ACS Applied Materials & Interfaces
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2024
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IF 8.3
Jiaojiao Li,Xuran Li,Xiangyu Li,Zhanping Liang,Zhao Wang,Khawar Ali Shahzad,Maoxiang Xu,Fei Tan
Traumatic brain injury poses serious physical, psychosocial, and economic threats. Although systemic administration of stem cell-derived exosomes has recently been proven to be a promising modality for traumatic brain injury treatment, they come with distinct drawbacks. Luckily, various biomaterials have been developed to assist local delivery of exosomes to improve the targeting of organs, minimize nonspecific accumulation in vital organs, and ensure the protection and release of exosomes. In this study, we developed an electrospun nanofibrous scaffold to provide sustained delivery of dual exosomes derived from mesenchymal stem cells and neural stem cells for traumatic brain injury treatment. The electrospun nanofibrous scaffold employed a functionalized layer of polydopamine on electrospun poly(ε-caprolactone) nanofibers, thereby enhancing the efficient incorporation of exosomes through a synergistic interplay of adhesive forces, hydrogen bonding, and electrostatic interactions. First, the mesenchymal stem cell-derived exosomes and the neural stem cell-derived exosomes were found to modulate microglial polarization toward M2 phenotype, play an important role in the modulation of inflammatory responses, and augment axonal outgrowth and neural repair in PC12 cells. Second, the nanofibrous scaffold loaded with dual stem cell-derived exosomes (Duo-Exo@NF) accelerated functional recovery in a murine traumatic brain injury model, as it mitigated the presence of reactive astrocytes and microglia while elevating the levels of growth associated protein-43 and doublecortin. Additionally, multiomics analysis provided mechanistic insights into how dual stem cell-derived exosomes exerted its therapeutic effects. These findings collectively suggest that our novel Duo-Exo@NF system could function as an effective treatment modality for traumatic brain injury using sustained local delivery of dual exosomes from stem cells.
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JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Tong Wang,Tianyi Chen,Dazhao Li,Xiaoxing Hang,Shuangshuang Zhang,Han Yi,Tianyue Jiang,Dawei Ding,Xuenong Zhang
Cancer stem cells (CSCs) play an important role in the development of triple-negative breast cancer (TNBC), including metastasis, invasion, tumorigenicity, and drug resistance. Moreover, non-CSCs can spontaneously transform into CSCs in special tumor microenvironments, thereby leading to poor prognosis or even failed treatments. Therefore, reversing CSCs into normal tumor cells in a sustained-acting manner is a promising strategy. It has been reported that down-regulation of FBXO44 protein expression inhibits tumor cell stemness. Moreover, CRISPR/Cas9 technology, a well-known precise gene editing tool, was adopted to permanently block FBXO44 within the genome upon its successful implementation. Given this, a core-shell nanoparticle (NP) consisting of amphiphilic polymer core and crosslinked-hyaluronic acid shell (nDOX-PL/pFBXO44 NPs) is developed in this work to concurrently deliver FBXO44-targeted CRISPR/Cas9 plasmids (pFBXO44) and doxorubicin (DOX) for combinational CSC reprogramming and chemotherapy of TNBC, which exhibits tumor cell targeting, endosomal escape, and reduction responsiveness to release DOX and plasmids in the cytoplasma. CRISPR/Cas9-mediated downregulation of FBXO44 expression could convert CSC into normal tumor cells, and effectively inhibit tumor growth without obvious side effects in vivo after combining with chemotherapy. In summary, we developed an intelligent system to co-deliver genetic and hydrophobic drugs, achieving effective cancer stemness reversal and synergistic suppression of contractable TNBC.
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Advanced Science
·
2025
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IF 14.1
Boyu Su,Qinjun Chen,Xuwen Li,Mingzhu Fang,Yu Wang,Haolin Song,Haoyu You,Zheng Zhou,Yuxing Wu,Zhenhao Zhao,Yun Chen,Hongrui Fan,Chufeng Li,Chen Jiang,Tao Sun
Epigenetic dysregulation is prevalent in human cancers, affecting gene expression and metabolic patterns to meet the demands of malignant evolution and abnormal epigenetic processes, and resulting in a protumor immune microenvironment. Tumors require a steady supply of methionine for maintaining epigenetic flexibility, which is the only exogenous precursor of methyl donor S-adenosylmethionine for methylation, crucial for their resistance to therapies and survival in a nutrient-deficient microenvironment. Thus, tumor cells upregulate the Lat4 transporter to compete and deprive methionine in the microenvironment, sustaining their malignant phenotypes and also impairing immune cell functions. Addressing this methionine addiction is the key to overcoming drug resistance and improving immune response. Despite the challenge of lacking specific Lat4 inhibitors, an oxaliplatin prodrug crosslinked fluorinated polycation/anti-Lat4 small interfering RNA complex nanoregulator (AS-F-NP) has been designed and developed here. This nanoregulator restricted the greedy methionine uptake of tumor cells by knocking down Lat4, which in turn inhibited the malignant evolution of the tumor while restoring the viability and function of tumor-infiltrating immune cells.
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International Journal of Nanomedicine
·
2024
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IF 6.6
Yue Fei,Zhichen Ling,Qian Tong,Jun Wang
Purpose Angiogenesis is a tightly controlled process that initiates the formation of new vessels and its dysfunction can lead to life-threatening diseases. Apoptotic extracellular vesicles (ApoEVs) have emerged as a proangiogenic agent with high safety and isolation efficiency profile, and ApoEVs from supernumerary tooth-derived pulp stem cells (SNTSC-ApoEVs) have their unique advantages with an easily accessible parental cell source and non-invasive cell harvesting. However, the detailed characteristics of SNTSC-ApoEVs are largely unknown. This study aimed to investigate the proangiogenic capacity and function molecule of SNTSC-ApoEVs.Methods SNTSC-ApoEVs were isolated and characterized. In vitro effects of SNTSC-ApoEVs on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) were evaluated by CCK-8, wound healing, transwell, and tube formation assays. The mRNA and protein levels of proangiogenic genes were quantified by qRT-PCR, Western blot, and immunofluorescence analysis. A Matrigel plug model was established in 6-week-old male nu/nu mice for one week, and the in vivo impact of SNTSC-ApoEVs on micro-vessel formation was assessed by histological analysis. Proteomic analysis and RNA sequencing were performed to explore the active ingredients and underlying mechanisms.Results SNTSC-ApoEVs enhanced the proliferation, migration, and angiogenesis of HUVECs in vitro. In the Matrigel plug model in vivo, SNTSC-ApoEVs promoted CD31-positive luminal structure formation. Apart from expressing general ApoEV markers, SNTSC-ApoEVs were enriched with multiple proteins related to extracellular matrix-cell interactions. Mechanistically, SNTSC-ApoEVs transferred COL1A1 to HUVECs and promoted endothelial functions by activating the PI3K/Akt/VEGF cascade.Conclusion SNTSC-ApoEVs can promote angiogenesis by transferring the functional molecule COL1A1 and activating the PI3K/Akt/VEGF pathway, making SNTSC-ApoEVs a promising strategy for the treatment of angiogenesis-related diseases.
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Neural Regeneration Research
·
2024
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IF 5.9
Ren Chunge,Chen Min,Ren Bangqi,Zeng Yuxiao,Tan Qiang,Li Qiyou,Zhang Xue,Fang Yajie,Zhou Yixiao,Zhang Weitao,Chen Fang,Bian Baishijiao,Liu Yong
Our previous study demonstrated that combined transplantation of bone marrow–derived mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone. Bone marrow- derived mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles. Small extracellular vesicles derived from bone marrow–derived mesenchymal stem cells, which offer low immunogenicity, minimal tumorigenic risk, and ease of transportation, have been utilized in the treatment of various neurological diseases. These vesicles exhibit various activities, including anti-inflammatory actions, promotion of tissue repair, and immune regulation. Therefore, novel strategies using human retinal progenitor cells combined with BMSC-derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration. In this study, we developed such an approach utilizing retinal progenitor cells combined with bone marrow–derived mesenchymal stem cell-derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats, a genetic model of retinal degeneration. Our findings revealed that the combination of bone marrow–derived mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats. The addition of bone marrow–derived mesenchymal stem cell-derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival, migration, and differentiation of the exogenous retinal progenitor cells. Concurrently, these small extracellular vesicles inhibited the activation of regional microglia, promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina, and facilitated their differentiation into photoreceptors and bipolar cells. These findings suggest that bone marrow–derived mesenchymal stem cell-derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation.
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American Journal of Translational Research
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2018
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IF 3.061
Qian Tang,Minji Tong,Gang Zheng,Liyan Shen,Ping Shang,Haixiao Liu
The Masquelet’s induced membrane (IM) technique is widely used to treat large segmental bone defects due to its physical priority and biological function. However, the underlying molecular mechanism of the IM on bone formation remains unknown. In the present study, rat bone marrow-derived mesenchymal stem cells (BMSCs) were used as an in vitro model and bone morphogenetic protein 2 (BMP-2) was used as a positive control to evaluate the effects of the IM on the osteogenic differentiation of BMSCs. Although the IM group did not exhibit a significant increase in the expression of Runt-related transcription factor 2 (Runx2), Collagen I (Col I), osteocalcin (OCN) and alkaline phosphatase (ALP) relative to the BMP-2 administration, the IM was considerably effective compared with the untreated group. Mechanistically, we found that the IM activated the Smad and mitogen-activated protein kinase (MAPK) pathways, which was further confirmed by application of specific inhibitors of Smad1/5/8 (LDN-193189) and ERK1/2 (U0126). After the combined treatment of the IM and LDN-193189 as well as U0126, the IM-induced increase in Runx2, Col I, and OCN expression was significantly inhibited. These results suggest that IM promotes the osteogenic differentiation of rat BMSCs by activating the Smad1/5/8 and MAPK pathways.
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International Journal of Clinical and Experimental Pathology
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2021
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IF 0
Dongying Zhang,Kun Yu,Xiao Hu,Aixia Jiang
Cardiac tissue engineering is a promising technique to regenerate cardiac tissue and treat cardiovascular disease. Here we applied a modified method to generate ultrafine uniformly-aligned composite gelatin/polycaprolactone fibers that mimic functional heart tissue. We tested the physical properties of these fibers and analyzed how these composite fibrous scaffolds affected growth and cardiac lineage differentiation in rat adipose-derived stem cells (rADSCs). We found that uniformly aligned composite fiber scaffolds had an anisotropic arrangement, functional mechanical properties, and strong hydrophilicity. The anisotropic scaffolds improved cell attachment, viability, and proliferative capacity of ADSCs over randomly-aligned scaffolds. Furthermore, uniformly aligned composite fiber scaffolds increased the efficiency of cardiomyogenic differentiation, but might reduce the efficiency of cardiac conduction system cell differentiation in ADSCs compared to randomly-oriented scaffolds and tissue culture polystyrene. However, the randomly-oriented composite scaffolds showed no obviously facilitated effects over tissue culture polystyrene on the two cells’ differentiation process. The above results indicate that the scaffold fiber alignment has a greater effect on cell differentiation than the composition of the scaffold. Together, the uniformly-aligned composite fibers displayed excellent physical and biocompatible properties, promoted ADSC proliferation, and played distinct roles in the differentiation of cardiomyogenic cells and cardiac conduction system cells from ADSCs. These results provide new insight for the application of anisotropic fibrous scaffolds in cardiac tissue engineering for both in vitro and in vivo research.
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Research
·
2024
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IF 8.5
Guanrui Huang,Haotian Shen,Kaiwang Xu,Yifan Shen,Jiale Jin,Guangyu Chu,Hongyuan Xing,Zhiyun Feng,Yue Wang
While mesenchymal stem cell (MSC) shows great potentials in treating intervertebral disc degeneration, most MSC die soon after intradiscal transplantation, resulting in inferior therapeutic efficacy. Currently, bulk hydrogels are the common solution to improve MSC survival in tissues, although hydrogel encapsulation impairs MSC migration and disrupts extracellular microenvironment. Cell hydrogel encapsulation has been proposed to overcome the limitation of traditional bulk hydrogels, yet this technique has not been used in treating disc degeneration. Using a layer-by-layer self-assembly technique, we fabricated alginate and gelatin microgel to encapsulate individual MSC for treating disc degeneration. The small size of microgel allowed intradiscal injection of coated MSC. We demonstrated that pyroptosis was involved in MSC death under oxidative stress stimulation, and microgel coating suppressed pyroptosis activation by maintaining mitochondria homeostasis. Microgel coating protected MSC in the harsh disc microenvironment, while retaining vital cellular functions such as migration, proliferation, and differentiation. In a rat model of disc degeneration, coated MSC exhibits prolonged retention in the disc and better efficacy of attenuating disc degeneration, as compared with bare MSC treatment alone. Further, microgel-coated MSC exhibited improved therapeutic effects in treating disc degeneration via suppressing the activation of pyroptosis in the disc. For the first time, microgel-encapsulated MSC was used to treat disc degeneration and obtain encouraging outcomes. The developed biocompatible single-cell hydrogel is an effective strategy to protect MSC and maintain cellular functions and may be an efficacious approach to improving the efficacy of MSC therapy in treating disc degeneration. The objective of this study is to improve the efficacy of cell therapy for treating disc degeneration using single-cell hydrogel encapsulation and further to understand related cytoprotective mechanisms.
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CTS-Clinical and Translational Science
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2024
·Vol. 17
·期 3
·e13748
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IF 3.1
Chenyu Song,Kaiyang Wang,Bangping Qian,Jingshun Lu,Mu Qiao,Yong Qiu,Bin Wang,Yang Yu
Ankylosing spondylitis (AS) is an immune chronic inflammatory disease, resulting in back pain, stiffness, and thoracolumbar kyphotic deformity. Based on the reported anti-inflammatory and antioxidant capacities of cynarin (Cyn), this study explored its protective role and molecular mechanisms in mesenchymal stem cells (MSCs) from AS. The target pathways and genes were verified using Western blotting, quantitative real-time polymerase chain reaction, and immunofluorescent staining, while molecular docking analysis was conducted. In AS-MSCs, we found that the expression levels of p-NF-κB, IL-6, IL-1β, and TNF-α were higher and IκB-α, Nrf-2, and HO-1 were lower compared with healthy control (HC)-MSCs. With molecular docking analysis, the biding affinities between Cyn and Keap1-Nrf-2 and p65-IκB-α were predicted. The mRNA and protein expression of p-NF-κB, IL-6, IL-1β, and TNF-α and the reactive oxygen species (ROS) generation were downregulated following Cyn administration. Meanwhile, the expression level of IκB-α, Nrf-2, and HO-1 were significantly increased after Cyn pretreatment. The results suggested that the protective mechanisms of Cyn in AS-MSCs were based on enhancing the antioxidation and suppression of excessive inflammatory responses via Nrf-2/ROS/NF-κB axis. Our findings demonstrate that Cyn is a potential candidate for alleviating inflammation in AS.
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ACS Nano
·
2024
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IF 15.8
Dun Liu,Runyan Niu,Siliang Wang,Lihua Shao,Xian Yang,Xuexue Liu,Xiaolong Ma,Zezhang Zhu,Jinping Zhang,Benlong Shi,Huanyu Ni,Xiao Du
Neural stem cell (NSCs) transplantation is a promising therapeutic strategy for spinal cord injury (SCI), but its efficacy is greatly limited by the local inhibitory microenvironment. In this study, based on l-arginine (l-Arg)-loaded mesoporous hollow cerium oxide (AhCeO2) nanospheres, we constructed an injectable composite hydrogel (AhCeO2-Gel) with microenvironment modulation capability. AhCeO2-Gel protected NSCs from oxidative damage by eliminating excess reactive oxygen species while continuously delivering Nitric Oxide to the lesion of SCI in a pathological microenvironment, the latter of which effectively promoted the neural differentiation of NSCs. The process was confirmed to be closely related to the up-regulation of the cAMP-PKA pathway after NO-induced calcium ion influx. In addition, AhCeO2-Gel significantly promoted the polarization of microglia toward the M2 subtype as well as enhanced the regeneration of spinal nerves and myelinated axons. The prepared bioactive hydrogel system also efficiently facilitated the integration of transplanted NSCs with host neural circuits, replenished damaged neurons, alleviated neuroinflammation, and inhibited glial scar formation, thus significantly accelerating the recovery of motor function in SCI rats. Therefore, AhCeO2-Gel synergized with NSCs transplantation has great potential as an integrated therapeutic strategy to treat SCI by comprehensively reversing the inhibitory microenvironment.
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Food Bioscience
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2025
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IF 5.9
Chentao Huang,Jiabei Xia,Jiayun Xu,Xingyu Mei,Huan Cheng,Shiguo Chen,Jinping Si,Xingqian Ye,Jianle Chen
Polygonatum a widely recognized medicinal and edible plant, exhibits several confirmed biological activities and holds significant market potential. Numerous studies have identified polysaccharides are one of the primary bioactive components in the rhizomes of Polygonatum . Our previous research identified a notable presence of fructo-oligosaccharides in the rhizomes of Polygonatum sibiricum , highlighting its largely overlooked potential as a natural source of bioactive compounds. Therefore, a more systematic and comprehensive analysis of water-soluble carbohydrates across different species and plant parts of Polygonatum is essential. The aim of this study was to investigate the carbohydrate composition in four different Polygonatum species, focusing on the rhizomes, roots, leaves, stems, and fruits. In particular, we utilized a self-established method for the determination of fructo-oligosaccharides. The results indicated the presence of small amounts of mono/disaccharides and polysaccharides, as well as a considerable quantity of fructo-oligosaccharides in rhizome, root, fruit of Polygonatum . The low-molecular-weight glycans was the predominant carbohydrate in the rhizomes of Polygonatum Mill. spp., comprising over 80% of the total soluble carbohydrates, with polysaccharides contributing approximately 11%, and mono/disaccharides less than 10%. Our study offers valuable insights and a meaningful basis for the excavation of the functional carbohydrate resources of the Polygonatum Mill.
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Journal of Neuroinflammation
·
2024
·Vol. 21
·期 1
·1-25
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IF 9.3
Cheng Shimei,Lu Qiying,Liu Qiuli,Ma Yuanchen,Chen Jinshuo,Lu Di,Huang Mudan,Huang Yinong,Zhao Erming,Luo Jing,Zheng Haiqing
Background Neuronal death is the primary cause of poor outcomes in cerebral ischemia. The inflammatory infiltration in the early phase of ischemic stroke plays a vital role in triggering neuronal death. Either transplantation of mesenchymal stem cells (MSCs) derived from humans or repetitive transcranial magnetic stimulation (rTMS) have respectively proved to be neuroprotective and anti-inflammatory in cerebral ischemia. However, either treatment above has its limitations. Whether these two therapies have synergistic effects on improving neurological function and the underlying mechanisms remains unclear. This investigation aims to elucidate the synergistic effects and underlying mechanisms of MSCs combined with rTMS treatment on the neurological function recovery post-ischemia.Methods A Sprague-Dawley rat model of cerebral infarction was induced via transient middle cerebral artery occlusion (tMCAO). The rats were divided into five groups (n = 50): sham, tMCAO, rTMS, MSCs, and MSCs + rTMS groups. Transplantation of human umbilical cord MSCs and rTMS intervention were performed 24 h post-stroke. Neurological function was further assessed via several behavioral tests and the 2,3,5-triphenyltetrazolium chloride (TTC) staining companied with Nissl staining were used to assess neuronal survival. TUNEL staining, western blotting, immunofluorescence, immunohistochemistry, ELISA, and flow cytometry were employed to measure the levels of neuroinflammation and PANoptosis. The molecular mechanisms underlying the special role of rTMS in the combined therapy were distinguished with transcriptome sequencing via PC12 cells in oxygen-glucose deprivation/reoxygenation (OGD/R) conditions.Results The combined therapy efficiently reduced lesion volume and improved neuronal survival (P < 0.05), subsequently improving functional recovery after ischemic stroke. MSCs + rTMS treatment ameliorated the PANoptosis in neurons (P < 0.05), accompanied by decreased levels of inflammatory factors in the cerebral tissue and serum during the subacute phase of cerebral infarction. To further explore the roles of either therapy on synergistic effect, we found that the transplanted MSCs primarily localized in the spleen and reduced cerebral inflammatory infiltration after ischemia via suppressed splenic inflammation. Meanwhile, rTMS significantly protects neurons from PANoptosis in MSCs-inhibited inflammatory conditions by downregulating REST unveiled by transcriptome sequencing.Conclusion sOur study elucidates an unidentified mechanism by which the combination of MSCs and rTMS could synergistically promote neuronal survival and suppress neuroinflammation during the subacute phase of cerebral infarction, thus improving neurological outcomes. The downregulating REST induced by rTMS may potentially contribute to the neuroprotective effect against PANoptosis in MSCs-inhibited inflammatory conditions. These results are expected to provide novel insights into the mechanisms of MSCs and rTMS combination therapy in synergistically protecting against cerebral ischemia injury and potential targets underlying neuronal PANoptosis in the early phase of stroke.
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