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Potentials of BMSCs for Regulating Osteogenic-Vascular-Neural- Lymphatic Coupling in Bone Regeneration

ABSTRACT: Background Bone regeneration assisted by synthetic bone substitutes largely depends on the integration of the vascular, neural, and lymphatic systems in the bone. BMSCs were considered to be the key cells for the process. However, their role in regulating the integration has not been fully characterized. Methods Human BMSCs (hBMSCs) were treated with osteogenic induction and collected from 0 to 504 h for bulk RNA sequencing (RNA-Seq). Differentially expressed genes (DEGs) were identified and Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Time-Series Transcriptomic Trend Analysis were used to comprehensively analyze the possible pathways and functions involved with these DEGs. Weighted Gene Co-expression Network Analysis (WGCNA) were constructed to identify the modules and hub genes of the process. qRT-PCR and Enzyme-linked immunosorbent assay (ELISA) were porformed to validate the expression of key genes identified by RNA-Seq. Results We found that the gene expression tendency of hBMSCs during osteogenic differentiation can be divided into a four-stage classification: the initial adaptation stage (1-24 h), the proliferation activation stage (24-72 h), the differentiation regulation stage (72-336 h) and the remodeling stability stage (336-504 h). And 72 h was identified as the key time of the osteogenic-vascular-neural-lymphatic coupling process, with typical activation of BMP, vascular endothelial growth factor (VEGF) and PPAR signaling pathways. Four modules and closely related hub genes such as GDF5, MGP and PAPPA2 whose expression were validated by qRT-PCR and ELISA were also identified and highlighted. Conclusions Our study revealed the time temporal trends of angiogenesis, lymphangiogenesis, and neurogenesis during BMSCs osteogenic differentiation, which not only supplemented the transcriptional regulation in bone regeneration, but also provide a theoretical basis for the design of synthetic bone substitutes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313550 | GEO | 2026/09/02

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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Potentials of BMSCs for Regulating Osteogenic-Vascular-Neural- Lymphatic Coupling in Bone Regeneration

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