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

Open access

Check for updates

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.