Exosomes derived from hypoxia preconditioned mesenchymal stem cells laden in a silk hydrogel promote cartilage regeneration via the miR-205–5p/PTEN/AKT pathway

Shen, Kai; Duan, Ao; Cheng, Jidong; Yuan, Tao; Zhou, Jiahui; Song, Huanghe; Chen, Zhefeng; Wan, Bin; Liu, Jiuxiang; Zhang, Xiao; Zhang, Yi; Xie, Rui; Liu, Feng; Fan, Weimin; Zuo, Qiang

doi:10.1016/j.actbio.2022.02.026

Cited by 67 publications

(55 citation statements)

References 58 publications

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“…Furthermore, preconditioning in hypoxia also increased the capacity of MSC-derived EV in cartilage regeneration by positively acting on chondrocytes. Thus, in vivo assays have shown that an injectable silk-fibroin hydrogel, containing articular chondrocytes and MSC-derived EV in hypoxia promoted cartilage regeneration[ 120 ]. Several miRNA were involved in this process, including miR-18a-3p, miR-181c-5p, miR-205-5p, miR-337-5p, and miR-376a-5p[ 120 , 121 ].…”

Section: Therapeutic Potential Of Ev Derived From Msc Preconditioned ...mentioning

confidence: 99%

Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles

Pulido-Escribano¹,

Torrecillas-Baena²,

Camacho-Cardeñosa³

et al. 2022

WJSC

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The use of mesenchymal stem-cells (MSC) in cell therapy has received considerable attention because of their properties. These properties include high expansion and differentiation in vitro , low immunogenicity, and modulation of biological processes, such as inflammation, angiogenesis and hematopoiesis. Curiously, the regenerative effect of MSC is partly due to their paracrine activity. This has prompted numerous studies, to investigate the therapeutic potential of their secretome in general, and specifically their extracellular vesicles (EV). The latter contain proteins, lipids, nucleic acids, and other metabolites, which can cause physiological changes when released into recipient cells. Interestingly, contents of EV can be modulated by preconditioning MSC under different culture conditions. Among them, exposure to hypoxia stands out; these cells respond by activating hypoxia-inducible factor (HIF) at low O 2 concentrations. HIF has direct and indirect pleiotropic effects, modulating expression of hundreds of genes involved in processes such as inflammation, migration, proliferation, differentiation, angiogenesis, metabolism, and cell apoptosis. Expression of these genes is reflected in the contents of secreted EV. Interestingly, numerous studies show that MSC-derived EV conditioned under hypoxia have a higher regenerative capacity than those obtained under normoxia. In this review, we show the implications of hypoxia responses in relation to tissue regeneration. In addition, hypoxia preconditioning of MSC is being evaluated as a very attractive strategy for isolation of EV, with a high potential for clinical use in regenerative medicine that can be applied to different pathologies.

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Section: Therapeutic Potential Of Ev Derived From Msc Preconditioned ...mentioning

confidence: 99%

Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles

Pulido-Escribano¹,

Torrecillas-Baena²,

Camacho-Cardeñosa³

et al. 2022

WJSC

View full text Add to dashboard Cite

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“…Wu et al reported that infrapatellar fat pad MSCs-derived exosomes protect against cartilage destruction by inhibiting the mTOR signaling pathway [ 29 ]. Shen et al reported that hypoxia-conditioned MSC-derived exosomes promote chondrogenesis in hydrogels [ 30 ]. Although we did not evaluate the effects of exosomes derived from HUCMSCs cultured with Exo(-)FBS, the therapeutic effect may partially depend on HUCMSC-derived exosomes.…”

Section: Discussionmentioning

confidence: 99%

Chondrogenic Potential of Human Umbilical Cord Mesenchymal Stem Cells Cultured with Exosome-Depleted Fetal Bovine Serum in an Osteoarthritis Mouse Model

Chang

Ding

2022

Biomedicines

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Osteoarthritis (OA) is characterized by the loss of articular cartilage and is also an age-related disease. Recently, stem cell therapy for cartilage repair has emerged. The stem cells need to be cultured with a fetal bovine serum (FBS)-supplemented medium. The effect of FBS-containing exosomes on the differentiation of human umbilical cord mesenchymal stem cells (HUCMSCs) is unknown. The morphology, proliferation, surface marker expressions, and trilineage differentiation ability of two groups of HUCMSCs, cultured with conventional (FBS) and exosome-depleted FBS (Exo(-)FBS), were evaluated. In a mouse OA model after two groups of HUCMSCs transplantation, the rotarod activity, histology, and immunohistochemistry (type II collagen, aggrecan, IL-1β, and MMP13) of the cartilage were evaluated. The Exo(-)FBS-cultured HUCMSCs, like FBS-cultured HUCMSCs, displayed classic MSC characteristics, including spindle-shaped morphology, surface marker expression (positive for CD44, CD73, CD90, CD105, and HLA-ABC and negative for CD34, CD45, and HLA-DR), and trilineage differentiation (chondrogenesis, osteogenesis, and adipogenesis). The Exo(-)FBS-cultured HUCMSCs proliferated significantly slower than those of the FBS-cultured HUCMSCs (p < 0.01). The trilineage gene expression of PPAR-γ, FABP4, APAL, type II collagen, aggrecan, and SOX9 was significantly increased in the Exo(-)FBS-cultured HUCMSCs than in the FBS-cultured HUCMSCs and undifferentiated controls. The Exo(-)FBS- and FBS-cultured HUCMSCs-transplanted mice showed a better rotarod activity than in the control OA mice (n = 3 in each group). A significant histological improvement in hyaline cartilage destruction after the transplantation of both types of FBS-cultured HUCMSCs was noted when compared with the OA knees. The Exo(-)FBS-cultured HUCMSCs-transplanted knees showed a higher International Cartilage Repair Society histological score (p < 0.05), staining intensity of type II collagen (p < 0.01), and aggrecan (p < 0.01) than in the control knees. Moreover, both types of the FBS-cultured HUCMSCs-transplanted knees significantly decreased the expression of MMP13 and IL-1β compared to that in the OA knees (p < 0.01). The Exo(-)FBS-cultured HUCMSCs harbor chondrogenic potential and attenuated cartilage destruction in a mouse OA model. Our study provides a basis for future clinical trials using Exo(-)FBS-cultured stem cells to treat OA.

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“… Hu et al (2020) creatively combined laponite nanoclay with gelatin methacrylate (Gelma) hydrogel and confirmed that the poor strength and the lack of ordered structure in the cartilage tissue of the hydrogel can be remedied by nanoclay, ensuring a favorable condition for cell proliferation and differentiation. Recently, Shen et al (2022) also fabricated a silk fibroin (SF) hydrogel that can be injected to support and maintain exosomes derived from hypoxia-pretreated mesenchymal stem cells for cartilage tissue engineering. The experiment revealed that the injectable silk hydrogel carrying articular chondrocytes and hypoxia-pretreated exosomes (H-Exos) was conducive to ameliorating cartilage degeneration as well as facilitating cartilage repair through the miR-205-5p/PTEN/AKT pathway, indicating a new therapeutic target for cartilage tissue engineering utilizing exosomes and articular chondrocytes loaded with SF hydrogel.…”

Section: Exosomes and Cartilage Tissue Engineeringmentioning

confidence: 99%

Exosomes in osteoarthritis: Updated insights on pathogenesis, diagnosis, and treatment

Fan

Liu

Pan

et al. 2022

Front. Cell Dev. Biol.

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Osteoarthritis (OA) has remained a prevalent public health problem worldwide over the past decades. OA is a global challenge because its specific pathogenesis is unclear, and no effective disease-modifying drugs are currently available. Exosomes are small and single-membrane vesicles secreted via the formation of endocytic vesicles and multivesicular bodies (MVBs), which are eventually released when MVBs fuse with the plasma membrane. Exosomes contain various integral surface proteins derived from cells, intercellular proteins, DNAs, RNAs, amino acids, and metabolites. By transferring complex constituents and promoting macrophages to generate chemokines and proinflammatory cytokines, exosomes function in pathophysiological processes in OA, including local inflammation, cartilage calcification and degradation of osteoarthritic joints. Exosomes are also detected in synovial fluid and plasma, and their levels continuously change with OA progression. Thus, exosomes, specifically exosomal miRNAs and lncRNAs, potentially represent multicomponent diagnostic biomarkers for OA. Exosomes derived from various types of mesenchymal stem cells and other cell or tissue types affect angiogenesis, inflammation, and bone remodeling. These exosomes exhibit promising capabilities to restore OA cartilage, attenuate inflammation, and balance cartilage matrix formation and degradation, thus demonstrating therapeutic potential in OA. In combination with biocompatible and highly adhesive materials, such as hydrogels and cryogels, exosomes may facilitate cartilage tissue engineering therapies for OA. Based on numerous recent studies, we summarized the latent mechanisms and clinical value of exosomes in OA in this review.

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Exosomes derived from hypoxia preconditioned mesenchymal stem cells laden in a silk hydrogel promote cartilage regeneration via the miR-205–5p/PTEN/AKT pathway

Cited by 67 publications

References 58 publications

Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles

Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles

Chondrogenic Potential of Human Umbilical Cord Mesenchymal Stem Cells Cultured with Exosome-Depleted Fetal Bovine Serum in an Osteoarthritis Mouse Model

Exosomes in osteoarthritis: Updated insights on pathogenesis, diagnosis, and treatment

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