Extracellular vesicles derived from human dental pulp stem cells promote osteogenesis of adipose-derived stem cells via the MAPK pathway

Jin, Qiaoqiao; Li, Peilun; Yuan, Kai; Zhao, Fen; Zhu, Xiaohan; Zhang, Pengfei; Huang, Zhengwei

doi:10.1177/2041731420975569

Cited by 37 publications

(27 citation statements)

References 68 publications

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“… 1 – 5 These therapeutic effects of MSCs result from transdifferentiation of stem cells, cell fusion, mitochondrial transfer, and paracrine effects of cells. 6 , 7 Paracrine factors, including chemokines, cytokines, and growth factors, have recently been widely studied with extensive use of MSCs in clinical trials. 8 In particular, extracellular vesicles (EVs) have been recognized as an important bioactive component for paracrine effects of MSCs.…”

Section: Introductionmentioning

confidence: 99%

Defined MSC exosome with high yield and purity to improve regenerative activity

et al. 2021

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Exosomes derived from mesenchymal stem cells (MSCs) have been studied as vital components of regenerative medicine. Typically, various isolation methods of exosomes from cell culture medium have been developed to increase the isolation yield of exosomes. Moreover, the exosome-depletion process of serum has been considered to result in clinically active and highly purified exosomes from the cell culture medium. Our aim was to compare isolation methods, ultracentrifuge (UC)-based conventional method, and tangential flow filtration (TFF) system-based method for separation with high yield, and the bioactivity of the exosome according to the purity of MSC-derived exosome was determined by the ratio of Fetal bovine serum (FBS)-derived exosome to MSC-derived exosome depending on exosome depletion processes of FBS. The TFF-based isolation yield of exosome derived from human umbilical cord MSC (UCMSC) increased two orders (92.5 times) compared to UC-based isolation method. Moreover, by optimizing the process of depleting FBS-derived exosome, the purity of UCMSC-derived exosome, evaluated using the expression level of MSC exosome surface marker (CD73), was about 15.6 times enhanced and the concentration of low-density lipoprotein-cholesterol (LDL-c), known as impurities resulting from FBS, proved to be negligibly detected. The wound healing and angiogenic effects of highly purified UCMSC-derived exosomes were improved about 23.1% and 71.4%, respectively, with human coronary artery endothelial cells (HCAEC). It suggests that the defined MSC exosome with high yield and purity could increase regenerative activity.

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Section: Introductionmentioning

confidence: 99%

Defined MSC exosome with high yield and purity to improve regenerative activity

et al. 2021

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“…The mechanisms for regenerative properties of transplanted MSCs are not still clearly unraveled [5]. However, many reports have demonstrated the potential of MSCs for transdifferentiation, cell fusion, mitochondrial transfer, and paracrine signaling [6,7]. Since the differentiations and survivals of MSCs are limited in the targeted lesions, a paracrine signaling from MSCs has been considered as a major mechanism of their therapeutic effects.…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of MSC-Derived Exosomes Depending on Cell Culture Media for Regenerative Bioactivity

Kim

Rhim

Seo

et al. 2021

Tissue Eng Regen Med

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BACKGROUND: In order to produce and isolate the exosome derived from the cell of interests, a serum free environment (starvation) has been essential for excluding the unknown effect from serum-derived exosomes. Recently, serum-free culture media have been developed as a substitute for serum supplemented media so that MSC proliferates with maintaining the original characteristics of the cells in a serum free condition. Due to the different properties of the exosomes representing the states and characteristics of the origin cells, a study is needed to compare the properties of the cell-derived exosomes according to the cell culture media. METHODS: To compare the cell culture condition on exosomes, human umbilical cord mesenchymal stem cells (UCMSCs) were cultured with two different media, serum containing media, 10% FBS supplemented DMEM (NM) and serum-free chemically defined media, CellCor TM CD MSC (CDM). To remove FBS-derived exosomes from UCMSC cultured with NM, the medium was replaced with FBS-free DMEM for starvation during exosome isolation. The production yield and expression levels of angiogenic and pro-inflammatory factors were compared. And, the subpopulations of exosome were classified depending on the surface properties and loaded cytokines. Finally, the wound healing and angiogenic effects have been evaluated using in vitro assays. RESULTS: The UCMSC-derived exosomes under two different cell culture media could be classified into subpopulations according to the surface composition and loaded cytokines. Especially, exosome derived from UCMSC cultured with CDM showed higher expression levels of cytokines related to regenerative bioactivities which resulted in enhanced wound healing and angiogenesis. CONCLUSION: CDM has the advantages to maintain cell proliferation even during the period of exosome isolations and eliminate unknown side effects caused by serumderived exosomes. Additionally, exosomes derived from UCMSC cultured with CDM show better wound healing and angiogenic effects due to a lot of regeneration-related cytokines and less pro-inflammatory cytokines compared to with NM.

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“… 18 Dental pulp stem cells-EVs also enhance osteogenesis of adipose-derived stem cells via the MAPK pathway. 19 Stem cells-EVs enhances cartilage repair, which is benefit to protect the osteoarthritis joint from damage. 20 Expanding on existing data, findings obtained in the current study highlight the inhibitory effect of miR-129-5p shuttled by BMSC-derived EVs on the IDD progression via suppression of LRG1-dependent p38 MAPK signaling pathway activation.…”

Section: Discussionmentioning

confidence: 99%

microRNA-129-5p shuttled by mesenchymal stem cell-derived extracellular vesicles alleviates intervertebral disc degeneration via blockade of LRG1-mediated p38 MAPK activation

Cui

Zhang

2021

J Tissue Eng

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Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been reported to deliver exogenous microRNAs (miRNAs or miRs) to reduce the progression of intervertebral disc degeneration (IDD). The purpose of the current study was to investigate the therapeutic potential of MSC-derived EVs delivering miR-129-5p in IDD. First, miR-129-5p expression levels were quantified in nucleus pulposus (NP) tissues of IDD patients. An IL-1β-induced NP cell model with IDD was then established, and co-cultured with EVs derived from MSCs that had been transfected with miR-129-5p mimic or inhibitor to elucidate the effects of miR-129-5p on cell viability, apoptosis, and ECM degradation. In addition, RAW264.7 cells were treated with the conditioned medium (CM) of NP cells. Next, the expression patterns of polarization markers and those of inflammatory factors in macrophages were detected using flow cytometry and ELISA, respectively. Lastly, rat models of IDD were established to validate the in vitro findings. It was found that miR-129-5p was poorly-expressed in NP tissues following IDD. Delivery of miR-129-5p to NP cells by MSC-derived EVs brought about a decrease in NP cell apoptosis, ECM degradation and M1 polarization of macrophages. Moreover, miR-129-5p directly-targeted LRG1, which subsequently promoted the activation of p38 MAPK signaling pathway, thus polarizing macrophages toward the M1 phenotype. Furthermore, MSC-derived EVs transferring miR-129-5p relieved IDD via inhibition of the LRG1/p38 MAPK signaling in vivo. Altogether, our findings indicated that MSC-derived EVs carrying miR-129-5p confer protection against IDD by targeting LRG1 and suppressing the p38 MAPK signaling pathway, offering a novel theranostic marker in IDD.

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Extracellular vesicles derived from human dental pulp stem cells promote osteogenesis of adipose-derived stem cells via the MAPK pathway

Cited by 37 publications

References 68 publications

Defined MSC exosome with high yield and purity to improve regenerative activity

Defined MSC exosome with high yield and purity to improve regenerative activity

Comparative Analysis of MSC-Derived Exosomes Depending on Cell Culture Media for Regenerative Bioactivity

microRNA-129-5p shuttled by mesenchymal stem cell-derived extracellular vesicles alleviates intervertebral disc degeneration via blockade of LRG1-mediated p38 MAPK activation

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