MFG-E8 promotes tendon-bone healing by regualting macrophage efferocytosis and M2 polarization after anterior cruciate ligament reconstruction

Geng, Rui; Ji, Ming-liang; Chang, Qing; Li, Zhuang; Xu, Li; Zhang, Weituo; Lü, Jun

doi:10.1016/j.jot.2022.04.002

Cited by 17 publications

(17 citation statements)

References 38 publications

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“… 26 , 27 It is well known that macrophages are mainly divided into M1-like and M2-like macrophages, and the regulation of the transition of macrophages from M1 to M2 phenotype can inhibit the inflammatory cascade and enhance subsequent reparative activities, thereby facilitating T-B healing. 1 , 28 , 29 Being consistent with previous research, 14 , 30 , 31 our results revealed that mechanical stimulation modulated macrophages to polarize toward the M2 phenotype both in vivo and in vitro, which highlighted the macrophages as a potential target of mechanical stimulation to manipulate T-B healing. Moreover, in vitrol assay, we found that 5% mechanical stretch exhibited superior positive role in macrophage M2 polarization when compared with 10% and 15% stretch, which indicates that the loading intensity played a crucial role in determining the polarization state of macrophages.…”

Section: Discussionsupporting

confidence: 91%

TGF-β1 derived from macrophages contributes to load-induced tendon-bone healing in the murine rotator cuff repair model by promoting chondrogenesis

Wang

Xiao

et al. 2023

Bone Joint Res

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AimsIt has been established that mechanical stimulation benefits tendon-bone (T-B) healing, and macrophage phenotype can be regulated by mechanical cues; moreover, the interaction between macrophages and mesenchymal stem cells (MSCs) plays a fundamental role in tissue repair. This study aimed to investigate the role of macrophage-mediated MSC chondrogenesis in load-induced T-B healing in depth.MethodsC57BL/6 mice rotator cuff (RC) repair model was established to explore the effects of mechanical stimulation on macrophage polarization, transforming growth factor (TGF)-β1 generation, and MSC chondrogenesis within T-B enthesis by immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Macrophage depletion was performed by clodronate liposomes, and T-B healing quality was evaluated by histology and biomechanics. In vitro, bone marrow-derived macrophages (BMDMs) were stretched with CELLOAD-300 load system and macrophage polarization was identified by flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR). MSC chondrogenic differentiation was measured by histochemical analysis and qRT-PCR. ELISA and qRT-PCR were performed to screen the candidate molecules that mediated the pro-chondrogenic function of mechanical stimulated BMDMs.ResultsMechanical stimulation promoted macrophage M2 polarization in vivo and in vitro. The conditioned media from mechanically stimulated BMDMs (MS-CM) enhanced MSC chondrogenic differentiation, and mechanically stimulated BMDMs generated more TGF-β1. Further, neutralizing TGF-β1 in MS-CM can attenuate its pro-chondrogenic effect. In vivo, mechanical stimulation promoted TGF-β1 generation, MSC chondrogenesis, and T-B healing, which were abolished following macrophage depletion.ConclusionMacrophages subjected to appropriate mechanical stimulation could polarize toward the M2 phenotype and secrete TGF-β1 to promote MSC chondrogenesis, which subsequently augments T-B healing.Cite this article: Bone Joint Res 2023;12(3):219–230.

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Section: Discussionsupporting

confidence: 91%

TGF-β1 derived from macrophages contributes to load-induced tendon-bone healing in the murine rotator cuff repair model by promoting chondrogenesis

Wang

Xiao

et al. 2023

Bone Joint Res

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“…It has been reported that MFGE8 is a secretory glycoprotein ubiquitously expressed in various organs and cells that can interact with macrophages, which can be combined with αvβ3-integrin and phosphorylated serine sites, respectively. 73 MFGE8 can reduce inflammation, 11 , 14 activate phagocytic signals, 12 induce polarization of M2-type macrophages, 13 , 74 promote angiogenesis, 34 and improve fibroblast migration. 74 It has been found that long-term hyperglycemia and advanced glycation end products deactivate MFGE8 in diabetic tissues, which is an important mechanism for the difficult healing of diabetic wounds.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…11 MFGE8 is a secreted glycoprotein that interacts with macrophages and binds to αvβ3-integrin and phosphorylated serine sites, respectively. It also plays an essential role in promoting macrophage phagocytosis, 12 polarization 13 and reducing apoptosis and organ damage. 14 Previous studies have confirmed that exosomes can act as a messenger to link keratinocytes (KCs) and macrophages in both directions.…”

Section: Introductionmentioning

confidence: 99%

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Human Keratinocyte-Derived Exosomal MALAT1 Promotes Diabetic Wound Healing by Upregulating MFGE8 via microRNA-1914-3p

Kuang¹,

Zhang²,

Li³

et al. 2023

IJN

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Purpose Diabetic wound is a highly prevalent and refractory disease. Extensive studies have confirmed that keratinocytes and macrophages play an important role in the process of wound healing. Additionally, exosomes are regarded as a vital intercellular communication tool. This study aimed to investigate the role of human keratinocyte-derived exosomal MALAT1 in the treatment of diabetic wound by influencing the biological function of macrophages. Methods We mainly assessed the function of MALAT1 on the biological changes of macrophages, and the expression of MALAT1 in the keratinocyte-exosomes analyzed by quantitative real-time polymerase chain reaction (RT-qPCR). The downstream interaction between RNAs or proteins was assessed by mechanistic experiments. Besides, we evaluated the effects of human keratinocyte-derived exosomal MALAT1 on diabetic wound healing in vivo to verify in vitro results. Results We demonstrated that human keratinocyte-derived exosomal MALAT1 enhanced the biological functions of high glucose-injured macrophages, including phagocytosis, converting to a pro-healing phenotype and reducing apoptosis. Mechanistically, MALAT1 accelerated the expression of MFGE8 by competitively binding to miR-1914-3p, thereby affecting the function of macrophages and the signal axis of TGFB1/SMAD3, and finally promoting the healing of diabetic wounds. Human keratinocyte-derived exosomal MALAT1 might promote collagen deposition, ECM remodeling, and expression of MFGE8, VEGF, and CD31 but reduce the expression of TGFB and SMAD3 in an in vivo model of diabetic mice wounds, which accelerated diabetic wound healing and restored its function. Conclusion The current study revealed that human keratinocyte-derived exosomal MALAT1 would suppress miR-1914-3p to activate MFGE8 and eventually promote wound healing by enhancing macrophage phagocytosis, converting to a pro-healing phenotype and reducing apoptosis. It proposed that keratinocyte-derived exosomes might have the capacity to serve as a new method for the clinical treatment of diabetic wound.

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“…Therefore, it is involved in the angiogenesis of skin wounds ( Uchiyama et al, 2014 ), as well as the healing of tendon rupture and other physiological processes ( Shi et al, 2019 ). Geng et al (2022) found in an animal model of ACL reconstruction that MFG-E8 attenuates the inflammatory response by enhancing macrophage secretion and M2 polarization, which ultimately leads to reduced inflammatory bone loss, increased new bone formation around the tunnel, and improved bone integration. Therefore, MFG-E8 can also be used as a novel therapeutic strategy to promote tendon-bone healing in ACL reconstruction patients.…”

Section: Preclinical Study Of Strategies To Promote Tendon-bone Heali...mentioning

confidence: 99%

Strategies to promote tendon-bone healing after anterior cruciate ligament reconstruction: Present and future

Tian

Zhang

Kang

2023

Front. Bioeng. Biotechnol.

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At present, anterior cruciate ligament (ACL) reconstruction still has a high failure rate. Tendon graft and bone tunnel surface angiogenesis and bony ingrowth are the main physiological processes of tendon-bone healing, and also the main reasons for the postoperative efficacy of ACL reconstruction. Poor tendon-bone healing has been also identified as one of the main causes of unsatisfactory treatment outcomes. The physiological process of tendon-bone healing is complicated because the tendon-bone junction requires the organic fusion of the tendon graft with the bone tissue. The failure of the operation is often caused by tendon dislocation or scar healing. Therefore, it is important to study the possible risk factors for tendon-bone healing and strategies to promote it. This review comprehensively analyzed the risk factors contributing to tendon-bone healing failure after ACL reconstruction. Additionally, we discuss the current strategies used to promote tendon-bone healing following ACL reconstruction.

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MFG-E8 promotes tendon-bone healing by regualting macrophage efferocytosis and M2 polarization after anterior cruciate ligament reconstruction

Cited by 17 publications

References 38 publications

TGF-β1 derived from macrophages contributes to load-induced tendon-bone healing in the murine rotator cuff repair model by promoting chondrogenesis

TGF-β1 derived from macrophages contributes to load-induced tendon-bone healing in the murine rotator cuff repair model by promoting chondrogenesis

Human Keratinocyte-Derived Exosomal MALAT1 Promotes Diabetic Wound Healing by Upregulating MFGE8 via microRNA-1914-3p

Strategies to promote tendon-bone healing after anterior cruciate ligament reconstruction: Present and future

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