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. 2026 Feb 13.
doi: 10.1186/s13287-026-04932-7. Online ahead of print.

Extracellular vesicles from human adipose-derived stem cells relieve pain and inflammation in a rat model of knee osteoarthritis

Woo Sung Kim  1 , Chang Hee Woo  1 , Kyoung Soo Lee  1 , Young Chan Choi  1 , Ye Eun Yun  2 , Ji Suk Choi  3 , Yong Woo Cho  4   5
Affiliations
Free article

Extracellular vesicles from human adipose-derived stem cells relieve pain and inflammation in a rat model of knee osteoarthritis

Woo Sung Kim et al. Stem Cell Res Ther. .
Free article

Abstract

Background: Inflammatory pain is a hallmark symptom of osteoarthritis (OA), characterized by spontaneous hypersensitivity resulting from tissue damage and chronic inflammation. This study investigates the pain-relieving and cartilage-protective potential of extracellular vesicles (EVs) derived from human adipose-derived stem cells (hASCs) as a cell-free therapeutic approach for OA.

Methods: hASC-EVs were isolated via multi-filtrations based on tangential flow filtration (TFF) and characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), dynamic light scattering (DLS), zeta potential measurement, flow cytometry and Liquid chromatography-mass spectrometry (LC-MS/MS)-based proteomic analysis. An in vitro inflammatory OA model was established by treating human osteoarthritic chondrocytes (HC-OA) with interleukin-1β (IL-1β). The expression of inflammation- and pain-related genes was assessed by quantitative PCR (qPCR), and modulation of the Phosphoinositide 3-kinase / Protein kinase B (PI3K/Akt) signaling pathway was analyzed using an antibody array. In vivo therapeutic effects were evaluated in seven-week-old male Wistar rats using a monosodium iodoacetate (MIA)-induced OA model following intra-articular injection of hASC-EVs. Pain behavior was assessed via paw withdrawal latency (PWL), paw withdrawal threshold (PWT), and weight-bearing tests. Cartilage protection was evaluated by histological and immunohistochemical stainings (IHC).

Results: hASC-EVs were efficiently internalized into chondrocytes and significantly suppressed IL-1β-induced expression of pain and inflammatory markers (TRPA1, COX-2, MMP-2, MMP-3, and MMP-9). Additionally, hASC-EVs down-regulated key PI3K/Akt signaling genes, such as PIK3CA and AKT1. In vivo, hASC-EV treatment markedly improved PWL, PWT, and weight-bearing performance compared with untreated OA rats. Histological and immunohistochemical analyses revealed reduction of inflammatory cytokine expression and preservation of collagen type II, indicating both anti-inflammatory and cartilage-protective effects.

Conclusions: hASC-EVs exhibited robust pain-relieving and cartilage-preserving effects in an OA rat model, highlighting their potential as a promising cell-free therapeutic strategy for the management of OA-related pain and joint degeneration.

Keywords: Cartilage protection; Extracellular vesicles; Human adipose-derived stem cells; Inflammatory pain; Osteoarthritis; PI3K/Akt signaling; Pain relief.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: HASCs and HC-OA cells were purchased from commercial vendors (Matica Biolabs and Cell Applications). Matica Biolabs confirmed that hASCs were obtained with Institutional Review Board (IRB) approval (CHAMC IRB 2019-05-040-036), and donor informed consent, in compliance with ethical guidelines. Furthermore, according to the vendor’s bioethical guidelines, we confirmed that HC-OA cells were obtained from procurement organizations in the United States including Organ Procurement Organization (OPO), Tissue Banks (TB), and Eye Banks (EB). These organizations operate in compliance with laws regarding informed consent, including guidelines from the office for human research protections (45 CFR Part 46) and protection of human subjects (21 CFR Part 50 Subpart B). All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the Catholic University of Korea (CUMC-2021-0260-01) and performed by National efficacy evaluation center for the health products targeting arthritis and immune diseases (CAID), which operates under its oversight. (Study title: “Evaluation of the efficacy of Cartisome in treating osteoarthritis”; approval number: CAID 034-0221-202121; approval date: Jul 16, 2021). Consent for publication: Not applicable. Competing interests: Y.W.C. are stockholders of Exostemtech, Inc. J.S.C., W.S.K., C.H.W., K.S.L., and Y.C.C. are employed by Exostemtech, Inc.

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