derived from lower mechanical stretch adipose-derived stromal cells can enhance fracture healing in a type 2 diabetes nonunion model.
Exosomes from lower mechanical stretch (LMS) adipose-derived stromal cells promote osteogenesis and angiogenesis in vitro.
is significantly upregulated in LMS-ADSC-Exos and can be transferred to bone marrow mesenchymal stromal cells and endothelial cells.
The presence of miR-877 is associated with enhanced osteogenic and angiogenic activity under diabetic conditions.
Transplantation of LMS-ADSC-Exos accelerates bone regeneration in a rat model of nonunion with type 2 diabetes.
Simplified
BACKGROUND: Bone nonunion or delayed union is a serious complication in diabetic patients with fractures, urgently requiring novel therapeutic strategies. derived from stromal cells are naturally occurring nanoparticles carrying bioactive molecules that mediate intercellular communication and play crucial roles in diabetic fracture repair. Importantly, mechanical stimuli can modulate the cargo composition of exosomes, influencing bone healing outcomes. Here, we investigate for the first time whether exosomes derived from mechanically stretched adipose-derived stromal cells (MS-ADSC-Exos) enhance fracture healing in a type 2 diabetes mellitus (T2DM) nonunion model, and elucidate their underlying mechanisms.
METHODS: Exosomes secreted by ADSCs subjected to different magnitudes of cyclic mechanical stretch (0%, 6%, 18%; designated NMS, LMS, and HMS-ADSC-Exos) were applied to rat bone marrow mesenchymal stromal cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) in vitro. Osteogenic differentiation, proliferation, migration, and angiogenesis were evaluated by Alizarin Red S and ALP staining, tube formation, scratch, and migration assays, respectively. Western blotting and immunofluorescence assessed osteogenic marker expression. In vivo, MS-ADSC-Exos or PBS were locally injected into the fracture sites of diabetic rat femoral nonunion models for 3 consecutive days post-operation. Bone regeneration was evaluated by micro-CT and histological analyses at 4 weeks. miRNA profiles of MS-ADSC-Exos were characterized by RNA sequencing, bioinformatics, and qRT-PCR. Functional roles of were further validated via mimic and inhibitor transfection assays.
RESULTS: In this study, it is shown that exosomes secreted from ADSCs induced via lower mechanical stretch can enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion with T2DM. Our results suggested miR-877 was significantly upregulated in LMS-ADSC-Exos, and can be transferred into BMSCs and HUVECs, which promotes osteogenesis and angiogenesis in diabetic conditions.
CONCLUSIONS: This study reveals a novel mechanobiological mechanism whereby mechanical stretch modulates exosomal miRNA content to potentiate fracture repair. Transplantation of LMS-ADSC-Exos accelerates bone regeneration via miR-877-mediated osteogenic and angiogenic pathways. These findings highlight the therapeutic potential of mechanically stimulated ADSC-derived exosomes as natural bioactive nanotherapeutics for diabetic fracture nonunion.
Key numbers
largest extent of expression upregulating
Increase in expression
was the most significantly upregulated miRNA in LMS--Exos.
600 µL
600 µL of - administered
- were injected into the fracture site every three days post-surgery.
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Declarations. Ethics approval and consent to participate: Rats in this study were purchased from the laboratory Animal Center of Wuhan University (China). All animal experiments were performed under the guidance of the Institutional Animal Care and Use Committee (IACUC) of Wuhan University. The experimental protocol was approved by the Committee on the Ethics of Animal Experiments of Wuhan University, Wuhan, China (Title of the approved project: "Research on the Role and Mechanism of Stress-Induced Adipose-derived Stromal cells in Promoting Bone Healing." Approval number: ZN2024028; Date of approval: April.1st.2024.). All efforts were made to minimize animal suffering. The human cells (HUVECs) were separated from human umbilical vein vascular wall, the HUVECs (PUMC-HUVEC-T1; Cat NO: CL-0675) used in our experiments were originally purchased from a commercial vendor (Wuhan Pricella Biotechnology Co.Ltd. Wuhan, China). The original source has confirmed that there was initial ethical approval for collection of human cells, and that the donors had signed informed consent ( https://www.procell.com.cn/ ). Consent for publication: Not applicable. Competing interests: The authors declared no potential conflicts of interest.
