FASEB JOURNAL
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2025
·Vol. 39
·期 24
·e71350
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IF 4.2
Shuwei Huang,Qinyao Zhang,Meijiu Zhang,Xiaoqian Liu,Mingzhu Liu,Jun Sun,Hemin Nie,Lei Lei
Traditional monolayer cultures of stem cells from the apical papilla (SCAP) fall short in their ability to replicate the anatomical organization of SCAP and often fail to provide high-quality SCAP suitable for dental root regeneration. This study aimed to employ agarose-based low-adhesion plates to induce the spontaneous formation of SCAP spheroids and disclose the biological impacts of SCAP in forming papilla-like structures in vivo. Compared with monolayer-cultured SCAP, spheroid-cultured SCAP exhibited enhanced in vitro and in vivo odontoblastic differentiation potentials. RNA sequencing identified the importance of N-cadherin downregulation in enhancing the odontoblastic differentiation potential of SCAP in spheroids compared with monolayer-cultured SCAP. Furthermore, N-cadherin knockdown in vitro significantly upregulated the β-catenin signaling pathway, further promoting SCAP odontoblastic differentiation. SCAP cultured on agarose-based plates spontaneously form spheroids and undergo odontoblastic differentiation through N-cadherin downregulation, offering new insights into SCAP-mediated dentin regeneration. Graphical (A) RNA-seq revealed that spheroid cultures downregulate N-cadherin of SCAP. (B) N-cadherin sequesters β-catenin at cell membrane adhesion sites and interacts with Wnt co-receptors LRP5/6, thereby promoting β-catenin degradation.
研究领域:
牙科干细胞生物学
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再生牙医学
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细胞分化
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分子信号传导
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DOI
PubMed
高影响因子
Stem Cells International
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2018
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IF 3.989
Yong-Heng Luo,Juan Chen,En-Hua Xiao,Qiu-Yun Li,Yong-Mei Luo
Demethylating agent zebularine is reported to be capable of inducing differentiation of stem cells by activation of methylated genes, though its function in hepatocyte differentiation is unclear. p38 signal pathway is involved in differentiation of hepatocytes and regulating of DNA methyltransferases 1 (DNMT1) expression. However, little is known about the impact of zebularine on bone marrow mesenchymal stem cells (BMMSCs) and p38 signaling during hepatic differentiation. The present study investigated the effects of zebularine on hepatic differentiation of rabbit BMMSCs, as well as the role of p38 on DNMT1 and hepatic differentiation, with the aim of developing a novel strategy for improving derivation of hepatocytes. BMMSCs were treated with zebularine at concentrations of 10, 20, 50, and 100 μM in the presence of hepatocyte growth factor; changes in the levels of hepatic-specific alpha-fetoprotein and albumin were detected and determined by RT-PCR, WB, and immunofluorescence staining. Expression of DNMT1 and phosphorylated p38 as well as urea production and ICG metabolism was also analyzed. Zebularine at concentrations of 10, 20, and 50 μM could not affect cell viability after 48 h. Zebularine treatment leads to an inhibition of DNMT activity and increase of hepatic-specific proteins alpha-fetoprotein and albumin in BMMSCs in vitro; zebularine addition also induced expression of urea production of and ICG metabolism. p38 signal was activated in BMMSCs simulated with HGF; inhibition of p38 facilitated the synthesis of DNMT1 and albumin in cells. Zebularine restrained DNMT1 and phosphorylated p38 which were induced by HGF. Therefore, this study demonstrated that treatment with zebularine exhibited terminal hepatic differentiation of BMMSCs in vitro in association with hepatocyte growth factor; p38 pathway at least partially participates in zebularine-induced hepatic differentiation of rabbit BMMSCs.
研究领域:
干细胞研究
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分子生物学
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细胞信号传导
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表观遗传学
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DOI
高影响因子
ADVANCED MATERIALS
·
2023
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IF 29.4
Yanan Zhang,Renwang Sheng,Jialin Chen,Hongmei Wang,Yue Zhu,Zhicheng Cao,Xinyi Zhao,Zhimei Wang,Chuanquan Liu,Zhixuan Chen,Po Zhang,Baian Kuang,Haotian Zheng,Chuanlai Shen,Qingqiang Yao,Wei Zhang
Silk fibroin (SF) and sericin (SS), the two major proteins of silk, are attractive biomaterials with great potential in tissue engineering and regenerative medicine. However, their biochemical interactions with stem cells remain unclear. In this study, multiomics are employed to obtain a global view of the cellular processes and pathways of mesenchymal stem cells (MSCs) triggered by SF and SS to discern cell–biomaterial interactions at an in-depth, high-throughput molecular level. Integrated RNA sequencing and proteomic analysis confirm that SF and SS initiate widespread but distinct cellular responses and potentiate the paracrine functions of MSCs that regulate extracellular matrix deposition, angiogenesis, and immunomodulation through differentially activating the integrin/PI3K/Akt and glycolysis signaling pathways. These paracrine signals of MSCs stimulated by SF and SS effectively improve skin regeneration by regulating the behavior of multiple resident cells (fibroblasts, endothelial cells, and macrophages) in the skin wound microenvironment. Compared to SS, SF exhibits better immunomodulatory effects in vitro and in vivo, indicating its greater potential as a carrier material of MSCs for skin regeneration. This study provides comprehensive and reliable insights into the cellular interactions with SF and SS, enabling the future development of silk-based therapeutics for tissue engineering and stem cell therapy.
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PubMed
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INJURY-INTERNATIONAL JOURNAL OF THE CARE OF THE INJURED
·
2023
·
IF 2.5
Fangyuan Lai,Shijie Dai,Ye Zhao,Yi Sun
Adipose-derived stem cells (ADSCs) have been widely proven to facilitate wound healing. Our study aimed to estimate the influence of combined ADSCs and platelet-derived growth factor-BB (PDGF-BB) on wound healing. We utilized 4 healthy SD rats to isolate ADSCs. Platelet-rich plasma (PRP) was acquired utilizing a two-step centrifugation technology. The role of PRP, PDGF-BB, and PDGF-BB combined with a PI3k inhibitor LY294002 on the viability, migration, and PTEN/AKT pathway in ADSCs were examined utilizing CCK-8, Transwell, and western blot assays. Then, we constructed an open trauma model in SD rats. Effects of ADSCs treated with PDGF-BB on pathological changes, CD31, and PTEN/AKT pathway of wound closure were assessed by hematoxylin & eosin (H&E) staining, Masson staining, immunohistochemical, and western blot assays, respectively. PRP and PDGF-BB intensified the viability and migration of ADSCs by modulating the PTEN/AKT pathway. Interestingly, LY294002 reversed the role of PDGF-BB on ADSCs. In vivo experiments, combined intervention with ADSCs plus PDGF-BB/PRP facilitated wound closure and ameliorated histological injury. Moreover, combined intervention with ADSCs and PDGF-BB attenuated the PTEN level and elevated the CD31 level as well as the ratio of p-AKT/AKT in the skin tissues. A combination of ADSCs and PDGF-BB facilitated wound healing might associate with the regulation of the PTEN/AKT pathway.
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PubMed
高影响因子
Advanced Healthcare Materials
·
2022
·Vol. 12
·期 9
·2202785
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IF 11.092
Jingzhi Xu,Kun Xi,Jincheng Tang,Juan Wang,Yunkai Tang,Liang Wu,Yichang Xu,Zonghan Xu,Liang Chen,Wenguo Cui,Yong Gu
Living biomaterials directly couple with live cells to synthesize functional molecules and respond to dynamic environments, allowing the design, construction and application of next generation composite materials. Improving the coordination and communication between artificial materials and living cells is essential. In this study, collagen self-assembly and micro-sol electrospinning techniques are used to prepare oriented living fiber bundles that can increase the transplantation rate of stem cells in the early stages of inflammation, indirectly enhancing the dynamic regulation of stem cells during inflammation. Additionally, brain-derived neurotrophic factor (BDNF) contained in the fiber can improve the differentiation of bone marrow mesenchymal stem cells (BMSCs) into neurons once the inflammatory storm subsides. The living oriented fiber bundles fully simulate the 3D structure of the central nervous system, activate integrin β 1, promote the growth and adhesion of stem cells in the acute stage of inflammation, upregulate anti-inflammatory genes by more than twofold via BMSCs in response to inflammation, and stably release BDNF for up to 4 weeks post-inflammation storm subsidence. Finally, the BDNF induces the differentiation of BMSCs to neurons by enhancing the expression of neural-related genes, which enables the recovery of neurological functions in the later stages of spinal cord injury.
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PubMed
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International Journal of Nanomedicine
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2023
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IF 8
Lijuan Lin,Xizhen Zhuang,Ruiqi Huang,Simin Song,Zhaojie Wang,Shilong Wang,Liming Cheng,Rongrong Zhu
Purpose In this study, we aim to explore the effects of graphene oxide (GO), a derivative of graphene, nanoparticles of four different sizes on the cellular fate of mouse neural stem cells (mNSCs).Methods GO NPs were characterized with transmission electron microscopy (TEM), scanning electron micrography (SEM), atomic force microscopy (AFM) and Raman Spectra analysis. The cytotoxic effects of the GO NPs of different sizes on the mNSCs were determined using CCK-8 assay, Annexin V-APC/ 7-AAD staining and EdU staining assays. We investigated the biological and the mechanisms of GO NPs on cells using immunofluorescence analysis and quantitative real-time PCR (qPCR).Results The average hydrodynamic sizes of the GO NPs were 417 nm, 663 nm, 1047 nm, and 4651 nm, with a thickness of approximately 22.5 nm, 17.7 nm, 22.4 nm, and 13.4 nm, respectively. GO NPs of all sizes showed low cytotoxicity at a concentration of 20 μg/mL on the mNSCs. Immunostaining demonstrated that treatment with GO NPs, especially the 663 nm ones, enhanced the self-renewal ability of mNSCs in the absence of EGF and bFGF. Under differentiation medium conditions that are free of mitogenic factors, all the GO NPs, particularly the 4651 nm ones, increased the expression level of Tuj1 and GFAP. With regards to the migration ability, we found that 417 nm GO-NP-treated mNSCs migrated over a longer distance than the control group obviously. In addition, higher expression of Rap1, Vinculin and Paxillin was observed in the GO NP-treated groups compared to the control group. mRNA-Sequence analysis and Western blotting results suggested that the 4651 nm GO NPs triggered positive neuronal differentiation through phosphorylation of ERK1/2 by the downregulating of TRPC2.Conclusion GO NPs play an important role in the applications of inducing self-renewal and differentiation of mNSC, and are promising in the future for further studies.
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International Journal of Nanomedicine
·
2023
·
IF 8
Hongxiang Wei,Jinyuan Chen,Shenglin Wang,Feihuan Fu,Xia Zhu,Chaoyang Wu,Zhoujie Liu,Guangxian Zhong,Jianhua Lin
Purpose The primary goal of the present study was to develop the nano-drug consisting of doxorubicin and exosome derived from mesenchymal stem cells, and to explore its effect on osteosarcoma in vitro.Methods The exosomes were isolated from bone marrow MSCs (BM-MSCs) by an Exosome Isolation Kit. The exosome-loaded doxorubicin (Exo-Dox) was prepared by mixing exosome with Dox-HCl, desalinizing with triethylamine and then dialyzing against PBS overnight. The nanoparticle tracking analysis (NTA) and transmission electron microscope (TEM) were used to characterize of the exosome and Exo-Dox. The cytotoxicity of Exo-Dox was determined by CCK-8 assay. Further, the cellular uptake of different drugs was analyzed using inverted fluorescence microscope and flow cytometry.Results The typical exosome structures can be observed by TEM. After loading with doxorubicin, its size is larger than free exosome. Compared with the free Dox, the prepared Exo-Dox showed enhanced cellular uptake efficiency and anti-tumor effect in osteosarcoma MG63 cell line but low cytotoxicity in myocardial H9C2 cell line.Conclusion The prepared Exo-Dox could be used as an excellent chemotherapeutic drug for treatment of osteosarcoma in vitro. Considering the tumor-homing feature of BM-MSCs, the Exo-Dox may be a good candidate for targeted osteosarcoma treatment in future study.
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高影响因子
Materials Today Bio
·
2023
·
IF 8.2
Yue Zhao,Lutong Song,Mengchen Li,Haoran Peng,Xinyi Qiu,Yuyang Li,Bijun Zhu,Chao Liu,Shuangshuang Ren,Leiying Miao
Vital pulp preservation, which is a clinical challenge of aseptic or iatrogenic accidental exposure of the pulp, in cases direct pulp capping is the main technology. Human dental pulp stem cells (hDPSCs) play a critical role in pulp tissue repair, but their differentiative ability could be inhibited by the potential infection and inflammatory response of the exposed pulp. Therefore, inflammatory regulation and differentiated promotion of hDPSCs are both essential for preserving living pulp teeth. In this study, we constructed a functional dental pulp-capping hydrogel by loading cerium oxide nanoparticles (CNPs) and dentin matrix protein-1 (DMP1) into an injectable Fmoc–triphenylalanine hydrogel (Fmoc-phe3 hydrogel) as CNPs/DMP1/Hydrogel for in situ drugs delivery. With a view to long-term storage and release of CNPs (anti-inflammatory and antioxidant) to regulate the local inflammatory environment and DMP1 to promote the regeneration of dentin. Results of CCK-8, LDH release, hemolysis, and Live/Dead assessment of cells demonstrated the good biocompatibility of CNPs/DMP1/Hydrogel. The levels of alkaline phosphatase activity, quantification of the mineralized nodules, expressions of osteogenic genes and proteins demonstrated CNPs/DMP1/Hydrogel could protect the activity of hDPSCs’ osteogenic/dentinogenic differentiation by reducing the inflammation response via releasing CNPs. The therapy effects were further confirmed in rat models, CNPs/DMP1/Hydrogel reduced the necrosis rate of damaged pulp and promoted injured pulp repair and reparative dentin formation with preserved vital pulps. In summary, the CNPs/DMP1/Hydrogel composite is an up-and-coming pulp-capping material candidate to induce reparative dentin formation, as well as provide a theoretical and experimental basis for developing pulp-capping materials.
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PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Abdullkhaleg Ali Albashari,Yan He,Yu Luo,Xingxiang Duan,Jihea Ali,Mingchang Li,Dehao Fu,Yangfan Xiang,Youjian Peng,Song Li,Lihua Luo,Xingjie Zan,Tushar Kumeria,Qingsong Ye
Spinal cord injury (SCI) commonly induces nerve damage and nerve cell degeneration. In this work, a novel dental pulp stem cells (DPSCs) encapsulated thermoresponsive injectable hydrogel with sustained hydrogen sulfide (H 2 S) delivery is demonstrated for SCI repair. For controlled and sustained H 2 S gas therapy, a clinically tested H 2 S donor (JK) loaded octysilane functionalized mesoporous silica nanoparticles (OMSNs) are incorporated into the thermosensitive hydrogel made from Pluronic F127 (PF-127). The JK-loaded functionalized MSNs (OMSF@JK) promote preferential M2-like polarization of macrophages and neuronal differentiation of DPSCs in vitro. OMSF@JK incorporated PF-127 injectable hydrogel (PF-OMSF@JK) has a soft consistency similar to that of the human spinal cord and thus, shows a high cytocompatibility with DPSCs. The cross-sectional micromorphology of the hydrogel shows a continuous porous structure. Last, the PF-OMSF@JK composite hydrogel considerably improves the in vivo SCI regeneration in Sprague–Dawley rats through a reduction in inflammation and neuronal differentiation of the incorporated stem cells as confirmed using western blotting and immunohistochemistry. The highly encouraging in vivo results prove that this novel design on hydrogel is a promising therapy for SCI regeneration with the potential for clinical translation.
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PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2023
·
IF 19
Ruiqi Li,Lian Chen,Qin Ji,Qing Liang,Ying Zhu,Wei Fu,Tianyou Chen,Hongwei Duan,Wenshan He,Zushun Xu,Xiaofang Dai,Jinghua Ren
Radiotherapy is identified as a crucial treatment for patients with glioblastoma, but recurrence is inevitable. The efficacy of radiotherapy is severely hampered partially due to the tumor evolution. Growing evidence suggests that proneural glioma stem cells can acquire mesenchymal features coupled with increased radioresistance. Thus, a better understanding of mechanisms underlying tumor subclonal evolution may develop new strategies. Herein, data highlighting a positive correlation between the accumulation of macrophage in the glioblastoma microenvironment after irradiation and mesenchymal transdifferentiation in glioblastoma are presented. Mechanistically, elevated production of inflammatory cytokines released by macrophages promotes mesenchymal transition in an NF- κ B-dependent manner. Hence, rationally designed macrophage membrane-coated porous mesoporous silica nanoparticles (MMNs) in which therapeutic anti-NF- κ B peptides are loaded for enhancing radiotherapy of glioblastoma are constructed. The combination of MMNs and fractionated irradiation results in the blockage of tumor evolution and therapy resistance in glioblastoma-bearing mice. Intriguingly, the macrophage invasion across the blood-brain barrier is inhibited competitively by MMNs, suggesting that these nanoparticles can fundamentally halt the evolution of radioresistant clones. Taken together, the biomimetic MMNs represent a promising strategy that prevents mesenchymal transition and improves therapeutic response to irradiation as well as overall survival in patients with glioblastoma.
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Small
·
2023
·
IF 13.3
Yuan Li,Kuo Zhang,Xuezheng Ai,Qingshi Zhang,Lu Jiang,Jiang Long,Huange Xu,Chencheng Feng,Yaqing Zhang,Guoke Tang,Fanli Chong,Lei Wang,Bo Huang
Maintaining quiescence of stem cells is a potential way to decrease cell nutrition demand for restoring the organization. Herein, a biomimetic peptide to maintain quiescence of stem cells through C-X-C motif chemokine ligand 8 (CXCL8)-C-X-C motif chemokine receptor 1 (CXCR1) pathway against intervertebral disc degeneration (IVDD) is developed. First, it is confirmed that quiescence can be induced via inhibiting phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in nucleus pulposus stem cells (NPSCs). Meanwhile, it is well known that CXCR1, a chemokine receptor, can be targeted by CXCL8, resulting in cell proliferation via activating PI3K/Akt/mTOR pathway. Second, a biomimetic peptide (OAFF) that can bind to CXCR1 and form fibrous networks on NPSCs, mimicking extracellular matrix formation is developed. The multivalent effect and long-term binding to CXCR1 on NPSCs of OAFF fibers offer forcefully competitive inhibition with natural CXCL8, which induces NPSCs quiescence and ultimately overcomes obstacle in intradiscal injection therapy. In rat caudal disc puncture model, OAFF nanofibers still maintain at 5 weeks after operation and inhibit degeneration process of intervertebral disc in terms of histopathology and imageology. In situ fibrillogenesis of biomimetic peptide on NPSCs provides promising stem cells for intradiscal injection therapy against IVDD.
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DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2023
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IF 19
Enhao Lu,Xi Yang,Tao Wang,Xueli Huang,Yiting Chen,Rui Wang,Kuankuan Luo,Zhiwen Zhang,Xiaoxi Lin,Xianyi Sha
Tissue repair and regeneration in ischemic areas require effective strategies for angiogenesis and microcirculation reconstruction. In this research, extracellular vesicles (EVs) derived from hemangioma stem cells (HemSC) are used as bio-functional materials for angiogenesis. In addition, a novel thermo-sensitive hydrogel based on chitosan (CS) and modified with hyaluronic oligosaccharides (oHA), is specially developed as an ideal carrier of HemSC-EVs. The oHA/CS gel provides a sustained-release delivery system for EVs, enhances the angiogenic function of HemSC-EVs, and exerts other bio-functions to comprehensively accelerate tissue repair. The physical properties of EVs@oHA/CS gel proved to be soft, highly elastic deformable, biocompatible, and can maintain the shape and structure of EVs. In vitro co-culture assay verifies the angiogenic effect of EVs@oHA/CS gel , and this effect is also evaluated in a diabetic wound model. Compared to untreated group, the EVs@oHA/CS gel group has only 26.9% wound area on day 14, and 226.8% blood flux mark on day 17. Pharmacological mechanisms of HemSC-EVs are predicted by RNA-seq, and cluster analysis of miRNAs predicted targets presents several up-regulated biological processes involving in angiogenesis and wound healing. In conclusion, it is suggested that EVs@oHA/CS gel as a satisfying therapeutic system for microcirculation reconstruction in tissue repair.
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