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Research Article | Open Access

Self-organizing three-dimensional dermal papilla cell spheroids yield therapeutic extracellular vesicles that target hypertrophic scar regression via the miR-26a-5p/CCNE2 axis

Yunwei Wang1,2,‡ , Luyang Zhao1,‡, Hao Ma3,‡, Ao Shi2,‡, Peng Cao4,‡, Feiyu Cai2,‡, Ruomei Zhao2, Gang Wang2 , Zhihan Hu2, Jiatong Wang2, Yuchen Kang2, Xiaoyu Di2 , Qingyi Zhang1, Hao Zhang1, Shuguang Hou1, Babo Zhang1, Liang Luo1, Han Wang5( ), Yi Liu2 ( ), Hao Guan1 ( )
Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi’an, Shaanxi 710032, China
Department of Burn Plastic and Wound Repair Surgery, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Lanzhou, Gansu 730030, China
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China
Burns & Trauma Treatment Center, Affiliated Hospital of Jiangnan University, No. 1000 Hefeng Road, Binhu District, Wuxi, Jiangsu 214122, China
Department of Orthopedics, Air Force Medical Center, No. 30, Fucheng Road, Beijing 100142, China

‡These authors contributed equally to this work.

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Highlights

• A SFL-3D enables scalable production of rejuvenated dermal papilla cell spheroids (tdDPCs) with enhanced proliferative capacity and EV biogenesis.

• tdDPC-EVs effectively attenuate hypertrophic scar formation by suppressing fibroblast proliferation, migration, and myofibroblast differentiation.

• Mechanistically, tdDPC-EVs deliver miR-26a-5p to target CCNE2, thereby inhibiting the PI3K/AKT signaling pathway and disrupting fibrotic progression both in vitro and in vivo.

• This study establishes a novel cell-free therapeutic strategy using engineered EVs for hypertrophic scar management, overcoming limitations of cellular therapies and conventional 3D culture systems.

Abstract

Background

Hypertrophic scarring remains a critical challenge in regenerative medicine because of the limited efficacy of current antifibrotic therapies. Although dermal papilla cells (DPCs) exhibit intrinsic scar-inhibitory potential, their therapeutic utility is constrained by rapid replicative senescence and poor scalability in traditional monolayer cultures, necessitating innovative strategies to enhance cellular functionality and manufacturing feasibility.

Methods

A self-feeder layer 3D (SFL-3D) platform was established to reprogram primary human DPCs into rejuvenated three-dimensional DPC (tdDPC) spheroids via autocrine–paracrine signalling activation. tdDPC-derived extracellular vesicles (tdDPC-EVs) were isolated from culture supernatants by differential centrifugation. The antifibrotic effects of tdDPC-EVs were systematically evaluated using human scar fibroblasts through scratch wound healing assays, CCK-8 proliferation assays, and fibrotic marker analysis [Western blotting and immunofluorescence staining for α-smooth muscle actin (α-SMA) and collagen I]. Bioinformatics was used to predict key pathways involved in hypertrophic scar (HS) pathogenesis, whereas gain/loss-of-function studies investigated the miR-26a-5p/CCNE2 regulatory axis. Therapeutic validation was performed in a rabbit ear hypertrophic scar model with histopathological and molecular profiling.

Results

Compared with conventional 3D cultures, the SFL-3D system demonstrated superior proliferative support, enabling stable tdDPC expansion beyond 10 passages while maintaining high viability and enhanced EV biogenesis. miR-26a-5p-enriched tdDPC-EVs attenuated fibrosis through two mechanisms: (1) silencing CCNE2 to block PI3K/AKT-driven collagen overproduction and (2) suppressing α-SMA + myofibroblast differentiation. In the rabbit ear HS model, tdDPC-EV administration reduced the scar elevation index and restored the collagen Ⅰ/Ⅲ ratio to near-physiological levels.

Conclusions

This study positions tdDPC-EVs as a scalable acellular therapy that overcomes the replicative senescence and manufacturing limitations of cellular approaches. The antiscarring efficacy of these EVs, which is mediated by the miR-26a-5p/CCNE2/PI3K/AKT axis, highlights their clinical potential as precision-targeted strategies for hypertrophic scar management. The SFL-3D platform further provides a translatable framework for EV-based regenerative therapeutics.

Graphical Abstract

Keywords

Hypertrophic scarExtracellular vesiclesThree-dimensional spheroidsDermal papilla cellsCCNE2microRNA-26a-5p

References

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Burns & Trauma
Volume 14 Issue 3,
March 2026
Article number: tkaf048
DOI: 10.1093/burnst/tkaf048

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Wang Y, Zhao L, Ma H, et al. Self-organizing three-dimensional dermal papilla cell spheroids yield therapeutic extracellular vesicles that target hypertrophic scar regression via the miR-26a-5p/CCNE2 axis. Burns & Trauma, 2026, 14(3): tkaf048. https://doi.org/10.1093/burnst/tkaf048

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Received: 27 February 2025
Revised: 04 July 2025
Accepted: 14 July 2025
Published: 22 July 2025
© The Author(s) 2025. Published by Oxford University Press.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.