Mechanical stimuli-induced CCL2 restores adult mouse cells to regenerate hair follicles

Wang Wu; Wei Zhou; Jingwei Jiang; Mengyue Wang; Jinwei Zhang; Jing Yang; Qu Tang; Huawen Liu; Deming Liu; Wei Xu; Julia Li Zhong; Li Yang; Mingxing Lei

doi:10.1016/j.omtn.2023.03.002

Mechanical stimuli-induced CCL2 restores adult mouse cells to regenerate hair follicles

Mol Ther Nucleic Acids. 2023 Mar 10:32:94-110. doi: 10.1016/j.omtn.2023.03.002. eCollection 2023 Jun 13.

Authors

Wang Wu^{1

2}, Wei Zhou³, Jingwei Jiang¹, Mengyue Wang¹, Jinwei Zhang¹, Jing Yang², Qu Tang², Huawen Liu², Deming Liu^{1

4}, Wei Xu⁴, Julia Li Zhong¹, Li Yang¹, Mingxing Lei¹

Affiliations

¹ 111 Project Laboratory of Biomechanics and Tissue Repair & Key Laboratory of Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
² Three Gorges Hospital, Chongqing University, Chongqing 404000, China.
³ Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
⁴ Department of Dermatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China.

Abstract

Aged cells have declined regenerative ability when subjected to environmental insult. Here we elucidate the mechanism by which mechanical stimulus induces hair regeneration at the microenvironmental regulation level using the hair plucking and organoid culture models. We observed that the skin cells harvested from post-plucking day 3 (PPD3) have the best self-organizing ability during skin organoid culture and have the highest hair regeneration upon transplantation. By bulk RNA sequencing (RNA-seq) and single-cell RNA-seq analysis and in situ hybridization, we identified that the chemokine signaling pathway genes including CCL2 are significantly increased in the skin at PPD3 and in skin organoid cultures. Immunostaining shows that the PPD3 skin epithelial cells have increased multipotency, which is verified by the ability to self-organize to form epidermal aggregates during organoid culture. By adding CCL2 recombinant protein to the organoid culture using an environmental reprogramming protocol, we observed the PPD0 adult skin cells, which lose their regenerative ability can self-organize in organoid culture and regenerate hair follicles robustly upon transplantation. Our study demonstrates that CCL2 functions in immune regulation of hair regeneration under mechanical stimulus, and enhances cell multipotency during organoid culture. This provides a therapeutic potential for future clinical application.

Keywords: MT: Special Issue - Exploiting Extracellular Vesicles as Therapeutic Agents; chemokine; hair regeneration; immune regulation; mechanical stimuli; organoids; stem cells.