Interleukin‐4 Gene Transfection and Spheroid Formation Potentiate Therapeutic Efficacy of Mesenchymal Stem Cells for Osteoarthritis

Song, Seuk Young; Hong, Jihye; Go, Seukhyeong; Lim, Songhyun; Sohn, Hee Su; Kang, Mikyung; Jung, Gun‐Jae; Yoon, Jeong‐Kee; Kang, Minchul; Im, Gun‐Il; Kim, Byungsoo

doi:10.1002/adhm.201901612

Cited by 28 publications

(24 citation statements)

References 104 publications

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“…IL-4 inhibits NO production in chondrocytes stimulated with proinflammatory cytokines, 8 , 24 - 27 , 30 , 50 although no effect was found on the IL-17-induced NO production in human OA chondrocytes. 51 IL-4 inhibited CCL5, CCL3, and CCL4 mRNA and protein expression, but did not affect C-X-C motif chemokine (CXCL) 1 and CXCL8 expression.…”

Section: Resultsmentioning

confidence: 90%

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The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review

et al. 2022

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Objective A fusion protein of interleukin-4 and interleukin-10 (IL4-10 FP) was developed as a disease-modifying osteoarthritis drug (DMOAD), and chondroprotection, anti-inflammation, and analgesia have been suggested. To better understand the mechanisms behind its potential as DMOAD, this systematic narrative review aims to assess the potential of IL-4, IL-10 and the combination of IL-4 and IL-10 for the treatment of osteoarthritis. It describes the chondroprotective, anti-inflammatory, and analgesic effects of IL-4, IL-10, and IL4-10 FP. Design PubMed and Embase were searched for publications that were published from 1990 until May 21, 2021 (moment of search). Key search terms were: Osteoarthritis, Interleukin-4, and Interleukin-10. This yielded 2,479 hits, of which 43 were included in this review. Results IL-4 and IL-10 showed mainly protective effects on osteoarthritic cartilage in vitro and in vivo, as did IL4-10 FP. Both cytokines showed anti-inflammatory effects, but also proinflammatory effects. Only in vitro IL4-10 FP showed purely anti-inflammatory effects, indicating that proinflammatory effects of one cytokine can be counteracted by the other when given as a combination. Only a few studies investigated the analgesic effects of IL-4, IL-10 or IL4-10 FP. In vitro, IL-4 and IL4-10 FP were able to decrease pain mediators. In vivo, IL-4, IL-10, and IL4-10 FP were able to reduce pain. Conclusions In conclusion, this review describes overlapping, but also different modes of action for the DMOAD effects of IL-4 and IL-10, giving an explanation for the synergistic effects found when applied as combination, as is the case for IL4-10 FP.

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Section: Resultsmentioning

confidence: 90%

“… 35 Intra-articular administered IL-4 MSC spheroids reduced the expression of the inflammatory mediators Traf6 and Tlr4. 26 …”

Section: Resultsmentioning

confidence: 99%

The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review

et al. 2022

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“…Along with inflammatory progression, the injured articular cartilage in TMD has limited capacity to heal. The application of MSCs and tissue engineering technology to repair cartilage destruction has become a hotspot in the field of TMD treatment[ 13 ]. MSCs can be derived from specific tissues including the bone marrow, blood, teeth, muscle, and skin, showing different advantages in the proliferation efficiency or pluripotency capacity.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin-Induced Autophagy Promotes the Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells in the Temporomandibular Joint in Response to IL-1β

Liu

Wang

et al. 2020

BioMed Research International

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Cartilage defects in temporomandibular disorders (TMD) lead to chronic pain and seldom heal. Synovium-derived mesenchymal stem cells (SMSCs) exhibit superior chondrogenesis and have become promising seed cells for cartilage tissue engineering. However, local inflammatory conditions that affect the repair of articular cartilage by SMSCs present a challenge, and the specific mechanism through which the function remains unclear. Thus, it is important to explore the chondrogenesis of SMSCs under inflammatory conditions of TMD such that they can be used more effectively in clinical treatment. In this study, we obtained SMSCs from TMD patients with severe cartilage injuries. In response to stimulation with IL-1β, which is well known as one of the most prevalent cytokines in TMD, MMP13 expression increased, while that of SOX9, aggrecan, and collagen II decreased during chondrogenic differentiation. At the same time, IL-1β upregulated the expression of mTOR and decreased the ratio of LC3-II/LC3-I and the formation of autophagosomes. Further study revealed that rapamycin pretreatment promoted the migration of SMSCs and the expression of chondrogenesis-related markers in the presence of IL-1β by inducing autophagy. 3-Benzyl-5-((2-nitrophenoxy)methyl)-dihydrofuran-2(3H)-one (3BDO), a new activator of mTOR, inhibited autophagy and increased the expression of p-GSK3βser9 and β-catenin, simulating the effect of IL-1β stimulation. Furthermore, rapamycin reduced the expression of mTOR, whereas the promotion of LC3-II/LC3-I was blocked by the GSK3β inhibitor TWS119. Taken together, these results indicate that rapamycin enhances the chondrogenesis of SMSCs by inducing autophagy, and GSK3β may be an important regulator in the process of rapamycin-induced autophagy. Thus, inducing autophagy may be a useful approach in the chondrogenic differentiation of SMSCs in the inflammatory microenvironment and may represent a novel TMD treatment.

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“…Furthermore, MSCs barely secrete IL-4, a potent anti-inflammatory cytokine. Seuk Young Song et al suggested a combination of both Il-4 gene transfection (using GFP-expressing plasmids and a cationic liposomebased reagent) and spheroid formation to potentiate the therapeutic efficacy of MSCs for osteoarthritis [127]. MSCs in spheroids depicted better survival compared to naïve MSCs in vitro and in vivo.…”

Section: Spheroidsmentioning

confidence: 99%

Mesenchymal Stem Cells as a Gene Delivery Tool: Promise, Problems, and Prospects

et al. 2021

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The cell-based approach in gene therapy arises as a promising strategy to provide safe, targeted, and efficient gene delivery. Owing to their unique features, as homing and tumor-tropism, mesenchymal stem cells (MSCs) have recently been introduced as an encouraging vehicle in gene therapy. Nevertheless, non-viral transfer of nucleic acids into MSCs remains limited due to various factors related to the main stakeholders of the process (e.g., nucleic acids, carriers, or cells). In this review, we have summarized the main types of nucleic acids used to transfect MSCs, the pros and cons, and applications of each. Then, we have emphasized on the most efficient lipid-based carriers for nucleic acids to MSCs, their main features, and some of their applications. While a myriad of studies have demonstrated the therapeutic potential for engineered MSCs therapy in various illnesses, optimization for clinical use is an ongoing challenge. On the way of improvement, genetically modified MSCs have been combined with various novel techniques and tools (e.g., exosomes, spheroids, 3D-Bioprinting, etc.,) aiming for more efficient and safe applications in biomedicine.

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Interleukin‐4 Gene Transfection and Spheroid Formation Potentiate Therapeutic Efficacy of Mesenchymal Stem Cells for Osteoarthritis

Cited by 28 publications

References 104 publications

The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review

The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review

Rapamycin-Induced Autophagy Promotes the Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells in the Temporomandibular Joint in Response to IL-1β

Mesenchymal Stem Cells as a Gene Delivery Tool: Promise, Problems, and Prospects

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