Letter to the Editor: Regulation of histone lactylation on exosomes derived from bone marrow mesenchymal stem cells promoting cartilage regeneration

Abstract

Histone lactylation, a novel chemical modification of histones, serves as a precise regulator of gene expression and cellular fate. It shows considerable potential in the regulation of bone metabolism. We read with interest the study by Zhang et al published in the World Journal of Stem Cells. In recent years, histone lactylation has attracted increasing attention in this field. Therefore, further investigation into the role and mechanisms of histone lactylation in cartilage regeneration provides new opportunities for regenerative medicine. This article aims to explore the regulation of tendon-bone healing after anterior cruciate ligament reconstruction (ACLR) by lactate dehydrogenase A in bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos). Specifically, this study highlights that lactate dehydrogenase A in BMSC-Exos promotes bone morphogenetic protein 7 expression via H3K18 lactylation, thereby facilitating tendon-bone healing after ACLR. These findings provide a theoretical basis for the clinical application of BMSC-Exos and identify a new therapeutic target for recovery after ACLR.

Key Words: Histone lactylation; Lactate dehydrogenase A; Exosomes; Bone marrow mesenchymal stem cells; Cartilage regeneration

Core Tip: The tendon-bone healing after anterior cruciate ligament reconstruction (ACLR) has troubled clinicians for a long time. Zhang et al found bone marrow mesenchymal stem cell-derived exosomes not only significantly promoted the generation of new bone tissue but also increased the regeneration of tendon and fibrocartilage in ACLR rats model, with lactate dehydrogenase A playing an important role in this process. The research elucidate a previously unknown molecular pathway involved in histone lactoylation, providing a more effective guarantee for the success rate and prognosis of ACLR.

TO THE EDITOR

We read with great interest the article titled “Bone marrow mesenchymal stem cell-derived exosomal lactate dehydrogenase A promotes tendon-bone healing via histone lactylation-mediated cartilage regeneration” by Zhang et al[1], recently published in the World Journal of Stem Cells. The study found that bone marrow mesenchymal stem cell (MSC)-derived exosomes (BMSC-Exos) can increase lactate secretion from cartilage stem/progenitor cells (CSPCs), thereby promoting bone formation and cartilage regeneration. The underlying mechanism was shown to involve histone lactylation mediated by lactate dehydrogenase A (LDHA), providing both a theoretical basis for the clinical application of BMSC-Exos and a new therapeutic target for tendon-bone healing after anterior cruciate ligament reconstruction (ACLR).

Exosomes are considered important mediators of intercellular communication and participate in numerous physiological and pathological processes[2]. In recent years, their role and therapeutic potential in bone and joint diseases have received growing attention. Many types of joint cells can produce and secrete exosomes, including chondrocytes, synovial fibroblasts, osteoblasts, and stem cells[3]. Recent studies have shown that stem cell-derived exosomes can protect joints from injury by promoting cartilage repair, suppressing synovitis, and modulating subchondral bone remodeling[4]. For example, Zheng et al[5] reported that exosomes derived from MSCs (MSC-Exos) significantly enhanced the chondrogenic potential of synovial MSCs via the miR-383-3p/Kdm2a/SOX2 axis. These studies demonstrate that stem cell-derived exosomes hold great promise in cartilage regeneration.

The anterior cruciate ligament (ACL) and rotator cuff injuries are common in clinical practice, and most require surgical intervention. However, re-tear rates after surgery remain high. Since healing at tendon-bone junctions primarily occurs via scar tissue formation, restoration of physiological structure and biomechanical properties is difficult. Poor tendon-bone integration remains a major clinical challenge. Studies have found that adipose-derived MSC-Exos enhanced tendon-bone integration following primary ACL repair in rabbits by reducing inflammation, promoting type I collagen synthesis, strengthening the ligament-bone interface, and lowering the risk of postoperative complications[6]. Similarly, a rat ACLR study showed that exosomes from infrapatellar fat pad MSCs accelerated tendon-bone healing, intra-articular graft remodeling, new bone formation, and fibrocartilage regeneration, thereby improving ligament-bone healing quality after surgery[7]. Consistent with these findings, Zhang et al[1] demonstrated that BMSC-Exos promoted tendon-bone healing in ACLR rats, as shown by micro-computed tomography, histological analysis, and staining methods (hematoxylin-eosin, Safranin O/Fast Green).

Histone lactylation is a post-translational modification in which lactyl groups are added to lysine residues on histones, thereby promoting gene transcription at the chromatin level and influencing cellular metabolism and function[8]. Initially discovered in tumor cells, histone lactylation has recently been recognized for its regulatory roles in bone and joint diseases[9]. For instance, lactylation at H3K18 can activate osteogenesis-related genes (e.g., JunB, Col1a2), promote BMSC differentiation into osteoblasts, and enhance bone formation[10]. Moreover, histone lactylation has been shown to facilitate cartilage matrix deposition by increasing chromatin accessibility at cartilage-specific genes (e.g., Sox5, Sox6, Col2a1), whereas inhibition of lactylation disrupts this process[11]. However, studies specifically addressing histone lactylation in cartilage regeneration remain limited. Zhang et al[1] discovered that LDHA is highly expressed in BMSC-Exos. Co-culture of CSPCs with LDHA-rich BMSC-Exos enhanced lactate secretion, increased cell viability, and upregulated proliferation and differentiation markers such as type II collagen, SOX9, and proteoglycans. In addition, BMSC-Exos elevated H3K18 lactylation levels and enriched H3K18 lactylation at the bone morphogenetic protein 7 promoter, thereby promoting CSPC proliferation. In addition, studies have found that extracellular vesicles derived from skeletal muscle can activate glycolysis in BMSCs by transporting LDHA, thereby promoting osteogenic differentiation[12]. Additionally, Nian et al[13] also found that LDHA is upregulated during osteogenic differentiation and mediates the lactylation of histone H3 at the K18 site (H3K18 Lac) through catalyzed lactate. H3K18 is specifically enriched in the promoter region of the bone morphogenetic protein 7 gene, thereby activating the expression of osteogenesis-related genes. These findings suggest that histone lactylation may represent a novel target for regulating cartilage regeneration.

Zhang et al[1] clarified for the first time that BMSC-Exos can promote tendon-bone healing after ACLR, potentially through LDHA-mediated histone lactylation. Their study provided extensive evidence on the impact of BMSC-Exos in ACLR healing. However, the animal experiment section could be further strengthened by including three-dimensional micro-computed tomography images with vertical and horizontal views. Moreover, while their work highlights cartilage regeneration, additional studies are needed to evaluate bone tissue healing. Future research should therefore incorporate biomarkers such as alkaline phosphatase, Alizarin Red staining, and osteoblast-associated protein expression analyses.

Future directions

In cartilage regeneration, particularly in osteoarthritis and cartilage injury, traditional treatments remain limited in efficacy, mainly reflected in the limited quality of regenerated tissues, short duration of efficacy, significant individual differences, and relatively fuzzy mechanisms of action. Exosomes have precise mechanisms of action, high potential for regenerative quality, and clear theoretical safety advantages, making them gradually become a research hotspot in the field of cartilage repair. However, its deep mechanism of action still requires further research. Histone lactylation, acting as a “master switch” of exosomes on cartilage regeneration, plays a crucial role in this process, which provides a new theoretical basis for the treatment of clinical cartilage repair, but there are still many potential hurdles (in terms of scaling up exosome procurement, cell sourcing, ethics of cell sourcing) in translating from rat model to larger animal models and eventual human clinical trials. Future studies should transition from descriptive mapping to more precisely describe the mechanism of action of the respective exosomes and ultimately develop targeted exosomes precision intervention strategies, opening new avenues for cartilage regeneration and the treatment of bone and joint diseases.