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Chondrogenic primed extracellular vesicles activate miR-455/SOX11/FOXO axis for cartilage regeneration and osteoarthritis treatment.

ABSTRACT: Osteoarthritis (OA) is the leading cause of disability worldwide. Considerable progress has been made using stem-cell-derived therapy. Increasing evidence has demonstrated that the therapeutic effects of BMSCs in chondrogenesis could be attributed to the secreted small extracellular vesicles (sEVs). Herein, we investigated the feasibility of applying engineered EVs with chondrogenic priming as a biomimetic tool in chondrogenesis. We demonstrated that EVs derived from TGFβ3-preconditioned BMSCs presented enriched specific miRNAs that could be transferred to native BMSCs to promote chondrogenesis. In addition, We found that EVs derived from TGFβ3-preconditioned BMSCs rich in miR-455 promoted OA alleviation and cartilage regeneration by activating the SOX11/FOXO signaling pathway. Moreover, the designed T3-EV hydrogel showed great potential in cartilage defect treatment. Our findings provide new means to apply biosafe engineered EVs from chondrogenic primed-BMSCs for cartilage repair and OA treatment, expanding the understanding of chondrogenesis and OA development modulated by EV-miRNAs in vivo.

SUBMITTER: Sun Y

PROVIDER: S-EPMC9481593 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Chondrogenic primed extracellular vesicles activate miR-455/SOX11/FOXO axis for cartilage regeneration and osteoarthritis treatment.

Sun Ye Y Zhao Jie J Wu Qiang Q Zhang Yuxin Y You Yongqing Y Jiang Wenbo W Dai Kerong K

NPJ Regenerative medicine 20220916 1

Osteoarthritis (OA) is the leading cause of disability worldwide. Considerable progress has been made using stem-cell-derived therapy. Increasing evidence has demonstrated that the therapeutic effects of BMSCs in chondrogenesis could be attributed to the secreted small extracellular vesicles (sEVs). Herein, we investigated the feasibility of applying engineered EVs with chondrogenic priming as a biomimetic tool in chondrogenesis. We demonstrated that EVs derived from TGFβ3-preconditioned BMSCs p ...[more]

PMID: 36114225

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Project description:Recent data suggest that cells isolated from osteoarthritic (OA) cartilage express mesenchymal progenitor cell (MPC) markers that have the capacity to form hyaline-like cartilage tissue. Whether or not these cells are influenced by the severity of OA remains unexplored. Therefore, we analyzed MPC marker expression and chondrogenetic potential of cells from mild, moderate and severe OA tissue. Human osteoarthritic tibial plateaus were obtained from 25 patients undergoing total knee replacement. Each sample was classified as mild, moderate or severe OA according to OARSI scoring. mRNA expression levels of MPC markers-CD105, CD166, Notch 1, Sox9; mature chondrocyte markers-Aggrecan (Acan), Col II A1, hypertrophic chondrocyte and osteoarthritis-related markers-Col I A1, MMP-13 and ALPL were measured at the tissue level (day 0), after 2 weeks of in vitro expansion (day 14) and following chondrogenic in vitro re-differentiation (day 35). Pellet matrix composition after in vitro chondrogenesis of different OA-derived cells was tested for proteoglycans, collagen II and I by safranin O and immunofluorescence staining. Multiple MPC markers were found in OA cartilage resident tissue within a single OA joint with no significant difference between grades except for Notch1, which was higher in severe OA tissues. Expression levels of CD105 and Notch 1 were comparable between OA cartilage-derived cells of different disease grades and bone marrow mesenchymal stem cell (BM-MSC) line (healthy control). However, the MPC marker Sox 9 was conserved after in vitro expansion and significantly higher in OA cartilage-derived cells compared to its levels in the BM-MSC. The in vitro expansion of cartilage-derived cells resulted in enrichment while re-differentiation in reduction of MPC markers for all three analyzed grades. However, only moderate OA-derived cells after the in vitro chondrogenesis resulted in the formation of hyaline cartilage-like tissue. The latter tissue samples were also highly positive for collagen II and proteoglycans with no expression of osteoarthritis-related markers (collagen I, ALPL and MMP13). MPC marker expression did not differ between OA grades at the tissue level. Interestingly after in vitro re-differentiation, only moderate OA-derived cells showed the capacity to form hyaline cartilage-like tissue. These findings may have implications for clinical practice to understand the intrinsic repair capacity of articular cartilage in OA tissues and raises the possibility of these progenitor cells as a candidate for articular cartilage repair.

Project description:BackgroundGEM (GTP-binding protein overexpressed in skeletal muscle) is one of the atypical small GTPase subfamily members recently identified as a regulator of cell differentiation. Abnormal chondrogenesis coupled with an imbalance in the turnover of cartilaginous matrix formation is highly relevant to the onset and progression of osteoarthritis (OA). However, how GEM regulates chondrogenic differentiation remains unexplored.MethodsCartilage tissues were obtained from OA patients and graded according to the ORASI and ICRS grading systems. The expression alteration of GEM was detected in the Grade 4 cartilage compared to Grade 0 and verified in OA mimic culture systems. Next, to investigate the specific function of GEM during these processes, we generated a Gem knockdown (Gem-Kd) system by transfecting siRNA targeting Gem into ATDC5 cells. Acan, Col2a1, Sox9, and Wnt target genes of Gem-Kd ATDC5 cells were detected during induction. The transcriptomic sequencing analysis was performed to investigate the mechanism of GEM regulation. Wnt signaling pathways were verified by real-time PCR and immunoblot analysis. Finally, a rescue model generated by treating Gem-KD ATDC5 cells with a Wnt signaling agonist was established to validate the mechanism identified by RNA sequencing analysis.ResultsA decreased expression of GEM in OA patients' cartilage tissues and OA mimic chondrocytes was observed. While during chondrogenesis differentiation and cartilage matrix formation, the expression of GEM was increased. Gem silencing suppressed chondrogenic differentiation and the expressions of Acan, Col2a1, and Sox9. RNA sequencing analysis revealed that Wnt signaling was downregulated in Gem-Kd cells. Decreased expression of Wnt signaling associated genes and the total β-CATENIN in the nucleus and cytoplasm were observed. The exogenous Wnt activation exhibited reversed effect on Gem loss-of-function cells.ConclusionThese findings collectively validated that GEM functions as a novel regulator mediating chondrogenic differentiation and cartilage matrix formation through Wnt/β-catenin signaling.

Project description:BackgroundArticular cartilage injuries can lead to pain, stiffness, and reduced mobility, and may eventually progress to osteoarthritis (OA). Despite substantial research efforts, effective therapies capable of regenerating cartilage are still lacking. Mesenchymal stromal cells (MSCs) are known for their differentiation and immunomodulatory capabilities, yet challenges such as limited survival post-injection and inconsistent therapeutic outcomes hinder their clinical application. Recent evidence suggests that the beneficial effects of MSCs are largely mediated by their secreted small extracellular vesicles (sEVs), which have been shown to promote tissue repair and reduce inflammation. MSC-derived sEVs have shown promise in mitigating cartilage degradation and chondrocyte apoptosis, positioning them as a promising alternative to MSC-based therapies for OA treatment. This review explores the potential and limitations of MSC-derived sEVs in cartilage regeneration.Main textThis systematic review was conducted following PRISMA guidelines, with a comprehensive search of the Web of Science and Scopus databases for studies published between 2019 and 2024. A total of 223 records were identified, of which 132 articles were assessed for eligibility based on general selection criteria. After full-text screening, 60 articles were initially selected, comprising 58 in vitro studies and 40 in vivo studies. Following further exclusion based on specific criteria, 33 in vitro and 28 in vivo studies from a total of 47 scientific papers were included in the final qualitative synthesis. Most studies indicate that MSC-derived sEVs enhance chondrocyte proliferation, improve cartilage extracellular matrix composition, and reduce matrix-degrading enzymes and inflammation, thereby delaying OA progression.ConclusionA growing body of evidence supports the use of MSC-derived sEVs as a therapeutic tool for preventing OA progression, with most studies reporting beneficial effects on cartilage structure and function. However, challenges remain in optimizing and standardizing sEVs isolation, dosage, and delivery methods for clinical application. Further research is necessary to elucidate the mechanisms underlying sEVs-mediated cartilage regeneration and to facilitate their translation into effective OA therapies.

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Chondrogenic primed extracellular vesicles activate miR-455/SOX11/FOXO axis for cartilage regeneration and osteoarthritis treatment.

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Chondrogenic primed extracellular vesicles activate miR-455/SOX11/FOXO axis for cartilage regeneration and osteoarthritis treatment.

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