Dual-Targeted Nanodiscs Revealing the Cross-Talk between Osteogenic Differentiation of Mesenchymal Stem Cells and Macrophages.
Lang ChenChenyan YuWanting XuYuan XiongPeng ChengZe LinZhenhe ZhangLeonard KnoedlerAdriana C PanayiSamuel KnoedlerJunqing WangBobin MiGuohui LiuPublished in: ACS nano (2023)
Ongoing research has highlighted the significance of the cross-play of macrophages and mesenchymal stem cells (MSCs). Lysine-specific demethylase 6B (KDM6B) has been shown to control osteogenic differentiation of MSCs by depleting trimethylated histone 3 lysine 27 (H3K27me3). However, to date, the role of KDM6B in bone marrow-derived macrophages (BMDMs) remains controversial. Here, a chromatin immunoprecipitation assay (ChIP) proved that KDM6B derived from osteogenic-induced BMSCs could bind to the promoter region of BMDMs' brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1) gene in a coculture system and activate BMAL1. Transcriptome sequencing and experiments in vitro showed that the overexpression of BMAL1 in BMDM could inhibit the TLR2/NF-κB signaling pathway, reduce pyroptosis, and decrease the M1/M2 ratio, thereby promoting osteogenic differentiation of BMSCs. Furthermore, bone and macrophage dual-targeted GSK-J4 (KDM6B inhibitor)-loaded nanodiscs were synthesized via binding SDSSD-apoA-1 peptide analogs (APA) peptide, which indirectly proved the critical role of KDM6B in osteogenesis in vivo . Overall, we demonstrated that KDM6B serves as a positive circulation trigger during osteogenic differentiation by decreasing the ratio of M1/M2 both in vitro and in vivo . Collectively, these results provide insight into basic research in the field of osteoporosis and bone repair.
Keyphrases
- mesenchymal stem cells
- umbilical cord
- signaling pathway
- bone marrow
- bone mineral density
- pi k akt
- gene expression
- dna methylation
- genome wide
- cancer therapy
- transcription factor
- cell therapy
- postmenopausal women
- single cell
- epithelial mesenchymal transition
- high throughput
- drug delivery
- toll like receptor
- immune response
- skeletal muscle
- stem cells
- dna damage
- diabetic rats
- oxidative stress
- adipose tissue
- cell proliferation
- body composition
- nuclear factor
- blood brain barrier
- induced apoptosis
- molecular docking
- binding protein
- drug induced
- brain injury