<p>Exosomes Derived from Bone Mesenchymal Stem Cells with the Stimulation of Fe₃O₄ Nanoparticles and Static Magnetic Field Enhance Wound Healing Through Upregulated miR-21-5p</p>

Abstract

Background: Both magnetic nanoparticles (MNPs) and exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been reported to improve wound healing. In this study, novel exosomes (mag-BMSC-Exos) would be fabricated from BMSCs with the stimulation of MNPs and a static magnetic field (SMF) to further enhance wound repair. Methods: Mag-BMSC-Exos, namely, exosomes derived from BMSCs preconditioned with Fe 3 O 4 nanoparticles and a SMF, together with BMSC-Exos were both first isolated by ultracentrifugation, respectively. Afterwards, we conducted in vitro experiments, including scratch wound assays, transwell assays, and tube formation assays, and established an in vivo wound healing model. The miRNA expression profiles were compared between BMSC-Exos and mag-BMSC-Exos to detect the potential mechanism of improving wound healing. At last, the function of exosomal miR-21-5p during wound healing was confirmed by utilizing a series of gain-and loss-of-function experiments in vitro. Results: The optimal working magnetic condition was 50 µg/mL Fe 3 O 4 nanoparticles combined with 100 mT SMF. In vitro, mag-BMSC-Exo administration promoted proliferation, migration and angiogenesis to a greater extent than BMSC-Exo administration. Local transplantation of mag-BMSC-Exos into rat skin wounds resulted in accelerated wound closure, narrower scar widths and enhanced angiogenesis compared with BMSC-Exo transplantation. Notably, miR-21-5p was found to be highly enriched in mag-BMSC-Exos and served as a critical mediator in mag-BMSC-Exo-induced regulatory effects through inhibition of SPRY2 and activation of the PI3K/AKT and ERK1/2 signaling pathways. Conclusion: Mag-BMSC-Exos can further enhance wound healing than BMSC-Exos by improving angiogenesis and fibroblast function, and miR-21-5p upregulation in mag-BMSC-Exos might be the potential mechanism. This work offers an effective and promising protocol to improve wound healing in clinic.

Bone mesenchymal stem cells stimulation by magnetic nanoparticles and a static magnetic field: release of exosomal miR-1260a improves osteogenesis and angiogenesis

“…For example, Qin et al summarized the recent reports using exosomes to regulate osteogenesis and accelerate bone regeneration [ 36 ]. Our recent study showed that exosomes derived from BMSCs cultured under magnetic conditions enhanced wound healing and the underlying mechanism was elucidated [ 37 ]. To further enhance the effects of BMSC-Exos for bone regeneration, we synthesized a new type of exosomes derived from BMSCs treated with the stimulations of MNPs (Fe 3 O 4 nanoparticles) and/or a SMF (BMSC-Fe 3 O 4 -Exos or BMSC-Fe 3 O 4 -SMF-Exos) in this study.…”

Nanohydroxyapatite (nHAp) Doped with Iron Oxide Nanoparticles (IO), miR-21 and miR-124 Under Magnetic Field Conditions Modulates Osteoblast Viability, Reduces Inflammation and Inhibits the Growth of Osteoclast – A Novel Concept for Osteoporosis Treatment: Part 1

“…Previously performed studies showed that microRNA-21 (miR-21) is particularly involved in osteogenic differentiation of bone marrow-derived stromal mesenchymal stem progenitor cells (BM-MSCs), and regulates downstream targets, including Sprouty 1 (Spry1) and Sprouty 2 (Spry2). 27 The miR-21 molecule is also involved in preventing bone loss through inhibition of osteoclasts activity and targeting programmed cell death protein 4 (PDCD4), despite the existence of RANKL. 28 In turn, microRNA-124 (miR-124) has been shown to play a critical role in the regulation of osteoclastogenesis in BM-MSCs through suppressing NFATc1 expression.…”

Iron Oxide Nanoparticles in Regenerative Medicine and Tissue Engineering

“…In a rat model of laser-induced skin injury, administration of IONP-loaded MSCs and their magnetically enhanced migration to the injury site improved skin regeneration and enhanced anti-inflammatory effects and angiogenesis, compared with MSC injection alone [ 614 ]. Improved wound healing through accelerated wound closure, reduced scar width, and enhanced angiogenesis was also achieved with exosomes derived from BMSCs preconditioned with IONPs and a static magnetic field compared with IONPs-free exosomes in a rat wound healing model [ 615 ]. Heun et al have developed a novel wound healing strategy for pathophysiological conditions with impaired wound healing using a site-specific gene transfer technique based on magnetic targeting of IONP-lentivirus complexes that ultimately controls hypoxia inducible factor 1α (HIF-1α)-dependent wound healing angiogenesis via modulation of the tyrosine phosphatase activity of SHP-2 [ 616 ].…”