterized by epidermal thickening and scaling resulting from keratinocyte hyperproliferation and impaired differentiation. Pathomechanistic studies in psoriasis are often limited by using whole skin tissue biopsies, neglecting their stratification and cellular diversity. This study aimed at characterizing epidermal alterations in psoriasis at the level of keratinocyte populations. Epidermal cell populations were purified from skin biopsies of psoriasis patients and healthy donors using a novel cell type-specific approach. Molecular characterization of the transit-amplifying cells (TAC), the key players of epidermal renewal, was performed using immunocytofluorescence-technique and integrated multiscale-omics analyses. Already TAC from non-lesional psoriatic skin showed altered methylation and differential expression in 1.7% and 1.0% of all protein-coding genes, respectively. In psoriatic lesions, TAC were strongly expanded showing further increased differentially methylated (10-fold) and expressed (22-fold) genes numbers. Importantly, 17.2% of differentially expressed genes were associated with respective gene methylations. Compared with non-lesional TAC, pathway analyses revealed metabolic alterations as one feature predominantly changed in TAC derived from active psoriatic lesions. Overall, our study showed stage-specific molecular alterations, allows new insights into the pathogenesis, and implies the involvement of epigenetic mechanisms in lesion development in psoriasis.

Key messages

  • Transit amplifying cell (TAC) numbers are highly increased in psoriatic lesions

  • Psoriatic TAC show profound molecular alterations & stage-specific identity

  • TAC from unaffected areas already show first signs of molecular alterations

  • Lesional TAC show a preference in metabolic-related alterations


Psoriasis Keratinocytes Transit amplifying cells Methylome Transcriptome Integrated multiscale-omics Epigenetic 



We would like to thank Jenny Kirsch and Toralf Kaiser from the Flow Cytometry Core Facility of the German Rheumatism Research Center (DRFZ, Berlin, Germany) for their kind support in performing cell sorting experiments.

Funding information

The study was partly supported by Novartis Pharma GmbH (grant to Charité Universitätsmedizin Berlin (RS)); the funder was not involved in the study design, data collection, data analysis, manuscript preparation, and/or publication decisions. Furthermore, the study was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-WI 4760/2-1.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics statement

All skin samples were approved by the clinical institutional review board of the Charité University Hospital, Berlin, and written informed consent was obtained from all participants. The study was conducted according to the Declaration of Helsinki Principles.

Supplementary material

109_2019_1860_MOESM1_ESM.docx (3.8 mb)
ESM 1 (DOCX 3877 kb)


  1. 1.
    Fuchs E (2008) Skin stem cells: rising to the surface. J Cell Biol 180:273–284CrossRefGoogle Scholar
  2. 2.
    Sabat R, Philipp S, Hoflich C, Kreutzer S, Wallace E, Asadullah K, Volk HD, Sterry W, Wolk K (2007) Immunopathogenesis of psoriasis. Exp Dermatol 16:779–798CrossRefGoogle Scholar
  3. 3.
    Schon MP, Boehncke WH (2005) Psoriasis. N Engl J Med 352:1899–1912CrossRefGoogle Scholar
  4. 4.
    Martin JC, Wolk K, Beriou G, Abidi A, Witte-Handel E, Louvet C, Kokolakis G, Drujont L, Dumoutier L, Renauld JC et al (2017) Limited presence of IL-22 binding protein, a natural IL-22 inhibitor, strengthens psoriatic skin inflammation. J Immunol 198:3671–3678CrossRefGoogle Scholar
  5. 5.
    Pfaff CM, Marquardt Y, Fietkau K, Baron JM, Luscher B (2017) The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function. Sci Rep 7:15631CrossRefGoogle Scholar
  6. 6.
    Sabat R, Wolk K, Loyal L, Docke WD, Ghoreschi K (2019) T cell pathology in skin inflammation. Semin Immunopathol 41:359–377CrossRefGoogle Scholar
  7. 7.
    Pollock RA, Abji F, Gladman DD (2017) Epigenetics of psoriatic disease: a systematic review and critical appraisal. J Autoimmun 78:29–38CrossRefGoogle Scholar
  8. 8.
    Roberson ED, Liu Y, Ryan C, Joyce CE, Duan S, Cao L, Martin A, Liao W, Menter A, Bowcock AM (2012) A subset of methylated CpG sites differentiate psoriatic from normal skin. J Invest Dermatol 132:583–592CrossRefGoogle Scholar
  9. 9.
    Verma D, Ekman AK, Bivik Eding C, Enerback C (2017) Genome-wide DNA methylation profiling identifies differential methylation in uninvolved psoriatic epidermis. J Invest DermatolGoogle Scholar
  10. 10.
    Zhang P, Zhao M, Liang G, Yin G, Huang D, Su F, Zhai H, Wang L, Su Y, Lu Q (2013) Whole-genome DNA methylation in skin lesions from patients with psoriasis vulgaris. J Autoimmun 41:17–24CrossRefGoogle Scholar
  11. 11.
    Zhou F, Wang W, Shen C, Li H, Zuo X, Zheng X, Yue M, Zhang C, Yu L, Chen M et al (2016) Epigenome-wide association analysis identified nine skin DNA methylation loci for psoriasis. J Invest Dermatol 136:779–787CrossRefGoogle Scholar
  12. 12.
    Wolk K, Wenzel J, Tsaousi A, Witte-Handel E, Babel N, Zelenak C, Volk HD, Sterry W, Schneider-Burrus S, Sabat R (2017) Lipocalin-2 is expressed by activated granulocytes and keratinocytes in affected skin and reflects disease activity in acne inversa/hidradenitis suppurativa. Br J Dermatol 177:1385–1393CrossRefGoogle Scholar
  13. 13.
    Wolk K, Witte K, Witte E, Raftery M, Kokolakis G, Philipp S, Schonrich G, Warszawska K, Kirsch S, Prosch S, et al. (2013) IL-29 is produced by T(H)17 cells and mediates the cutaneous antiviral competence in psoriasis. Sci Transl Med 5: 204ra129CrossRefGoogle Scholar
  14. 14.
    Lienhard M, Grimm C, Morkel M, Herwig R, Chavez L (2014) MEDIPS: genome-wide differential coverage analysis of sequencing data derived from DNA enrichment experiments. Bioinformatics 30:284–286CrossRefGoogle Scholar
  15. 15.
    Witte-Handel E, Wolk K, Tsaousi A, Irmer ML, Mossner R, Shomroni O, Lingner T, Witte K, Kunkel D, Salinas G et al (2019) The IL-1 pathway is hyperactive in Hidradenitis Suppurativa and contributes to skin infiltration and destruction. J Invest Dermatol 139:1294–1305CrossRefGoogle Scholar
  16. 16.
    Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550CrossRefGoogle Scholar
  17. 17.
    Durinck S, Spellman PT, Birney E, Huber W (2009) Mapping identifiers for the integration of genomic datasets with the R/bioconductor package biomaRt. Nat Protoc 4:1184–1191CrossRefGoogle Scholar
  18. 18.
    Yates A, Akanni W, Amode MR, Barrell D, Billis K, Carvalho-Silva D, Cummins C, Clapham P, Fitzgerald S, Gil L et al (2016) Ensembl 2016. Nucleic Acids Res 44:D710–D716CrossRefGoogle Scholar
  19. 19.
    Webb A, Li A, Kaur P (2004) Location and phenotype of human adult keratinocyte stem cells of the skin. Differentiation 72:387–395CrossRefGoogle Scholar
  20. 20.
    Weinstein GD, McCullough JL, Ross PA (1985) Cell kinetic basis for pathophysiology of psoriasis. J Invest Dermatol 85:579–583CrossRefGoogle Scholar
  21. 21.
    Gangatirkar P, Paquet-Fifield S, Li A, Rossi R, Kaur P (2007) Establishment of 3D organotypic cultures using human neonatal epidermal cells. Nat Protoc 2:178–186CrossRefGoogle Scholar
  22. 22.
    Hsu YC, Li L, Fuchs E (2014) Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157:935–949CrossRefGoogle Scholar
  23. 23.
    Strickland FM, Richardson BC (2008) Epigenetics in human autoimmunity. Epigenetics in autoimmunity-DNA methylation in systemic lupus erythematosus and beyond Autoimmunity 41:278–286PubMedGoogle Scholar
  24. 24.
    Rodriguez E, Baurecht H, Wahn AF, Kretschmer A, Hotze M, Zeilinger S, Klopp N, Illig T, Schramm K, Prokisch H et al (2014) An integrated epigenetic and transcriptomic analysis reveals distinct tissue-specific patterns of DNA methylation associated with atopic dermatitis. J Invest Dermatol 134:1873–1883CrossRefGoogle Scholar
  25. 25.
    Gu X, Nylander E, Coates PJ, Fahraeus R, Nylander K (2015) Correlation between reversal of DNA methylation and clinical symptoms in psoriatic epidermis following narrow-band UVB phototherapy. J Invest Dermatol 135:2077–2083CrossRefGoogle Scholar
  26. 26.
    Bock C, Tomazou EM, Brinkman AB, Muller F, Simmer F, Gu H, Jager N, Gnirke A, Stunnenberg HG, Meissner A (2010) Quantitative comparison of genome-wide DNA methylation mapping technologies. Nat Biotechnol 28:1106–1114CrossRefGoogle Scholar
  27. 27.
    Yong WS, Hsu FM, Chen PY (2016) Profiling genome-wide DNA methylation. Epigenetics Chromatin 9:26CrossRefGoogle Scholar
  28. 28.
    De Meyer T, Bady P, Trooskens G, Kurscheid S, Bloch J, Kros JM, Hainfellner JA, Stupp R, Delorenzi M, Hegi ME et al (2015) Genome-wide DNA methylation detection by MethylCap-seq and Infinium HumanMethylation450 BeadChips: an independent large-scale comparison. Sci Rep 5:15375CrossRefGoogle Scholar
  29. 29.
    Trimarchi MP, Murphy M, Frankhouser D, Rodriguez BA, Curfman J, Marcucci G, Yan P, Bundschuh R (2012) Enrichment-based DNA methylation analysis using next-generation sequencing: sample exclusion, estimating changes in global methylation, and the contribution of replicate lanes. BMC genomics 13(Suppl 8):S6CrossRefGoogle Scholar
  30. 30.
    Brinkman AB, Simmer F, Ma K, Kaan A, Zhu J, Stunnenberg HG (2010) Whole-genome DNA methylation profiling using MethylCap-seq. Methods 52:232–236CrossRefGoogle Scholar
  31. 31.
    Ai R, Hammaker D, Boyle DL, Morgan R, Walsh AM, Fan S, Firestein GS, Wang W (2016) Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat Commun 7:11849CrossRefGoogle Scholar
  32. 32.
    Sadler T, Bhasin JM, Xu Y, Barnholz-Sloan J, Chen Y, Ting AH, Stylianou E (2016) Genome-wide analysis of DNA methylation and gene expression defines molecular characteristics of Crohn’s disease-associated fibrosis. Clin Epigenetics 8:30CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.BIH Center for Regenerative Therapies (BCRT)Charité–UniversitätsmedizinBerlinGermany
  2. 2.Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical ImmunologyCharité–UniversitätsmedizinBerlinGermany
  3. 3.Psoriasis Research and Treatment Center, Department of Dermatology and Allergy and Institute of Medical ImmunologyCharité–UniversitätsmedizinBerlinGermany
  4. 4.Institute for Medical ImmunologyCharité–UniversitätsmedizinBerlinGermany
  5. 5.Centre for Genomic Regulation (CRG)BarcelonaSpain
  6. 6.Department of Developmental Biochemistry, Transcriptome and Genome Analysis FacilityUniversity of GöttingenGöttingenGermany
  7. 7.Department of DermatologyUniversity Medical Center GöttingenGöttingenGermany

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