Zhang T, Huang Q, Gan KF. Bone marrow mesenchymal stem cell-derived exosomal lactate dehydrogenase A promotes tendon-bone healing via histone lactylation-mediated cartilage regeneration. World J Stem Cells 2025; 17(9): 106282 [DOI: 10.4252/wjsc.v17.i9.106282]
Corresponding Author of This Article
Kai-Feng Gan, Department of Orthopedics, The Affiliated Lihuili Hospital of Ningbo University, No. 57 Xingning Road, Ningbo 315211, Zhejiang Province, China. gankaifeng@163.com
Research Domain of This Article
Orthopedics
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Stem Cells. Sep 26, 2025; 17(9): 106282 Published online Sep 26, 2025. doi: 10.4252/wjsc.v17.i9.106282
Bone marrow mesenchymal stem cell-derived exosomal lactate dehydrogenase A promotes tendon-bone healing via histone lactylation-mediated cartilage regeneration
Ting Zhang, Qing Huang, Kai-Feng Gan
Ting Zhang, Kai-Feng Gan, Department of Orthopedics, The Affiliated Lihuili Hospital of Ningbo University, Ningbo 315211, Zhejiang Province, China
Qing Huang, Department of Gynaecology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo 315211, Zhejiang Province, China
Author contributions: Zhang T designed the study; Huang Q conduced the experiments; Gan KF wrote the manuscript.
Institutional review board statement: The study was approved by the Affiliated Lihuili Hospital of Ningbo University Medical Ethics Committee (Approval No. LHL112532).
Institutional animal care and use committee statement: The study was approved by the Affiliated Lihuili Hospital of Ningbo University Medical Ethics Committee for Laboratory Animals (Approval No. LHLS-1059), and complied with the Guidelines for the Management and Use of Laboratory Animals.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets used and analysed during the current study are available from the corresponding author on reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Kai-Feng Gan, Department of Orthopedics, The Affiliated Lihuili Hospital of Ningbo University, No. 57 Xingning Road, Ningbo 315211, Zhejiang Province, China. gankaifeng@163.com
Received: February 26, 2025 Revised: March 27, 2025 Accepted: September 5, 2025 Published online: September 26, 2025 Processing time: 209 Days and 20.8 Hours
Abstract
BACKGROUND
Anterior cruciate ligament reconstruction (ACLR) is the dominant clinical modality for the treatment of anterior cruciate ligament injuries. The success of ACLR is largely dependent on tendon-bone healing, and stem cell biotherapies are often used to facilitate this process. Histone lactylation modifications are involved in the regulation of various diseases. Lactate dehydrogenase A (LDHA) has been shown to play an important role in exosomes.
AIM
To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos).
METHODS
BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy, qNano, immunofluorescence and western blotting assay. The corresponding low expression cell lines were obtained using RNA interference transfection; LDHA expression in rat bone tissues after ACLR was analyzed by western blotting. The volume of newborn bone tissues was monitored by micro-computed tomography imaging. Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis, including hematoxylin and eosin and Safranin O-Fast green staining, respectively; LDHA levels of chondrocyte stem cells (CSPCs) after co-incubation with BMSC-Exos were analyzed by western blotting. Extracellularly secreted lactic acid content was determined by lactate assay kit. Cell viability was assessed by cell counting kit 8 assay, and the proliferation and differentiation ability of cells was further examined by the expression of collagen II, SOX9 and aggrecan. Histone H3K18 lactylation modification was analyzed by western blotting. H3K18 La binding on bone morphogenetic protein 7 (BMP7) promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction; BMP7 promoter activity was analyzed by dual luciferase reporter gene; BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting. Then, the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA, BMP7, collagen II, SOX9, aggrecan, extracellular lactate content, and cell counting kit 8 assay.
RESULTS
The spherical nanosized BMSC-Exos could be uptaken by CSPCs. LDHA was highly expressed in BMSC-Exos, which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue, as well as significantly increased the regeneration of tendon and fibrocartilage. Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs, cell viability, and the expression of markers related to cell proliferation and differentiation, including collagen II, SOX9, and aggrecan; LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification; high LDHA expression reversed the knockdown of BMP7, further increasing the proliferation and differentiation of CSPCs, thereby inducing cartilage formation.
CONCLUSION
LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification, which further promotes tendon-bone healing after ACLR.
Core Tip: This study reveals that lactate dehydrogenase A (LDHA) in exosomes from bone marrow mesenchymal stem cells significantly enhances tendon-bone healing after anterior cruciate ligament reconstruction. LDHA promotes chondrocyte stem cell proliferation and differentiation by increasing lactate secretion and upregulating bone morphogenetic protein 7 via histone H3K18 lactylation. High LDHA expression boosts cartilage and fibrocartilage regeneration, accelerates new bone formation, and reverses bone morphogenetic protein 7 knockdown effects. These findings highlight LDHA-rich exosomes from bone marrow mesenchymal stem cells as a promising therapeutic strategy for improving anterior cruciate ligament reconstruction outcomes.
