Spatial organization of epithelial heterogeneity through undulating structures of the skin and oral mucosa

Mizuho Ishikawa; Yen Xuan Ngo; Ikuto Nishikawa; Hiroko Kato; Ryo Maeda; Ryosuke Mizuno; Jun Mizuno; Kenji Izumi; Hiromi Yanagisawa; Aiko Sada

doi:10.1016/j.jid.2026.02.014

Spatial organization of epithelial heterogeneity through undulating structures of the skin and oral mucosa

J Invest Dermatol. 2026 Mar 3:S0022-202X(26)00138-7. doi: 10.1016/j.jid.2026.02.014. Online ahead of print.

Authors

Mizuho Ishikawa¹, Yen Xuan Ngo², Ikuto Nishikawa³, Hiroko Kato⁴, Ryo Maeda⁵, Ryosuke Mizuno⁶, Jun Mizuno⁷, Kenji Izumi⁸, Hiromi Yanagisawa⁹, Aiko Sada¹⁰

Affiliations

¹ Division of Skin Regeneration and Aging, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
² International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan; Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Japan.
³ Division of Skin Regeneration and Aging, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan; Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
⁴ Division of Biomimetics, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan; Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
⁵ Taki Chemical, Kakogawa, Japan.
⁶ Komatsuseiki Kosakusho, Suwa, Japan.
⁷ National Cheng Kung University, Tainan, Taiwan.
⁸ Division of Biomimetics, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
⁹ Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan; Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
¹⁰ Division of Skin Regeneration and Aging, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan. Electronic address: aiko.sada@bioreg.kyushu-u.ac.jp.

PMID: 41786124
DOI: 10.1016/j.jid.2026.02.014

Abstract

Epithelial basal cells exhibit heterogeneity, with populations occupying specific tissue regions. Human skin displays an undulating (rete ridge) structure at the epidermal-dermal junction that supports the mechanical integrity of tissue. By contrast, murine dorsal skin lacks such pronounced undulations, limiting analyses of how tissue architecture affects the localization and behavior of distinct epithelial populations. In this study, murine oral mucosa, which possesses an undulating structure, is used to characterize the spatial organization of epithelial heterogeneity in vivo. H2B-GFP label-retaining cells (LRCs) and non-LRCs exhibit spatially biased distributions along the undulating structure, with LRC and non-LRC populations enriched in the inter-ridge and rete ridge regions, respectively. Lineage tracing with Dlx1- and Slc1a3-CreER shows that labeled cells preferentially localize to the inter-ridge and rete ridge, respectively, and that their lineage contribution to epithelial maintenance is regionally biased. RNA sequencing of the LRC and non-LRC fractions suggests their transcriptional differences and identifies Il1r2 and Slc1a3 as genes enriched in these epithelial populations. A 3-dimensional culture using micropatterned collagen scaffolds that reproduce undulating structures partially induces a spatial bias in epithelial cell proliferation. Thus, this study proposes the undulating structure as a topographical microenvironment that contributes to the spatial organization of epithelial heterogeneity in stratified epithelia.

Keywords: 3D culture; Epithelial stem cells; Lineage tracing; Oral epithelium; Rete ridge.