Metformin facilitates mesenchymal stem cell-derived extracellular nanovesicles release and optimizes therapeutic efficacy in intervertebral disc degeneration

Liao, Zhiwei; Li, Shuai; Lu, Shuaicheng; Liu, Hui; Li, Gaocai; Ma, Liang; Luo, Rongjin; Ke, Wencan; Wang, Bingjin; Xiang, Qian; Song, Yu; Feng, Xiaobo; Zhang, Yukun; Wu, Xinghuo; Hua, Wenbin; Yang, Cao

doi:10.1016/j.biomaterials.2021.120850

Cited by 89 publications

(76 citation statements)

References 63 publications

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“…Metformin promotes EVs generation by an autophagy-related axis concurrently with the phosphorylation of synaptosome-associated protein 29 (SNAP29). Interestingly, this ingredient affect both the quantity and the quality of MSCs-derived EVs, as documented by an elevation in the content of EVs participated in cell growth through proteomic analysis [ 50 ]. Another study showed that preconditioning of MSCs with lithium could ameliorate the neuroregenerative capacities of MSCs mediated by elevated secretion of EVs.…”

Section: Mscs- Exosomes Biogenesismentioning

confidence: 99%

A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine

et al. 2021

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Recently, mesenchymal stem/stromal cells (MSCs) due to their pro-angiogenic, anti-apoptotic, and immunoregulatory competencies along with fewer ethical issues are presented as a rational strategy for regenerative medicine. Current reports have signified that the pleiotropic effects of MSCs are not related to their differentiation potentials, but rather are exerted through the release of soluble paracrine molecules. Being nano-sized, non-toxic, biocompatible, barely immunogenic, and owning targeting capability and organotropism, exosomes are considered nanocarriers for their possible use in diagnosis and therapy. Exosomes convey functional molecules such as long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs), proteins (e.g., chemokine and cytokine), and lipids from MSCs to the target cells. They participate in intercellular interaction procedures and enable the repair of damaged or diseased tissues and organs. Findings have evidenced that exosomes alone are liable for the beneficial influences of MSCs in a myriad of experimental models, suggesting that MSC- exosomes can be utilized to establish a novel cell-free therapeutic strategy for the treatment of varied human disorders, encompassing myocardial infarction (MI), CNS-related disorders, musculoskeletal disorders (e.g. arthritis), kidney diseases, liver diseases, lung diseases, as well as cutaneous wounds. Importantly, compared with MSCs, MSC- exosomes serve more steady entities and reduced safety risks concerning the injection of live cells, such as microvasculature occlusion risk. In the current review, we will discuss the therapeutic potential of MSC- exosomes as an innovative approach in the context of regenerative medicine and highlight the recent knowledge on MSC- exosomes in translational medicine, focusing on in vivo researches.

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Section: Mscs- Exosomes Biogenesismentioning

confidence: 99%

A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine

et al. 2021

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“…Intervertebral disk degeneration remains a chief cause of morbidity and disability and medical costs around the world ( Kos et al, 2019 ). MSC-EVs are regarded as a novel therapeutic approach for IDD ( Liao et al, 2021 ). The present study elicited that hBMSC-EVs promoted DNPCs proliferation and ECM synthesis by carrying miR-129-5p into DNPCs to target SOX4 and inhibit the activation of the Wnt/β-catenin axis.…”

Section: Discussionmentioning

confidence: 99%

Human Bone Marrow Mesenchymal Stromal Cell-Derived Extracellular Vesicles Promote Proliferation of Degenerated Nucleus Pulposus Cells and the Synthesis of Extracellular Matrix Through the SOX4/Wnt/β-Catenin Axis

Wang

Ban

et al. 2021

Front. Physiol.

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Objective: Intervertebral disk degeneration (IDD) is a major cause of pain in the back, neck, and radiculus. Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) are therapeutic in musculoskeletal degenerative diseases such as IDD. This study explored the effect and functional mechanism of human bone MSCs (hBMSCs)-derived EVs in proliferation and apoptosis of degenerated nucleus pulposus cells (DNPCs) and extracellular matrix (ECM) synthesis.Methods: Extracellular vesicles were isolated from hBMSCs and identified. DNPCs were induced by TNF-α. EVs were incubated with DNPCs for 24h. Internalization of EVs by DNPCs, DNPCs proliferation, apoptosis, and expressions of ECM synthetic genes, degrading genes and miR-129-5p were assessed. Downstream target genes of miR-129-5p were predicted. Target relation between miR-129-5p and SRY-box transcription factor 4 (SOX4) was verified. DNPCs proliferation, apoptosis, and ECM synthesis were measured after treatment with EVs and miR-129-5p inhibitor or SOX4 overexpression. Expressions of SOX4 and Wnt/β-catenin pathway-related proteins were determined.Results: hBMSC-EVs promoted DNPCs proliferation, inhibited apoptosis, increased expressions of ECM synthetic genes, and reduced expressions of ECM degrading genes. hBMSC-EVs carried miR-129-5p into DNPCs. Silencing miR-129-5p in EVs partially inverted the effect of EVs on DNPCs proliferation and ECM synthesis. miR-129-5p targeted SOX4. SOX4 overexpression annulled the effect of EVs on DNPCs proliferation and ECM synthesis. Expressions of Wnt1 and β-catenin were decreased in EVs-treated DNPCs, while silencing miR-129-5p in EVs promoted expressions of Wnt1 and β-catenin.Conclusion: hBMSC-EVs promoted DNPCs proliferation and ECM synthesis by carrying miR-129-5p into DNPCs to target SOX4 and deactivating the Wnt/β-catenin axis.

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“…Peremajaan sel NP atau pemulihan viabilitas sel adalah tantangan kritis untuk regenerasi diskus intervertebralis. 83 Metode terapi yang digunakan sampai saat ini untuk menangani IDD salah satunya yaitu perawatan bedah yang umumnya untuk meredakan gejala yang ditimbulkan. Selanjutnya terapi biologis untuk IDD berfokus pada regenerasi sel diskus yang menetap dan pemulihan sel yang cedera, sehingga dapat memberikan efek terapeutik jangka panjang.…”

Section: Mesenchymal Stem Cells Untuk Terapi Intervertebral Disc Dege...unclassified

“…EVs yang diturunkan dari MSCs menunjukkan potensi terapeutik yaitu dalam perbaikan dan regenerasi jaringan. 83 Bukti yang berkembang menunjukkan efektivitasnya dalam menghambat perkembangan IDD dan berfungsi sebagai pengobatan yang efektif untuk IDD. 86,87 Dalam penelitian yang dilakukan oleh Liao et al, (2021) menunjukkan bahwa metformin dapat digunakan sebagai sarana untuk mengoptimalkan terapi IDD berbasis MSCs, hal ini dikarenakan metformin secara efektif dapat meningkatkan sekresi EVs.…”

Section: Mesenchymal Stem Cells Untuk Terapi Intervertebral Disc Dege...unclassified

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Generasi Berikutnya: Sel Punca Mesenkim Sebagai Sistem Penghantaran Obat Berbasis Sel

2022

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Mesenchymal Stem Cells (MSCs) atau sel punca mesenkim merupakan sel punca dewasa yang bersifat multipoten unik yang berasal dari sumsum tulang. MSCs memiliki sifat regeneratif yang luas dan imunomodulator yang dapat digunakan dalam perbaikan jaringan dan penyembuhan luka. MSCs juga mampu bermigrasi ke tempat peradangan, lokasi jaringan yang cedera, infeksi, dan tumor dengan imunomodulasi lingkungan mikro melalui kontak sel ke sel dan pelepasan faktor terlarut sehingga memfasilitasi adanya perbaikan pada jaringan yang rusak serta merespons kemokin, sitokin, dan faktor pertumbuhan. Berkat adanya karakteristik tersebut MSCs mulai gencar dikembangkan sebagai vektor terapi gen untuk berbagai penyakit termasuk kanker, IDD, epilepsi, gangguan pendengaran sensorineural hingga stroke iskemik. Metode yang digunakan dalam artikel review ini yaitu dengan melakukan peninjauan terhadap literatur, sehingga di dapatkan 6 jurnal internasional yang diperoleh dari PubMed dan ScienceDirect yang telah memenuhi kriteria inklusi, sumber data dipublikasi paling lambat 10 tahun terakhir. Dari beberapa hasil penelitian praklinis yang dilakukan, ditemukan bahwa MSCs memiliki potensi untuk dikembangkan sebagai sistem penghantaran obat berbasis sel generasi berikutnya, yang menjanjikan dalam terapi penyakit glioblastoma, gangguan pendengaran sensorineural, kanker kolekteral, epilepsi, stroke iskemik dan Intervertebral Disc Degeneration (IDD). Namun pada pengembangannya masih ditemui adanya tantangan dalam sistem tersebut, sehingga MSCs saat ini masih memerlukan penelitian lebih lanjut agar ke depannya dapat digunakan secara optimal sebagai sistem penghantaran obat serta dapat dikembangkan secara lebih luas.

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Metformin facilitates mesenchymal stem cell-derived extracellular nanovesicles release and optimizes therapeutic efficacy in intervertebral disc degeneration

Cited by 89 publications

References 63 publications

A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine

A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine

Human Bone Marrow Mesenchymal Stromal Cell-Derived Extracellular Vesicles Promote Proliferation of Degenerated Nucleus Pulposus Cells and the Synthesis of Extracellular Matrix Through the SOX4/Wnt/β-Catenin Axis

Generasi Berikutnya: Sel Punca Mesenkim Sebagai Sistem Penghantaran Obat Berbasis Sel

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