Marta Arnal‑Forné1  · Tamara Molina‑García2  · María Ortega2  · Víctor Marcos‑Garcés2,3 · Pilar Molina4  · Antonio Ferrández‑Izquierdo1,2,5 · Pilar Sepulveda1,6,7 · Vicente Bodí2,3,6,8 · César Ríos‑Navarro1,2,6 · Amparo Ruiz‑Saurí1,2,6

Accepted: 10 June 2024 / Published online: 2 July 2024

© The Author(s) 2024

Abstract

Skin represents the main barrier against the external environment, but also plays a role in human relations, as one of the prime determinants of beauty, resulting in a high consumer demand for skincare-related pharmaceutical products. Given the importance of skin aging in both medical and social spheres, the present research aims to characterize microscopic changes in human skin composition due to intrinsic aging (as opposed to aging infuenced by external factors) via histological analysis of a photoprotected body region. Samples from 25 autopsies were taken from the periumbilical area and classifed into four age groups: group 1 (0–12 years), group 2 (13–25 years), group 3 (26–54 years), and group 4 (≥55 years). Diferent traditional histological (hematoxylin–eosin, Masson’s trichrome, orcein, toluidine, Alcian blue, and Feulgen reaction) and immunohistochemical (CK20, CD1a, Ki67, and CD31) stains were performed. A total of 1879 images photographed with a Leica DM3000 optical microscope were morphometrically analyzed using Image ProPlus 7.0 for further statistical analysis with GraphPad 9.0. Our results showed a reduction in epidermis thickness, interdigitation and mitotic indexes, while melanocyte count was raised. Papillary but not reticular dermis showed increased thickness with aging. Specifcally, in the papillary layer mast cells and glycosaminoglycans were expanded, whereas the reticular dermis displayed a diminution in glycosaminoglycans and elastic fbers. Moreover, total cellularity and vascularization of both dermises were diminished with aging. This morphometric analysis of photoprotected areas reveals that intrinsic aging signifcantly infuences human skin composition. This study paves the way for further research into the molecular basis underpinning these alterations, and into potential antiaging strategies.

Keywords Skin aging · Intrinsic aging · Morphometric analysis · Human biopsies

César Ríos-Navarro 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。

* Amparo Ruiz-Saurí 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。; 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。

1 Department of Pathology, University of Valencia, Avda. Blasco Ibáñez 15. 46010, Valencia, Spain

2 Instituto de Investigación Sanitaria INCLIVA Biomedical Research Institute, Avda. Menéndez Pelayo 4acc, 46010 Valencia, Spain

3 Cardiology Department, Hospital Clínico Universitario, Valencia, Spain

4 Department of Pathology, Instituto de Medicina Legal y Ciencias Forenses, Valencia, Spain

5 Anatomic Pathology Department, Hospital Clínico Universitario, Valencia, Spain

6 Centro de Investigación Biomédica en Red (CIBER)-CV, Madrid, Spain

7 Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain

8 Department of Medicine, University of Valencia, Valencia, Spain

Anna Nicolaou a,b, ⁎, Alexandra C. Kendall a

a Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK

b Lydia Becker Institute of Immunology and Inflammation; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK

article info

Available online 17 June 2024

Associate editor: Dr. M. Curtis

Keywords:

Skin barrier

Microbiota

Bioactive lipids

Ceramides

Skin disease

Skin immunology

abstract

Our skin protects us from external threats including ultraviolet radiation, pathogens and chemicals, and prevents excessive trans-epidermal water loss. These varied activities are reliant on a vast array of lipids, many of which are unique to skin, and that support physical, microbiological and immunological barriers. The cutaneous physical barrier is dependent on a specific lipid matrix that surrounds terminally-differentiated keratinocytes in the stratum corneum. Sebum- and keratinocyte-derived lipids cover the skin's surface and support and regulate the skin microbiota. Meanwhile, lipids signal between resident and infiltrating cutaneous immune cells, driving in-flammation and its resolution in response to pathogens and other threats. Lipids of particular importance include ceramides, which are crucial for stratum corneum lipid matrix formation and therefore physical barrier functionality, fatty acids, which contribute to the acidic pH of the skin surface and regulate the microbiota, as well as the stratum corneum lipid matrix, and bioactive metabolites of these fatty acids, involved in cell signalling, inflammation, and numerous other cutaneous processes. These diverse and complex lipids maintain homeostasis in healthy skin, and are implicated in many cutaneous diseases, as well as unrelated systemic conditions with skin manifestations, and processes such as ageing. Lipids also contribute to the gut-skin axis, signalling between the two barrier sites. Therefore, skin lipids provide a valuable resource for exploration of healthy cutaneous processes, local and systemic disease development and progression, and accessible biomarker discovery for systemic disease, as well as an opportunity to fully understand the relationship between the host and the skin microbiota. Investigation of skin lipids could provide diagnostic and prognostic biomarkers, and help identify new targets for interventions. Development and improvement of existing in vitro and in silico approaches to explore the cutaneous lipidome, as well as advances in skin lipidomics technologies, will facilitate ongoing progress in skin lipid research.

© 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://

creativecommons.org/licenses/by/4.0/).

Abbreviations: ASM, Acid sphingomyelinase; ALA, α-linolenic acid; AA, arachidonic acid; AEA, arachidonoyl ethanolamine; AG, arachidonoyl glycerol; AD, atopic dermatitis; BM, basement membrane; CerS, ceramide synthase; CLA, conjugated linoleic acid; COX, cyclooxygenase; CYP450, cytochrome P450 monooxygenase; DC, dendritic cell; DGAT, diacylglycerol acyltransferase; DGLA, dihomo-γ-linolenic acid; DHA, docosahexaenoic acid; DHEA, docosahexaenoyl ethanolamine; EPA, eicosapentaenoic acid; EPA, eicosapentaenoyl ethanolamine; EV, extracellular vesicles; FATP, fatty acid transfer protein; GBA, glucocerebrosidase; GCS, glucosylceramide synthase; PC, phosphatidylcholine; HYA, 10-hydroxy cis-10-octadecanoid acid; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecaenoic acid; LC, Langerhans cell; LA, linoleic acid; LOX, lipoxygenase; LC-MS/MS, liquid chromatography coupled to tandem mass spectrometry; LPA, lysophosphatidic acid; MAG, monoacylglycerol; NSAID, non-steroidal anti-inflammatory drug; NAE, N-acyl ethanolamine; OA, oleic acid; OEA, oleoyl ethanolamine; n-3, omega-3; n-6, omega-6; C1P, phosphorylated ceramide; PEA, palmitoyl ethanolamine; PNPLA1, patatin-like phospholipase domain-containing protein 1; PPAR, peroxisome proliferator-activated receptor; PAF, platelet activating factor; PUFA, polyunsaturated fatty acid; PGI2, prostacyclin; PG, prostaglandin; SCFA, short chain fatty acid; SPT, serine palmitoyl transferase; DEGS, sphingolipid desaturase; SMS, sphingomyelin synthase; S1P, sphingosine-1-phosphate; SEA, stearoyl ethanolamine; SB, stratum basale; SC, stratum corneum; SG, stratum granulosum; SS, stratum spinosum; TX, thromboxane; TJ, tight junction; TEWL, trans-epidermal water loss; TGase, transglutaminase; Tri-HOME, trihydroxy octadecenoic acid; UVR, ultraviolet radiation; ELOVL., very long fatty acid elongase.

⁎ Corresponding author at: Division of Pharmacy and Optometry, Stopford Building, Oxford Road, University of Manchester, Manchester M13 9PT, UK.

E-mail address: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (A. Nicolaou).

This article is excerpted from the Nature | Vol 635 | 21 November 2024 by Wound World.

Nusayhah Hudaa Gopee1,2,18, Elena Winheim3,18, Bayanne Olabi1,2,18, Chloe Admane1,3, April Rose Foster3 , Ni Huang3 , Rachel A. Botting1 , Fereshteh Torabi3 , Dinithi Sumanaweera3 , Anh Phuong Le4,5,6, Jin Kim4,5,6, Luca Verger7 , Emily Stephenson1,3, Diana Adão3 , Clarisse Ganier8 , Kelly Y. Gim4,5,6, Sara A. Serdy4,5,6, CiCi Deakin4,5,6, Issac Goh1,3, Lloyd Steele3 , Karl Annusver9 , Mohi-Uddin Miah1 , Win Min Tun1,3, Pejvak Moghimi3 , Kwasi Amoako Kwakwa3 , Tong Li3 , Daniela Basurto Lozada1 , Ben Rumney3 , Catherine L. Tudor3 , Kenny Roberts3 , Nana-Jane Chipampe3 , Keval Sidhpura1 , Justin Englebert1 , Laura Jardine1 , Gary Reynolds1 , Antony Rose1,3, Vicky Rowe3 , Sophie Pritchard3 , Ilaria Mulas3 , James Fletcher1 , Dorin-Mirel Popescu1 , Elizabeth Poyner1,2, Anna Dubois2 , Alyson Guy10, Andrew Filby1 , Steven Lisgo1 , Roger A. Barker11, Ian A. Glass12, Jong-Eun Park3 , Roser Vento-Tormo3 , Marina Tsvetomilova Nikolova13, Peng He3,14, John E. G. Lawrence3 , Josh Moore15, Stephane Ballereau3 , Christine B. Hale3 , Vijaya Shanmugiah3 , David Horsfall1 , Neil Rajan1,2, John A. McGrath16, Edel A. O’Toole17, Barbara Treutlein13, Omer Bayraktar3 , Maria Kasper9 , Fränze Progatzky7 , Pavel Mazin3 , Jiyoon Lee4,5,6, Laure Gambardella3 , Karl R. Koehler4,5,6,19 ✉, Sarah A. Teichmann3,19 ✉ & Muzlifah Haniffa1,2,3,19 ✉

https://doi.org/10.1038/s41586-024-08002-x

Received: 4 August 2023

Accepted: 28 August 2024

Published online: 16 October 2024

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Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7–17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin1 . The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells.