Cell-Free Osteoarthritis Treatment with Sustained-Release of Chondrocyte-Targeting Exosomes from Umbilical Cord-Derived Mesenchymal Stem Cells to Rejuvenate Aging Chondrocytes

Cao, Hanwen; Chen, Manyu; Cui, Xiaolin; Liu, Yuan; Liu, Yuhan; Deng, Shuai; Yuan, Tun; Fan, Yujiang; Wang, Qiguang; Zhang, Xingdong

doi:10.1021/acsnano.3c01612

Cited by 35 publications

(12 citation statements)

References 77 publications

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“…This was the rationale for investigating the impact of S-EVs in resting conditions although most of the studies used chondrocytes cultured in proliferative conditions [ 10 , 26 , 27 ]. In a single study, umbilical cord MSC-EVs were described to improve the anabolic and hypertrophic markers of chondrocytes cultured in low SVF (1%) [ 28 ], which is in line with our findings with H-EVs. By contrast, the catabolic and inflammatory markers and the CDKIs were up-regulated by S-EVs, and not H-EVs, when OA chondrocytes were cultured in proliferative conditions.…”

Section: Discussionsupporting

confidence: 90%

Extracellular vesicles from senescent mesenchymal stromal cells are defective and cannot prevent osteoarthritis

Boulestreau,

Maumus,

Bertolino

et al. 2024

J Nanobiotechnol

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Age is the most important risk factor in degenerative diseases such as osteoarthritis (OA), which is associated with the accumulation of senescent cells in the joints. Here, we aimed to assess the impact of senescence on the therapeutic properties of extracellular vesicles (EVs) from human fat mesenchymal stromal cells (ASCs) in OA. We generated a model of DNA damage-induced senescence in ASCs using etoposide and characterized EVs isolated from their conditioned medium (CM). Senescent ASCs (S-ASCs) produced 3-fold more EVs (S-EVs) with a slightly bigger size and that contain 2-fold less total RNA. Coculture experiments showed that S-ASCs were as efficient as healthy ASCs (H-ASCs) in improving the phenotype of OA chondrocytes cultured in resting conditions but were defective when chondrocytes were proliferating. S-EVs were also impaired in their capacity to polarize synovial macrophages towards an anti-inflammatory phenotype. A differential protein cargo mainly related to inflammation and senescence was detected in S-EVs and H-EVs. Using the collagenase-induced OA model, we found that contrary to H-EVs, S-EVs could not protect mice from cartilage damage and joint calcifications, and were less efficient in protecting subchondral bone degradation. In addition, S-EVs induced a pro-catabolic and pro-inflammatory gene signature in the joints of mice shortly after injection, while H-EVs decreased hypertrophic, catabolic and inflammatory pathways. In conclusion, S-EVs are functionally impaired and cannot protect mice from developing OA.

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Section: Discussionsupporting

confidence: 90%

Extracellular vesicles from senescent mesenchymal stromal cells are defective and cannot prevent osteoarthritis

Boulestreau,

Maumus,

Bertolino

et al. 2024

J Nanobiotechnol

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“…EVs have important research significance in regenerative medicine and are widely used to promote the repair and regeneration of various tissues and organs [ 12 , 36 , 37 ]. Therefore, we evaluated the effect of each hydrogel group on cell function using HSFs and HUVECs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Microenvironment Remodeling Self-Healing Hydrogel for Promoting Flap Survival

Ju,

Yang,

Liu

et al. 2024

Biomater Res

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Random flap grafting is a routine procedure used in plastic and reconstructive surgery to repair and reconstruct large tissue defects. Flap necrosis is primarily caused by ischemia–reperfusion injury and inadequate blood supply to the distal flap. Ischemia–reperfusion injury leads to the production of excessive reactive oxygen species, creating a pathological microenvironment that impairs cellular function and angiogenesis. In this study, we developed a microenvironment remodeling self-healing hydrogel [laminarin–chitosan-based hydrogel-loaded extracellular vesicles and ceria nanozymes (LCH@EVs&CNZs)] to improve the flap microenvironment and synergistically promote flap regeneration and survival. The natural self-healing hydrogel (LCH) was created by the oxidation laminarin and carboxymethylated chitosan via a Schiff base reaction. We loaded this hydrogel with CNZs and EVs. CNZs are a class of nanomaterials with enzymatic activity known for their strong scavenging capacity for reactive oxygen species, thus alleviating oxidative stress. EVs are cell-secreted vesicular structures containing thousands of bioactive substances that can promote cell proliferation, migration, differentiation, and angiogenesis. The constructed LCH@EVs&CNZs demonstrated a robust capacity for scavenging excess reactive oxygen species, thereby conferring cellular protection in oxidative stress environments. Moreover, these constructs notably enhance cell migration and angiogenesis. Our results demonstrate that LCH@EVs&CNZs effectively remodel the pathological skin flap microenvironment and marked improve flap survival. This approach introduces a new therapeutic strategy combining microenvironmental remodeling with EV therapy, which holds promise for promoting flap survival.

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“…The ability to inhibit chondrocyte apoptosis in OA was also observed in sEVs derived from BMSCs [13,18,33,[35][36][37][38][39][40], human umbilical cord MSCs [65] (hUC-MSCs), dental pulp stem cells [18] (DPSCs), human synovial MSCs [17,66] (hS-MSCs) and infrapatellar fat pad (IPFP)-MSCs [21]. And sEVs derived from BMSCs [19], UC-MSCs [67,68] and hypoxia-cultured human adipose-derived stem cells [69] have been reported to be able to restore aging chondrocytes. In terms of inflammatory response, BMSCs-sEVs [15] and DPSCs [70] could inhibit the production of inflammatory factors, such as IL-1, IL-6 and TNF-α.…”

Section: Therapeutic Sevs In Oa 321 Effects Of Therapeutic Sevs On Ch...mentioning

confidence: 92%

The Dual Role of Small Extracellular Vesicles in Joint Osteoarthritis: Their Global and Non-Coding Regulatory RNA Molecule-Based Pathogenic and Therapeutic Effects

Li,

Bi,

Zhu

2023

Biomolecules

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OA is the most common joint disease that affects approximately 7% of the global population. Current treatment methods mainly relieve its symptoms with limited repairing effect on joint destructions, which ultimately contributes to the high morbidity rate of OA. Stem cell treatment is a potential regenerative medical therapy for joint repair in OA, but the uncertainty in differentiation direction and immunogenicity limits its clinical usage. Small extracellular vesicles (sEVs), the by-products secreted by stem cells, show similar efficacy levels but have safer regenerative repair effect without potential adverse outcomes, and have recently drawn attention from the broader research community. A series of research works and reviews have been performed in the last decade, providing references for the application of various exogenous therapeutic sEVs for treating OA. However, the clinical potential of target intervention involving endogenous pathogenic sEVs in the treatment of OA is still under-explored and under-discussed. In this review, and for the first time, we emphasize the dual role of sEVs in OA and explain the effects of sEVs on various joint tissues from both the pathogenic and therapeutic aspects. Our aim is to provide a reference for future research in the field.

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Cell-Free Osteoarthritis Treatment with Sustained-Release of Chondrocyte-Targeting Exosomes from Umbilical Cord-Derived Mesenchymal Stem Cells to Rejuvenate Aging Chondrocytes

Cited by 35 publications

References 77 publications

Extracellular vesicles from senescent mesenchymal stromal cells are defective and cannot prevent osteoarthritis

Extracellular vesicles from senescent mesenchymal stromal cells are defective and cannot prevent osteoarthritis

Microenvironment Remodeling Self-Healing Hydrogel for Promoting Flap Survival

The Dual Role of Small Extracellular Vesicles in Joint Osteoarthritis: Their Global and Non-Coding Regulatory RNA Molecule-Based Pathogenic and Therapeutic Effects

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