Li JP, Chen XY, Wang Q, Du YY, Guo TT, Lin JN, Fu JY, Xie ML, Liu JH, Gao JL, Wang MM, Luo S. Regenerative-system dysfunction in organ fibrosis: Maladaptive regeneration, fibrotic memory, and therapeutic reprogramming. World J Stem Cells 2026; 18(10): 125689 [DOI: 10.4252/wjsc.125689]
Corresponding Author of This Article
Sai Luo, MD, PhD, Full Professor, Department of Plastic and Cosmetic Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China. 101301@hrbmu.edu.cn
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Medicine, Research & Experimental
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Li JP, Chen XY, Wang Q, Du YY, Guo TT, Lin JN, Fu JY, Xie ML, Liu JH, Gao JL, Wang MM, Luo S. Regenerative-system dysfunction in organ fibrosis: Maladaptive regeneration, fibrotic memory, and therapeutic reprogramming. World J Stem Cells 2026; 18(10): 125689 [DOI: 10.4252/wjsc.125689]
World J Stem Cells. Oct 26, 2026; 18(10): 125689 Published online Oct 26, 2026. doi: 10.4252/wjsc.125689
Regenerative-system dysfunction in organ fibrosis: Maladaptive regeneration, fibrotic memory, and therapeutic reprogramming
Jia-Peng Li, Xin-Yao Chen, Qing Wang, Yu-Yang Du, Ting-Ting Guo, Jia-Ni Lin, Jia-Yue Fu, Ming-Li Xie, Jia-Hui Liu, Jian-Lu Gao, Ming-Ming Wang, Sai Luo
Jia-Peng Li, Xin-Yao Chen, Qing Wang, Yu-Yang Du, Ting-Ting Guo, Jia-Ni Lin, Jia-Yue Fu, Ming-Li Xie, Jia-Hui Liu, Jian-Lu Gao, Ming-Ming Wang, Sai Luo, Department of Plastic and Cosmetic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
Co-first authors: Jia-Peng Li and Xin-Yao Chen.
Author contributions: Li JP and Chen XY contributed equally to conceptualization, literature search, evidence synthesis, and drafting, they are co-first authors of this manuscript. Wang Q, Du YY, and Guo TT contributed to literature screening and evidence curation; Lin JN and Fu JY contributed to evidence verification; Xie ML and Liu JH prepared the figures and tables; Gao JL and Wang MM critically revised the manuscript; Luo S supervised the work. All authors reviewed and approved the final manuscript.
AI contribution statement: Portions of this manuscript were edited using AI tools solely for language refinement. The authors carefully reviewed and verified all AI-assisted outputs and take full responsibility for the scientific content of the manuscript.
Supported by the Heilongjiang Provincial Natural Science Foundation, No. PL2025H085 and No. QC2018102 to Luo S; the National Natural Science Foundation of China, No. 82102356 to Luo S; the Outstanding Young Medical Talents Training Funding Project of the First Affiliated Hospital of Harbin Medical University, No. 2021J05 to Luo S; the Scientific Research Innovation Fund of the First Affiliated Hospital of Harbin Medical University, No. 2019B24 to Luo S; the Heilongjiang Provincial Natural Science Foundation, No. PL2024H066 to Chen XY; the Fundamental Research Funds for Provincial Universities in Heilongjiang Province, No. 2025-KYYWF-ZR0190 to Li JP; the Fundamental Research Funds for Provincial Universities in Heilongjiang Province, No. 2025-KYYWF-ZR0177 to Du YY; the Heilongjiang Provincial Natural Science Foundation, No. BS2025H007 to Du YY; the “New Era Heilongjiang Province Excellent Master’s and Doctoral Dissertation” Funding Project, No. LJYXL2022-079 to Chen XY; the Undergraduate Innovation and Entrepreneurship Training Program of Heilongjiang Province, No. S202310226027 to Chen XY; the Undergraduate Innovation and Entrepreneurship Training Program of Harbin Medical University, No. 202310226027 to Chen XY; the Harbin Medical University Youth Science Foundation, No. 2023-KYYWF-0142 to Chen XY; and the Graduate Research and Practice Innovation Project of Harbin Medical University, No. YJSCX2023-206HYD to Li JP.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Sai Luo, MD, PhD, Full Professor, Department of Plastic and Cosmetic Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China. 101301@hrbmu.edu.cn
Received: July 17, 2026 Revised: September 4, 2026 Accepted: October 13, 2026 Published online: October 26, 2026 Processing time: 104 Days and 22.2 Hours
Abstract
Organ fibrosis involves extracellular matrix accumulation and dysfunction of interacting regenerative, immune, and stromal compartments. This narrative review integrates evidence from seven organs within an injury-repair-memory framework while distinguishing bona fide stem/progenitor cells from differentiated parenchymal cells and niche components. Maladaptive regeneration includes impaired lineage progression, senescence, persistent injury-associated states, and pathological cell-niche signaling. Fibrotic memory is evaluated using explicit persistence, stimulus-withdrawal, re-exposure, and causal-maintenance criteria rather than equated with ongoing disease. Direct evidence is restricted to particular models, including cultured fibroblast mechanical memory, selected stromal epigenetic and activation states, conditioned immune responses, and post-obstructive renal epithelial senescence. Cross-organ generalization, metabolic-memory mechanisms, and cell-autonomous memory in transitional epithelia remain incompletely established. Therapeutic reprogramming denotes controlled, durable correction of pathological cell states, identities, or differentiation trajectories; senolysis, niche modulation, cell replacement, and organoid-guided screening are distinct complementary approaches. Conflicting findings underscore disease-stage and cell-type dependence. We propose a translational roadmap prioritizing biomarkers and human-relevant models before durable therapeutic state correction, with explicit assessment of function, safety, and persistence after treatment withdrawal.
Core Tip: Fibrosis can involve failed tissue regeneration as well as scar accumulation. This review compares organ-specific evidence for maladaptive repair and fibrotic memory without treating all repair-associated cells as stem cells. Direct memory evidence is separated from persistent abnormalities during ongoing disease. Therapeutic reprogramming requires controlled, durable cellular-state or lineage correction; extracellular matrix normalization, immune and metabolic modulation, cell replacement, and organoid-guided screening remain distinct. The proposed framework prioritizes testable mechanisms, context-dependent reversibility, and safety rather than assuming that preclinical state changes restore human tissue function.
