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HDAC4 regulates hASCs osteogenesis and bone regeneration by mediating SMAD4 via histone acetylation

ABSTRACT: Bone defects in the craniofacial region, such as mandibular critical-sized defects (CSDs), represent a significant clinical challenge due to the limited self-healing capacity and shortcomings of current therapeutic options. Bone tissue engineering using human adipose-derived stem cells (hASCs) offers a promising alternative. This study investigates the role of histone deacetylase 4 (HDAC4) and its inhibition as a therapeutic strategy in regulating hASCs osteogenic differentiation via histone acetylation. Using CUT&Tag sequencing, we identified HDAC4-regulated histone acetylation sites that modulate the expression of osteogenesis-related factors, including the key transcription factor SMAD4. HDAC4 knockdown enhanced histone acetylation, promoted SMAD4 expression, and significantly improved osteogenic differentiation of hASCs. These findings were further validated in vivo using calvarial and mandibular defect models in nude mice. As an alternative inhibition strategy, the selective HDAC4 inhibitor Tasquinimod (Tasq) was evaluated. At 1 µM, Tasq enhanced hASCs proliferation, promoted histone acetylation, upregulated SMAD4, and stimulated osteogenic differentiation markers (ALP, OSX, COL1A1), mimicking the effects of HDAC4 knockdown. To enable localized delivery, a Tasq-loaded GelMA-F127 composite hydrogel was developed. This hydrogel exhibited excellent mechanical properties, biocompatibility, and sustained release. Applied to mandibular defects, GelMA-F127-Tasq significantly enhanced bone regeneration. In conclusion, this study elucidates the epigenetic mechanisms of HDAC4 in hASCs osteogenesis and highlights the potential of Tasq-loaded hydrogels as a therapeutic strategy for bone defect repair.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308788 | GEO | 2026/07/29

REPOSITORIES: GEO

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Project description:Biomaterial-based bone tissue engineering offers a promising prospect for the treatment of bone defects. In particular, the ability of biomaterials to regulate the immune microenvironment of the defect site is essential for effective bone regeneration. Electro-biomaterials have been confirmed to induce macrophage M2 polarization through metabolic pathways, thereby enhancing bone regeneration. Considering the central role of mitochondria in cellular metabolism and their ability to influence the function of neighboring cells through intercellular transfer, and inspired by the fact that tumor cells can uptake mitochondria from immune cells to generate energy, we hypothesize that the metabolic activation of immune cells by electro-materials can be transmitted to preosteoblasts through mitochondria to promote bone repair. Therefore, this study proposed a conductive micro-hydrogel (CMH) system composed of conductive hydrogel microspheres made from GelMA and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), which served as scaffolds for defect filling, and a biomimetic periosteum made from poly-l-lactic acid (PLLA) and polydopamine (PDA) for microsphere immobilization and isolation of soft tissue. The microspheres exhibited excellent tissue support and degradation properties, their high specific surface area enhanced tissue remodeling, and their good conductivity eliminated free radicals and induced macrophage M2 polarization, which were confirmed by tests of mechanical property, swelling and degradation, conductivity and assays of cellular biocompatibility, ROS generation, and macrophage phenotype. In vivo experiments using a rat mandibular defect model confirmed the excellent bone repair capabilities of the CMH system, and transcriptomics, metabolomics, and metabolic testing revealed that the CMH system upregulated the oxidative phosphorylation pathway of macrophage, enhancing mitochondrial respiration and ATP production. Mitochondrial tracing experiments demonstrated the transfer of macrophage mitochondria to preosteoblasts, resulting in enhanced metabolic activity and osteogenic differentiation of preosteoblasts. This study may be the first suggest that conductive biomaterials facilitate osteogenic immunomodulation through mitochondrial transfer, which provides a promising method for regulating the immune microenvironment and reveals a novel pathway by which M2 macrophages enhance osteogenesis.

Project description:Reversible protein acetylation provides a central mechanism for controlling gene expression and cellular signaling events. It is governed by the antagonistic commitment of two enzymes families: the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). HDAC4, like its class IIa counterparts, is a potent transcriptional repressor through interactions with tissue-specific transcription factors via its N-terminal domain. Whilst the lysine deacetylase activity of the class IIa HDACs is much less potent than that of the class I enzymes, HDAC4 has been reported to influence protein deacetylation through its interaction with HDAC3. To investigate the influence of HDAC4 on protein acetylation, we employed the unbiased AcetylScan proteomic screen. We identified many proteins known to be modified by acetylation, but found that the absence of HDAC4 had no effect on the acetylation profile of the murine neonate brain. This is consistent with the biochemical data suggesting that HDAC4 may not function as a lysine deacetylase, but these in vivo data do not support the previous report showing that the enzymatic activity of HDAC3 might be modified by its interaction with HDAC4. To complement this work, we used Affymetrix arrays to investigate the effect of HDAC4 knock-out on the transcriptional profile of the postnatal murine brain. There was no effect on global transcription, consistent with the absence of a differential histone acetylation profile. Validation of the array data by Taq-man qPCR indicated that only protamine 1 and Igfbp6 mRNA levels were increased by more than one-fold and only CamK4 was decreased. The lack of a major effect on the transcriptional profile is consistent with the cytoplasmic location of HDAC4 in the P3 murine brain. mRNA expression analysis was performed by microarray in 3-day-old HDAC4 KO pups and WT littermates. Ten samples were analysed for each genotype. Microarray quality control was performed using the software package provided on RACE (http://race.unil.ch).

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HDAC4 regulates hASCs osteogenesis and bone regeneration by mediating SMAD4 via histone acetylation

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