@article{Wang2026, 
author = {Yunwei Wang and Luyang Zhao and Hao Ma and Ao Shi and Peng Cao and Feiyu Cai and Ruomei Zhao and Gang Wang and Zhihan Hu and Jiatong Wang and Yuchen Kang and Xiaoyu Di and Qingyi Zhang and Hao Zhang and Shuguang Hou and Babo Zhang and Liang Luo and Han Wang and Yi Liu and Hao Guan},
title = {Self-organizing three-dimensional dermal papilla cell spheroids yield therapeutic extracellular vesicles that target hypertrophic scar regression via the miR-26a-5p/CCNE2 axis},
year = {2026},
journal = {Burns & Trauma},
volume = {14},
number = {3},
pages = {tkaf048},
keywords = {Hypertrophic scar, Extracellular vesicles, Three-dimensional spheroids, Dermal papilla cells, CCNE2, microRNA-26a-5p},
url = {https://www.sciopen.com/article/10.1093/burnst/tkaf048},
doi = {10.1093/burnst/tkaf048},
abstract = {BackgroundHypertrophic 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.MethodsA 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.ResultsCompared 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.ConclusionsThis 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.}
}