YAP/TAZ signalling pathway in modelling human skin development using induced pluripotent cells

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Directed three-dimensional differentiation of induced human pluripotent cells resulted in dermal organoids with hair follicles, keratinising epidermis and a number of other skin derivatives formation. The analysis of gene expression at different stages of dermal organoid development revealed patterns of expression dynamics and co-expression patterns of YAP/TAZ signalling pathway components both in this model of three-dimensional differentiation and in the analysis of data from the differentiation of neural stem progenitor cells in the mesenchymal direction under two-dimensional conditions. Based on these results, we hypothesise that YAP together with TEAD3 regulates the formation of multilayered epidermis and hair follicles, while TAZ is predominantly involved in mesenchyme development and TEAD2 is involved in early neural crest differentiation. The YAP/TAZ signalling cascade is involved in epithelio-mesenchyme interactions in human skin development, as activity of this cascade has been detected in both epidermis and dermis. Thus, in the course of this work, the expression and coexpression patterns of members of the YAP/TAZ signalling cascade were characterised for the first time in the modelling of human facial scalp skin morphogenesis.

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M. Pankratova

Koltzov Institute of Developmental Biology of the Russian Academy of Sciences

编辑信件的主要联系方式.
Email: masha.pankratova25@bk.ru
俄罗斯联邦, Moscow

A. Riabinin

Koltzov Institute of Developmental Biology of the Russian Academy of Sciences

Email: andrey951233@mail.ru
俄罗斯联邦, Moscow

Е. Kalabusheva

Koltzov Institute of Developmental Biology of the Russian Academy of Sciences

Email: masha.pankratova25@bk.ru
俄罗斯联邦, Moscow

Z. Starinnov

Koltzov Institute of Developmental Biology of the Russian Academy of Sciences

Email: masha.pankratova25@bk.ru
俄罗斯联邦, Moscow

E. Vorotelyak

Koltzov Institute of Developmental Biology of the Russian Academy of Sciences

Email: masha.pankratova25@bk.ru
俄罗斯联邦, Moscow

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3. Fig. 1. Experimental scheme.

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4. Fig. 2. Morphology of developing skin organoids at different stages during induced differentiation. Arrows indicate forming HF rudiments. Scale bars are given in each image (100 and 200 μm). Phase contrast microscopy.

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5. Fig. 3. Immunohistochemical detection of p63, Epcam at day 6 (a) and vimentin (Vim), K18, collagen IV and Sox2 at day 15 of differentiation (b) in skin organoids. Scale bars are given in each image (200 μm and 400 μm). Nuclei are stained with DAPI. Fluorescence microscopy.

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6. Fig. 4. Immunohistochemical detection of vimentin (Vim), K1 and K14 in skin organoids at day 29 (a), Twist1, Sox2 at day 60 (b) and Sox2 at day 72 of differentiation (c). DC – dermal condensate, DP – dermal papilla. Scale bars are given in each image (200 and 400 μm). Nuclei are stained with DAPI. Fluorescence microscopy.

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7. Fig. 5. Immunohistochemical detection of K15, K10, vimentin (Vim), K71, AE13, and loricrin in skin organoids at day 110 of differentiation. DL – differentiated layers, BS – basal layer, HS – hair shaft, IRS – inner root sheath. Scale bars are given in each image (100 and 400 μm). Nuclei are stained with DAPI. Fluorescence microscopy.

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8. Fig. 6. Results of identification of different cell populations in skin organoids based on spatial analysis of the transcriptome on days 29, 60, 72, 90, and 110 of differentiation. Top — distribution of cell population clusters in the section plane, bottom — clusters in two-dimensional t-SNE space. Scale bar 250 μm.

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9. Fig. 7. Violin plots showing the expression of YAP1 (a), TAZ (b), CYR61 (c), and CTGF (d) in isolated cell populations within skin organoids at five differentiation time points (days 29, 60, 72, 90, and 110). The height of the plot reflects the level of gene expression, and the width represents the percentage of cells in the population expressing the gene at a given level.

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10. Fig. 8. Violin plots showing the expression of TEAD1 (a), TEAD2 (b), TEAD3 (c), TEAD4 (d) in isolated cell populations within skin organoids at five differentiation time points (days 29, 60, 72, 90, and 110). The height of the graph reflects the level of gene expression, the width is the percentage of cells in the population expressing the gene at a given level.

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11. Fig. 9. Immunohistochemical detection of p63 and YAP in skin organoids at days 6, 29, 60, 72, and 110 of differentiation. Nuclei were stained with DAPI. Fluorescence microscopy. Scale bars are given in each image (50, 200, and 500 μm).

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12. Fig. 10. Immunohistochemical detection of p63 and TAZ in skin organoids at days 6, 29, 60, 72, and 110 of differentiation. Nuclei are stained with DAPI. Fluorescence microscopy. Scale bars are given in each image (50, 200, and 500 μm).

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13. Fig. 11. Immunohistochemical detection of collagen III, Twist1, and YAP (a) together with TAZ (b) in skin organoids at days 60 and 110 of organoid differentiation. Nuclei are stained with DAPI. Fluorescence microscopy. Scale bars are given in each image (100 and 500 μm).

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14. Fig. 12. Heat map illustrating co-expression of the major genes involved in the YAP/TAZ cascade at the same transcript capture sites in the epidermal, mesenchymal, dermal, and neuroglial clusters of organoids at days 6, 29, 60, 72, 90, and 110 of development. Co-expression levels are given as decimal fractions of 1, where 1 is 100% colocalization.

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15. Fig. 13. Heat map illustrating the expression of the main genes participating in the YAP/TAZ cascade for all samples (hIPSC-NSPC [negative control], hIPSC-DP after 2, 4, 6 and 8 weeks of differentiation and hDP [positive control]).

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16. Fig. 14. In the epidermal group of cells, the active form of YAP is localized in the nuclei at late stages of differentiation, where it forms a complex with TEAD3 and participates in the development of the epidermis and the epithelial part of the HF. In the dermal group, at late stages, TAZ is localized in the nuclei of fibroblasts, forming a complex with various TEADs and participating in the morphogenesis of the dermis. In the neuroglial group of cells as part of organoids and at different points of differentiation of hIPSC-NSPCs into hIPSC-DPs, the transcription factor YAP/TAZ-TEAD2 is involved in YAP/TAZ signaling.

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1 Дополнительные материалы доступны в электронном виде по DOI статьи: 10.31857/S0475145025020018


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