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HDGFR2 regulates osteogenic differentiation by balancing histone crotonoylation and acetylation modifications [RNA-Seq]

ABSTRACT: Epigenetics regulates the expression of osteogenic genes and mediates the osteogenic differentiation of MSCs. It was found that hepatoma-derived growth factor (HDGFR2) is a histone methylated reader protein, which can recognize histone methylation modification and play an important "switch" role in gene transcriptional regulation. It is unclear whether HDGFR2 is involved in bone formation studies. Our study aims to investigate the effect of HDGFR2 on osteogenic differentiation and provide evidence for BMSCs as seed cells for tissue regeneration. We found that compared with the wild-type (WT) mice, the bone mass of the femur and the root furcation bone in HDGFR2-KO mice was significantly elevated to attenuate age-related bone loss. Compared with the BMSCs in WT mice, the cloning and osteogenic differentiation of BMSCs in HDGFR2-KO mice were significantly accelerated, and vice versa when HDGFR2 was overexpressed. GO analysis suggested that differential genes were mainly involved in osteoblast differentiation, ossification, collagen fiber tissue and mineralization. The bone defect repair ability of HDGFR2-KO mice was significantly enhanced compared to the control group. Moreover, the depletion of HDGFR2 suppressed periodontal bone loss. The HDGFR2 interacts with the active regulator of SIRT1 (AROS) and sirtuin family deacetylases to form a chromatin remodeling complex, and AROS regulated osteogenesis through combining with HDFGR2. The decreased ratio of H3K18 crotonylation to acetylation improved the transcription of osteogenic genes in HDGFR2 knockout BMSCs. Taken together, these data demonstrated that the knockdown of HDGFR2 could promote osteogenic differentiation and bone repair, providing a new theoretical basis for bone tissue regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE263962 | GEO | 2024/04/19

REPOSITORIES: GEO

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Project description:The treatment of bone defects caused by infection, trauma or neoplasms remains a clinical challenge. Autologous bone transplantation is limited by availability, donor site morbidity and surgical risk factors. This has given rise to stromal/stem-cell based therapy. Bone marrow derived stromal cells (BMSCs) have been studied to a large extent and show high regenerative potential but their use is limited by availability, donor site morbidity and the relatively low cell yield as they represent only <0.1% of cell harvested from bone marrow aspirate. At the same time, they are the closest mesenchymal stromal cells for bone tissue engineering given their tissue origin and, unlike other mesenchymal stromal cells, can support the formation of hematopoietic marrow. Adipose tissue derived stromal cells (ASCs) as part of the stromal vascular fraction of adipose tissue can as well undergo osteogenic differentiation but can be additionally isolated in a sufficient quantity from lipoaspirate after liposuction of abundant subcutaneous fat tissue. Here, it has been shown that there are no major differences in regard to proliferation or differentiation capacity of ASCs derived from subcutaneous fat of different anatomical regions. It has been shown that BMSCs are more prone to senescence during expansion and passage than ASCs and that ageing impacts proliferative capabilities of BMSCs more than that of ASCs while it has also been reported that osteogenic differentiation capacity is least impacted by age. Multiple studies have compared the characteristics of these two mesenchymal stromal cells in regard to bone tissue engineering in vitro. Most studies point to inferior extracellular matrix mineralization and lower expression of key osteogenic transcription markers like Runx2 in osteogenic differentiated ASCs compared to BMSCs. On the other hand, a study by Rath et al. found contrary results using particular culturing conditions like 3D bioglass scaffolds. An intraindividual comparison of human MSCs of three donors cultured on decellularized porcine bone confirmed superior osteogenic capacity of BMSCs compared to ASCs. In contrast to BMSCs, ASCs were not able to induce heterogenic ossification in a mouse model. In a sheep tibia defect model application of BMSCs resulted in a significantly higher amount of newly formed bone tissue. Importantly, Osteogenic differentiated ASCs do not support the formation of a hematopoietic marrow. Proteomics enables large-scale analysis of proteins present in a cell type and can be used to identify differentially regulated key proteins in a comparative approach. A comparative proteomic analysis of BMSCs and ASCs by Roche et al. in 2009 identified 556 proteins with 78% of these not being differentially regulated between these two cell populations, regarded as high similarity. Another comparative proteomic study of 2016 by Jeon et al. found 90 differentially regulated proteins out of 3000 total identified proteins. Both studies do not specify a number of different tissue donors and in part using cell lines. Looking for differences upon osteogenic differentiation, transcriptomic comparison of osteogenic differentiated porcine ASCs and BMSCs has been performed, resulting in 21 differentially expressed genes after 21 days of osteogenic culture conditions. Still, it remains unanswered, which are the key distinctive features of osteogenic differentiated ASCs and BMSCs at protein level that might help address the abovementioned weaknesses of ASCs in bone tissue engineering/regeneration for translational research. To overcome this need, an intraindividual comparative DIA based proteomic analysis of osteogenic differentiated human BMSC and ASCs was performed in this study.

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HDGFR2 regulates osteogenic differentiation by balancing histone crotonoylation and acetylation modifications [RNA-Seq]

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