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Tricarboxylic Acid Cycle Metabolite-Coordinated Biohydrogels Augment Cranial Bone Regeneration Through Neutrophil-Stimulated MSCs Recruitment and Histone Acetylation-Mediated Osteogenesis [scRNA-Seq]

ABSTRACT: Cranial bone defect is a major clinical challenge that increases the life burden of patients. Tricarboxylic acid (TCA) cycle metabolites have recently drawn considerable attention in the field of bone tissue regeneration due to their bio-safety, low cost, structural stability, and effectiveness. However, the development of TCA cycle metabolite-modified biomimetic grafts for skull bone regeneration via a facile and general approach remains lacking. Moreover, the mechanism underlying the release of TCA cycle metabolites from biomaterials in immune responses and mesenchymal stem cells (MSCs) fate (migration and differentiation) remain unknown. Herein, inspired by the Hofmeister effects, we developed a series of TCA metabolite (in the form of sodium salt)-coordinated biomimetic hydrogels (CGG) with strong mechanical and anti-swelling performances. Importantly, the sodium citrate (Na3Cit)-treated CGG hydrogels (CGG-Cit) with the highest mechanical modulus and strength significantly promoted skull bone regeneration in rats and mice. Mechanistically, using a transgenic mouse model, bulk RNA sequencing, and single-cell RNA sequencing, we demonstrated that CGG-Cit promotes Gli1+ MSCs migration via neutrophil-secreted OSM. Our results also indicate that CGG-Cit improved osteogenesis via enhanced H3K9ac modification on osteogenic master genes. Taken together, the immune microenvironments and MSCs fate-regulated biomimetic hydrogels developed herein represent a highly efficient and facile approach toward skull bone tissue regeneration with great potential for bench-to-bedside translation.

ORGANISM(S): Mus musculus

PROVIDER: GSE235943 | GEO | 2024/02/15

REPOSITORIES: GEO

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Project description:Objective: Craniofacial bone defects caused by injuries and congenital diseases are a formidable challenge to clinicians. Research has shown promise in using bone marrow mesenchymal stem cells (BM-MSCs) from limb bones for craniofacial bone regeneration; yet little is known about the potential of BM-MSCs from craniofacial bones. This study compared BM-MSCs isolated from limb and craniofacial bones in pigs, a preclinical model closely resembling humans. Design: Bone marrow was aspirated from the tibia and mandible of four-month-old pigs (n=4), followed by BM-MSC isolation, culture-expansion and confirmation by flow cytometry. Proliferation rates were compared using population doubling times. Osteogenic differentiation was evaluated by quantifying alkaline phosphatase (ALP) activity. Total mRNA was extracted from freshly isolated BM-MSCs and analyzed to compare gene expressions of tibial and mandibular BM-MSCs using an Affymetrix GeneChip porcine genome array, followed by real-time RT-PCR evaluation of two neural crest markers. Results: BM-MSCs from both locations expressed MSC markers without expression of hematopoietic markers. Mandibular BM-MSCs proliferated significantly faster than tibial BM-MSCs. Without osteogenic inducers, mandibular BM-MSC alkaline phosphatase activities were 3.3-fold greater than those of tibial origin. Microarray analysis identified 383 differentially expressed genes in mandibular and tibial BM-MSCs, including higher expression of cranial neural crest-related genes nestin and BMP-4 in mandibular BM-MSCs, a trend also confirmed by real-time RT-PCR. Among differently expressed genes, only 47 showed greater than 1.5-fold differences in expression. Conclusions: These data indicate that despite many similarities in gene expression, mandibular BM-MSCs express of number of genes differently than tibial BM-MSCs and have a phenotypic profile that may make them advantageous for craniofacial bone regeneration. Bone marrow was aspirated from the mandibular symphyseal region and the tibia of 3 pigs. Mesenchymal stem cells were isolated from the bone marrow and cultured to 80% confluence. Cells were harvested for total RNA extraction and the RNA was analyzed by Affymetrix GeneChip porcine genome array.

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Tricarboxylic Acid Cycle Metabolite-Coordinated Biohydrogels Augment Cranial Bone Regeneration Through Neutrophil-Stimulated MSCs Recruitment and Histone Acetylation-Mediated Osteogenesis [scRNA-Seq]

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