Nano Energy
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2022
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IF 19.069
Guangbo Xia,Guobao Wang,Huiyi Yang,Wenbo Wang,Jian Fang
Cell-traction driven electrical stimulation on piezoelectric nanofibers mediates cell behavior without chemical factors or external stimuli, indicating a promising therapy at cell level. Generally, surface modification is required to achieve favorable cell adhesion for efficient electromechanical signal transmission. Nevertheless, common modification methodologies either easily fade away or destroy the nanostructure of piezoelectric nanofibers. Herein, with the assistance of ultrasound activated surface charges, in situ hydrophilic modification on piezoelectric poly( L -lactic acid) nanofibers is first proposed for cell adhesion. Due to the electrostatic interaction between dopamine and activated piezoelectric nanofiber, the efficient and robust in situ modification is obtained without compromising the nanofibrous structure. Stimulated by the piezoelectric nanofibers with modification, neural stem cells differentiate significantly into nerve cells on day 7 without exogenous growth factors . To our knowledge, the effect of inducing stem cell differentiation far outperforms that in previous reports. In addition, it has been demonstrated that the level of both cell differentiation and directional expansion is consistent with that of cell adhesion condition regardless of the intensity of electrical cue. This connection of cell adhesion and electro-topographical stimulation effects may guide the efforts in the design of electroactive scaffolds.
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Regenerative Medicine
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2022
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IF 3.21
Ming-Zhi Huang,Hong-Yan Chen,Guo-Xuan Peng,Hong Sun,Hong-Cheng Peng,Hai-Yang Li,Xiang-Hui Liu,Qing Li
Aim: Effect of artesunate (ART)-treated bone marrow-derived mesenchymal stem cells-derived exosomes (BMSC-Exos) on osteogenesis and its underlying mechanisms were investigated. Materials & methods: Proliferation, alkaline phosphatase activity and calcified nodule formation of osteoblasts were determined. A mouse model of osteoporosis was established by ovariectomy. Results:SNHG7 was upregulated in BMSC-Exos by twofold, which was further enhanced in ART-BMSC-Exos by about twofold. ART intensified BMSC-Exos-induced proliferation, alkaline phosphatase activity by about fourfold, calcified nodule formation by about threefold and upregulation of osteogenesis related molecules RUNX2 (by 50%), BMP2 (by 30%) and ATF4 (by 40%) via delivering SNHG7. Mechanistically, SNHG7 recruited TAF15 to facilitate RUNX2 stability. Conclusion: ART-BMSC-Exos facilitated osteogenesis via delivering SNHG7 by modulating TAF15/RUNX2 axis.Plain language summaryOsteoporosis is the most common and complex skeletal disorder worldwide. Exosomes derived from bone marrow-derived mesenchymal stem cells (BMSC-Exos) have been recognized as an ideal seed source for bone tissue regeneration. We aimed to explore the effect of artesunate (ART)-BMSC-Exos on osteogenesis and its underlying mechanisms. The results showed that ART-BMSC derived exosomal SNHG7 facilitated osteoblast activity and attenuated osteogenesis in mice by modulating TAF15/RUNX2 pathway. Our findings contribute to a better understanding of the therapeutic mechanisms of ART-BMSCs-Exos for osteoporosis and suggest ART-BMSC-Exos as a novel therapeutic option for osteoporosis.
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Biomaterials Advances
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2022
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IF 0
Yufeng Wang,Chen Ling,Jialin Chen,Haoyang Liu,Qingyun Mo,Wei Zhang,Qingqiang Yao
The fabrication of osteochondral scaffolds with both structural and biochemical cues to regulate endogenous bone marrow-derived mesenchymal stem cells (BMSCs) behavior for cartilage and subchondral bone regeneration is still a challenge. To this end, a composite scaffold (BE-PSA) with gradient structure and programmed biomolecule delivery was prepared by fused deposition modeling (FDM) 3D printing and multi-material-based modification. The 3D-printed polycaprolactone (PCL) scaffold included upper pores of 200 μm for cartilage regeneration and lower pores of 400 μm for bone regeneration. For a sequential modulation of BMSCs behavior, fast-degrading sodium alginate (SA) hydrogel was used to deliver a burst release of E7 peptide to enhance BMSCs migration within 72 h, while a slowly-degrading silk fibroin (SF) porous matrix was used to provide a sustained release of B2A peptide to improve BMSCs dual-lineage differentiation lasting for >300 h, depending on the different degradation rates of SA hydrogel and SF matrix. The BE-PSA scaffold had good biocompatibility and could improve the migration and osteogenic/chondrogenic differentiation of BMSCs. Benefiting from the synergistic effects of spatial structures and programmed biomolecule delivery, the BE-PSA scaffold showed enhanced cartilage and subchondral bone regeneration in rabbit osteochondral defect model. This work not only provides a promising scaffold to guide BMSCs behavior for osteochondral regeneration but also offers a method for the fabrication of tissue engineering biomaterials based on the structural and biochemical modification.
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BIOMATERIALS
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2021
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IF 12.479
Chuanchuan Lin,Ye He,Qian Feng,Kun Xu,Zhe Chen,Bailong Tao,Xuemin Li,Zengzilu Xia,Hong Jiang,Kaiyong Cai
To control the fate of mesenchymal stem cells (MSCs) in a 3D environment by adjusting the mechanical parameters of MSC-loading scaffolds, is one of the hot topics in the field of regenerative biomaterials. However, a thorough understanding of the relevant MSCs behaviors affected by viscoelasticity , a dynamic physical parameter of scaffolds, is still lacking. Herein, we established an alginate hydrogel system with constant stiffness and tunable stress relaxation rate, which is a key parameter for the viscoelastic property of material. MSCs were cultured inside three groups of alginate hydrogels with various stress relaxation rates, and then RNA-seq analysis of cells was performed. Results showed that the change of stress relaxation rates of hydrogels regulated the most of the different expression genes of MSCs, which were enriched in cell proliferation-related pathways. MSCs cultured in hydrogels with fast stress relaxation rate presented a high self-renewal proliferation profile via activating phosphatidylinositol 3- kinase (PI3K)/protein kinase B (Akt) pathway. In contrast, a slow stress relaxation rate of hydrogels induced MSCs to enter a reversible quiescence state due to the weakened PI3K/Akt activation. Combined with a further finite element analysis , we speculated that the quiescence of MSCs could be served as a positive strategy for MSCs to deal with the matrix with a low deformation to keep stemness. Based on the results, we identified that stress relaxation rate of hydrogel was a potential physical factor of hydrogel to regulate the self-renewal or quiescence of MSCs. Thus, our findings provide a significant guiding principle for the design of MSCs-encapsulated biomaterials.
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Stem Cell Research & Therapy
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2021
·Vol. 12
·期 1
·1-16
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IF 6.832
Zhang Xinxin,Jiang Xiaorui,Jiang Shan,Cai Xiyu,Yu Shengji,Pei Guoxian
Background Tissue-engineered bone grafts (TEBGs) that undergo vascularization and neurotization evolve into functioning bone tissue. Previously, we verified that implanting sensory nerve tracts into TEBGs promoted osteogenesis. However, the precise mechanisms and interaction between seed cells were not explored. In this study, we hypothesized that neurotization may influence the osteogenesis of TEBGs through vascularization. Methods We cultured rat Schwann cells (SCs), aortic endothelial cells (AECs), and bone marrow-derived mesenchymal stem cells (BM-MSCs) and then obtained BM-MSC-derived induced endothelial cells (IECs) and induced osteoblasts (IOBs). IECs and AECs were cultured in an SC-conditioned medium (SC-CM) to assess proliferation, migration, capillary-like tube formation, and angiogenesis, and the vascular endothelial growth factor (VEGF) levels in the supernatants were detected. We established an indirect coculture model to detect the expression of nestin and VEGF receptors in IECs and tissue inhibitor of metalloproteinase (TIMP)-2 in SCs. Then, SCs, IECs, and IOBs were labeled and loaded into a β-tricalcium phosphate scaffold to induce prevascularization, and the scaffold was implanted into a 6-mm-long defect of rat femurs. Three groups were set up according to the loaded cells: I, SCs, and IECs (coculture for 3 days) plus IOBs; II, IECs (culture for 3 days) plus IOBs; III, IOBs. Nestin and TIMP-2 expression and osteogenesis of TEBGs were evaluated at 12 weeks post-implantation through histological and radiological assessments. Results We found that SC-CM promoted IEC proliferation, migration, capillary-like tube formation, and angiogenesis, but no similar effects were observed for AECs. IECs expressed nestin extensively, while AECs barely expressed nestin, and SC-CM promoted the VEGF secretion of IECs. In the coculture model, SCs promoted nestin and VEGF receptor expression in IECs, and IECs inhibited TIMP-2 expression in SCs. The promotion of prevascularized TEBGs by SCs and IECs in group I augmented new bone formation at 6 and 12 weeks. Nestin expression was higher in group I than in the other groups, while TIMP-2 expression was lower at 12 weeks. Conclusions This study demonstrated that SCs can promote TEBG osteogenesis via IECs and further revealed the related specific characteristics of IECs, providing preliminary cytological evidence for neurotization of TEBGs.
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BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY
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2021
·Vol. 69
·期 3
·906-919
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IF 2.431
Tamrin Nuge,Xiaoling Liu,Kim Yeow Tshai,Siew Shee Lim,Norshariza Nordin,Md. Enamul Hoque,Ziqian Liu
Despite a lot of intensive research on cell–scaffold interaction, the focus is mainly on the capacity of construct scaffolds to regulate cell mobility, migration, and cytotoxicity. The effect of the scaffold's topographical and material properties on the expression of biologically active compounds from stem cells is not well understood. In this study, the influence of cellulose acetate (CA) on the electrospinnability of gelatin and the roles of gelatin–cellulose acetate (Ge-CA) on modulating the release of biologically active compounds from amniotic fluid stem cells (AFSCs) is emphasized. It was found that the presence of a small amount of CA could provide a better microenvironment that mimics AFSCs' niche. However, a large amount of CA exhibited no significant effect on AFSCs migration and infiltration. Further study on the effect of surface topography and mechanical properties on AFSCs showed that the tailored microenvironment provided by the Ge-CA scaffolds had transduced physical cues to biomolecules released into the culture media. It was found that the AFSCs seeded on electrospun scaffolds with less CA proportions have profound effects on the secretion of metabolic compounds compared to those with higher CA contained and gelatin coating. The enhanced secretion of biologically active molecules by the AFSCs on the electrospun scaffolds was proven by the accelerated wound closure on the injured human dermal fibroblast (HDF) model. The rapid HDF cell migration could be anticipated due to a higher level of paracrine factors in AFSCs media. Our study demonstrates that the fibrous topography and mechanical properties of the scaffold are a key material property that modulates the high expression of biologically active compounds from the AFSCs. The discovery elucidates a new aspect of material functions and scaffolds material–AFSC interaction for regulating biomolecules release to promote tissue regeneration/repair. To the best of our knowledge, this is the first report describing the scaffolds material–AFSC interaction and the efficacy of scratch assays on quantifying the cell migration in response to the AFSCs metabolic products.
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OncoTargets and Therapy
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2021
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IF 4.147
Jie Wu,Lulu Sun,Tingting Liu,Gang Dong
Background Cancer cells could show the characteristics of cancer stem cells (CSCs) through epithelial-mesenchymal transition (EMT). EZH2 was associated with EMT. Ultrasound-targeted microbubble destruction (UTMD) could enhance gene transfection efficiency. Here, we explored the effect of UTMD-mediated shEZH2 on liver CSCs. Methods EZH2 expression in liver cancer and the overall survival of liver cancer patients were analyzed by bioinformatics. Liver CSCs (CD133 + HuH7) were sorted by flow cytometry. After transfection of shEZH2 through UTMD (UTMD-shEZH2) or liposome (LIP-shEZH2), the viability, proliferation, sphere formation, migration, and invasion of CD133 + HuH7 cells were detected by MTT, colony formation, tumor-sphere formation, wound healing, and transwell assays, respectively. A mice subcutaneous-xenotransplant tumor model was established by injecting CD133 + HuH7 or CD133 − HuH7 cells into the limbs of mice. Tumor weight and volume were documented. The expressions of EZH2, EMT-related factors, and STAT3/PI3K/AKT pathway-related factors in CD133 + HuH7 cells or tumor tissues were detected by RT-qPCR, Western blot, or immunohistochemical. Results EZH2 was high-expressed in liver cancer, and the patients with high expression of EZH2 had a poor survival. CD133 + HuH7 cells had higher EZH2 expression, higher viability, and stronger sphere-forming and tumor-forming abilities than CD133 − HuH7 cells. ShEZH2 inhibited the viability, proliferation, sphere formation, migration, and invasion of CD133 + HuH7 cells, decreased the weight and volume of the xenotransplant tumor, inhibited the expressions of EZH2, Vimentin, N-Cadherin, Twist-1, p-STAT3, p-PI3K, and p-AKT, and increased E-Cadherin expression. UTMD-shEZH2 caused a stronger effect on CD133 + HuH7 cells than LIP-shEZH2. Conclusion UTMD-mediated shEZH2 inhibited the stemness and EMT of liver CSCs in vitro and in vivo through regulating the STAT3/PI3K/AKT pathway.
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MOLECULAR PHARMACEUTICS
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2021
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IF 4.939
Leyi Liang,Ling Zhao,Ying Wang,Yan Wang
Mesenchymal stem cell-derived exosomes (MSC-Exos) have potential as drug-delivery vehicles and exhibit great promise for hepatocellular carcinoma (HCC) therapy. Here, we consider bone mesenchymal stem cell-derived exosomes (BMSC-Exos) as drug carriers to encase anticancer drug norcantharidin (NCTD) and explore their potential therapeutic effects against HCC. NCTD was loaded into purified exosomes from BMSCs via electroporation, and an in vitro drug release study showed that BMSC-Exos–NCTD provided a continuous and slow release of the drug. A series of in vitro and in vivo pharmacodynamic evaluations based on the HCC cell line HepG2 were conducted. The results showed that the BMSC-Exos–NCTD delivery system effectively promoted cellular uptake, induced cell cycle arrest, reduced tumor cell proliferation, increased apoptosis, and exerted obvious in vivo antitumor effects compared with the NCTD treatment alone, with BMSC-Exos–NCTD showing more significant antitumor effects. Furthermore, the in vivo detection results of the homing effect using the probe Cy5.5 showed that the BMSC-Exos carrier has an in situ homing effect on the tumor sites of HCC in mice. Moreover, BMSC-Exos–NCTD did not show body toxicity. Excitedly, BMSC-Exos–NCTD repaired damaged liver tissues in liver sections; specifically, the experimental effectiveness of the exosomes on the normal liver cell line L02 indicated that the damaged liver cells were repaired by the exosomes, as reflected by the increase in cellular proliferation and the inhibition of liver cell oxidation. Our results suggest that BMSC-Exos, as drug carriers with specific functions, have great potential in the HCC treatment in combination with anticancer drugs.
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POULTRY SCIENCE
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2020
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IF 2.659
Lingzi Yu,Xiaochen Xie,Keyang Jiang,Yi Hong,Zhou Zhou,Yuling Mi,Caiqiao Zhang,Jian Li
The rapid renewal and repair of the intestinal mucosa are based on intestinal stem cells ( ISC ), which are located at the crypt bottom. Paneth cells are an essential component in the crypt, which served as the niche for ISC development. However, in the chicken, how the function of Paneth cells changes during intestinal inflammation is unclear and is the key to understand the mechanism of mucosal repair. In the present study, 36 HyLine White chickens (7 d of age, n = 6) were randomly divided into 1 control and 5 lipopolysaccharide ( LPS ) injection groups. The chickens were injected (i.p.) with PBS in the control group, however, were injected (i.p.) with LPS (10 mg/kg BW) in the LPS injection groups, which would be sampled at 5 time points (1 h postinjection [ hpi ], 2 hpi, 4 hpi, 6 hpi, and 8 hpi). Results showed that tumor necrosis factor-α mRNA transcription in duodenal tissue increased gradually since 1 hpi, peaked at 4 hpi, and then reduced remarkably, indicating that 4 hpi of LPS was the early stage of intestinal inflammation. Meanwhile, the MUC2 expression in duodenal tissue was dramatically reduced since 1 hpi of LPS. The ISC marker, Lgr5 and Bmi1 , in the duodenal crypt were reduced from 1 hpi to 4 hpi and elevated later. Accordingly, the hydroethidine staining showed that the reactive oxygen species level, which drives the differentiation of ISC, in the duodenal crypt reduced obviously at 1 hpi and recovered gradually since 4 hpi. The analysis of Paneth cells showed that many swollen mitochondria appeared in Paneth cells at 4 hpi of LPS. Meanwhile, the Lysozyme transcription in the duodenal crypt was substantially decreased since 1 hpi of LPS. However, the Wnt3a and Dll1 in duodenal crypt decreased at 1 hpi of LPS, then increased gradually. In conclusion, Paneth cells were impaired at the early stage of intestinal inflammation, then recovered rapidly. Thus, the ISC activity was reduced at first and recovery soon.
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Journal of Tissue Engineering and Regenerative Medicine
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2020
·Vol. 14
·期 3
·497-509
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IF 3.078
Yizhong Peng,Donghua Huang,Jinye Li,Sheng Liu,Xiangcheng Qing,Zengwu Shao
Biomaterial-based therapy that can restore annulus fibrosus (AF) function in early stage and promote endogenous repair of AF tissues is a promising approach for AF tissue repair. In this study, we established a genipin-crosslinked decellularized AF hydrogels (g-DAF-G) that are injectable and could manifest better in situ formability than noncrosslinked decellularized AF hydrogel, while preserving the capacity of directing differentiation of human bone mesenchymal stem cells (hBMSCs) towards AF cells. Hematoxylin and eosin staining, 4',6-diamidino-2-phenylindole staining, and so forth showed that the majority of cellular components were removed, whereas extracellular matrix and microstructure were largely preserved. The storage modulus increased from 465.5 ± 9.4 Pa to 3.29 ± 0.24 MPa after 0.02% genipin crosslinking of decellularized AF hydrogels (DAF-G) to form g-DAF-G. AF-specific genes (COL1A1, COL5A1, TNMD, IBSP, FBLN1) were significantly higher in DAF-G and g-DAF-G groups than that in control group after 21 days of culturing. g-DAF-G significantly restored nucleus pulposus water content and preserved intervertebral structure in vivo. Summarily, we produced a novel AF regeneration biomaterial, g-DAF-G, which exhibited well biocompatibility, great bioactivity, and much higher mechanical strength than DAF-G. This study will provide an easy and fast therapeutic alternative to repair AF injuries or tears.
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Biomedical Physics & Engineering Express
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2020
·Vol. 6
·期 2
·025005
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IF 0
Guirong Wang,Linzi Qiu,Xinqing Li,Yan Pan,Yang Sheng,Kevin Neumann,Yixin Sun,Yiwen Wang,Lefeng Liu,Linhong Deng,Mark Bradley,Rong Zhang
Human adipose derived stem cells (hASCs) were seeded onto polymer microarrays that had been fabricated using a variety of acrylate monomers to discover novel substrates that induced differentiation towards chondrocytes and osteoblasts. Flow cytometric analysis showed that both CD105 and CD49d positive hASCs increased rapidly with passage number on the lead polymers, while quantitative PCR analysis showed that the substrate synthesized from methacryloxyethyltrimethyl ammonium chloride, N,N-diethylaminoethyl methacrylate and cyclohexyl methacrylate enhanced chondrogenesis and osteogenensis some 4 and 25 times respectively in terms of the expression of SOX9 and ALP in differentiated stem cells. These copolymers substrates thus have great potential for application in the purification, generation and expansion of defined hASC's and the controlled differentiation of of cells for possible clinical application.
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Aging-US
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2020
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IF 4.831
Xiao Chen,Can-Xin Xu,Huaibin Liang,Zhiyu Xi,Jiaji Pan,Yong Yang,Qingfang Sun,Guoyuan Yang,Yuhao Sun,Liuguan Bian
Intracerebral hemorrhage (ICH) is a common acute nervous system disease with high mortality and severe disability. Mesenchymal stem cells (MSCs) have been reported to promote neurogenesis and to alleviate side effects in areas of brain injury areas. The Hippo pathway regulates diverse cellular processes, including cell survival, proliferation, differentiation, and organ size. Here, we found that transplantation of bone marrow MSCs (BM-MSCs) into the brains of mice could alleviate ICH-mediated injury and protect astrocytes from apoptosis by regulating mammalian sterile 20-like kinase (MST)1 and Yes-associated protein (YAP). Knocking down of MST1 by si-RNA triggered YAP nuclear translocation. We further demonstrated that astrocytes undergo astroglial-mesenchymal phenotype switching and become capable of proliferating after BM-MSC transplantation via the Hippo signaling pathway. Together, our identification of the Hippo pathway in mediating the beneficial effects of BM-MSCs may provide a novel therapeutic target in the treatment and management of ICH.
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