Exosomes derived from mesenchymal stromal cells promote bone regeneration by delivering miR-182–5p-inhibitor

Zhu, Quing; Tang, Yuting; Zhou, Tian; Yang, Li; Zhang, Gao; Meng, Ying; Zhang, Huixin; Gao, Jun; Wang, Chenxing; Su, Youfeng; Ye, Jinhai

doi:10.1016/j.phrs.2023.106798

Cited by 12 publications

(5 citation statements)

References 58 publications

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“…In mice models, BMSCs secreted exosomes, and then alleviated osteoporosis by regulating USP7/YAP1 and Wnt/β-catenin signaling pathways [ 37 ]. BMSCs secreted exosomes containing miR-182-5p-inhibitor and further promoted the bone regeneration of BMSCs [ 38 ]. Total flavonoids of Rhizoma drynariae were reported to promote the osteogenic differentiation of BMSCs via affecting ERR1/2-Gga1-TGF β-MAPK axis [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

CRYAB suppresses ferroptosis and promotes osteogenic differentiation of human bone marrow stem cells via binding and stabilizing FTH1

Tian,

Li,

et al. 2024

Aging

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Background: Bone formation and homeostasis are greatly dependent on the osteogenic differentiation of human bone marrow stem cells (BMSCs). Therefore, revealing the mechanisms underlying osteogenic differentiation of BMSCs will provide new candidate therapeutic targets for osteoporosis. Methods: The osteogenic differentiation of BMSCs was measured by analyzing ALP activity and expression levels of osteogenic markers. Cellular Fe and ROS levels and cell viability were applied to evaluate the ferroptosis of BMSCs. qRT-PCR, Western blotting, and co-immunoprecipitation assays were harnessed to study the molecular mechanism. Results: The mRNA level of CRYAB was decreased in the plasma of osteoporosis patients. Overexpression of CRYAB increased the expression of osteogenic markers including OCN, OPN, RUNX2, and COLI, and also augmented the ALP activity in BMSCs, on the contrary, knockdown of CRYAB had opposite effects. IP-MS technology identified CRYAB-interacted proteins and further found that CRYAB interacted with ferritin heavy chain 1 (FTH1) and maintained the stability of FTH1 via the proteasome mechanism. Mechanically, we unraveled that CRYAB regulated FTH1 protein stability in a lactylation-dependent manner. Knockdown of FTH1 suppressed the osteogenic differentiation of BMSCs, and increased the cellular Fe and ROS levels, and eventually promoted ferroptosis. Rescue experiments revealed that CRYAB suppressed ferroptosis and promoted osteogenic differentiation of BMSCs via regulating FTH1. The mRNA level of FTH1 was decreased in the plasma of osteoporosis patients. Conclusions: Downregulation of CRYAB boosted FTH1 degradation and increased cellular Fe and ROS levels, and finally improved the ferroptosis and lessened the osteogenic differentiation of BMSCs.

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Section: Discussionmentioning

confidence: 99%

CRYAB suppresses ferroptosis and promotes osteogenic differentiation of human bone marrow stem cells via binding and stabilizing FTH1

Tian,

Li,

et al. 2024

Aging

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“…We found that the effects of LPS-Exo were not affected by proteinase K, whereas RNase eliminated the protective effects of LPS-Exo, indicating that miRNAs were the key molecules responsible for the sepsis-alleviating effect of LPS-Exo. Previous studies have proven that exosomes are effective vehicles for delivering miRNAs ( 44 , 45 ), which are implicated in the pathogenesis of various inflammatory diseases and emerged as novel targets for intervention therapy ( 20 , 46 ). In view of the better effect of LPS-Exo on the modulation of macrophage plasticity compared to that of Exo, we suggest that LPS precondition may change the miRNA profiles of exosomes, some remarkably expressed miRNAs in LPS-Exo account for their superior immuno-modulatory properties.…”

Section: Discussionmentioning

confidence: 99%

Exosome-shuttled miR-150–5p from LPS-preconditioned mesenchymal stem cells down-regulate PI3K/Akt/mTOR pathway via Irs1 to enhance M2 macrophage polarization and confer protection against sepsis

Zheng,

Li,

Zhang

et al. 2024

Front. Immunol.

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RationaleSepsis is a life-threatening organ dysfunction and lack of effective measures in the current. Exosomes from mesenchymal stem cells (MSCs) reported to alleviate inflammation during sepsis, and the preconditioning of MSCs could enhance their paracrine potential. Therefore, this study investigated whether exosomes secreted by lipopolysaccharide (LPS)-pretreated MSCs exert superior antiseptic effects, and explored the underlying molecular mechanisms.MethodsExosomes were isolated and characterized from the supernatants of MSCs. The therapeutic efficacy of normal exosomes (Exo) and LPS-pretreated exosomes (LPS-Exo) were evaluated in terms of survival rates, inflammatory response, and organ damage in an LPS-induced sepsis model. Macrophages were stimulated with LPS and treated with Exo or LPS-Exo to confirm the results of the in vivo studies, and to explain the potential mechanisms.ResultsLPS-Exo were shown to inhibit aberrant pro-inflammatory cytokines, prevent organ damages, and improve survival rates of the septic mice to a greater extent than Exo. In vitro, LPS-Exo significantly promoted the M2 polarization of macrophages exposed to inflammation. miRNA sequencing and qRT-PCR analysis identified the remarkable expression of miR-150–5p in LPS-Exo compared to that in Exo, and exosomal miR-150–5p was transferred into recipient macrophages and mediated macrophage polarization. Further investigation demonstrated that miR-150–5p targets Irs1 in recipient macrophages and subsequently modulates macrophage plasticity by down-regulating the PI3K/Akt/mTOR pathway.ConclusionThe current findings highly suggest that exosomes derived from LPS pre-conditioned MSCs represent a promising cell-free therapeutic method and highlight miR-150–5p as a novel molecular target for regulating immune hyperactivation during sepsis.

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“…M0, M1 and M2 macrophages were seeded in plates for 24 h. After that, the medium was removed and 3 ml DMEM was applied to wells. The culture supernatants of macrophages were collected after 24 h. The supernatants were mixed with α-MEM complete medium at a ratio of 1:1, and 50 μg/ml vitamin C, 10 mM β-glycerophosphate and 10 nM dexamethasone were added to prepare osteogenic induction solution [ 16 ]. They were named CM0, CM1 and M2 macrophage conditioned medium (CM2).…”

Section: Methodsmentioning

confidence: 99%

Macrophage exosomes modified by miR-365-2-5p promoted osteoblast osteogenic differentiation by targeting OLFML1

Hou,

Zhang,

et al. 2024

Regenerative Biomaterials

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In the bone immune microenvironment, immune cells can regulate osteoblasts through a complex communication network. Macrophages play a central role in mediating immune osteogenesis, exosomes derived from them have osteogenic regulation and can be used as carriers in bone tissue engineering. However, there are problems with exosomal therapy alone, such as poor targeting, and the content of loaded molecules cannot reach the therapeutic concentration. In this study, macrophage-derived exosomes modified with miR-365-2-5p were developed to accelerate bone healing. MC3T3-E1 cells were incubated with the culture supernatants of M0, M1 and M2 macrophages, and it was found that the culture medium of M2 macrophages had the most significant effects in contributing to osteogenesis. High-throughput sequencing identified that miR-365-2-5p was significantly expressed in exosomes derived from M2 macrophages. We incubated MC3T3-E1 with exosomes overexpressing or knocking down miR-365-2-5p to examine the biological function of exosome miR-365-2-5p on MC3T3-E1 differentiation. This findings suggested that miR-365-2-5p secreted by exosomes increased the osteogenesis of MC3T3-E1. Moreover, miR-365-2-5p had a direct influence over osteogenesis for MC3T3-E1. Sequencing analysis combined with dual luciferase detection indicated that miR-365-2-5p binded to the 3'UTR of OLFML1. In summary, exosomes secreted by M2 macrophages targeted OLFML1 through miR-365-2-5p to facilitate osteogenesis.

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Exosomes derived from mesenchymal stromal cells promote bone regeneration by delivering miR-182–5p-inhibitor

Cited by 12 publications

References 58 publications

CRYAB suppresses ferroptosis and promotes osteogenic differentiation of human bone marrow stem cells via binding and stabilizing FTH1

CRYAB suppresses ferroptosis and promotes osteogenic differentiation of human bone marrow stem cells via binding and stabilizing FTH1

Exosome-shuttled miR-150–5p from LPS-preconditioned mesenchymal stem cells down-regulate PI3K/Akt/mTOR pathway via Irs1 to enhance M2 macrophage polarization and confer protection against sepsis

Macrophage exosomes modified by miR-365-2-5p promoted osteoblast osteogenic differentiation by targeting OLFML1

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