Cell Reports
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2025
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IF 6.9
Zhao Cui,Jiameng Li,Caifeng Li,Shiwen Deng,Wei Liu,Tong Lei,Junxian Cao,Ziyi Wang,Xiaoxu Wang,Shuhua Ma,Yinhua Zhu,Hongjun Yang,Peng Chen
α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed hydroxylation of ribosomal protein S23 (RPS23) at proline 62. Mechanistically, AKG stabilizes the OGFOD1-RPS23 complex, enhancing translation accuracy to limit misfolded protein accumulation while sustaining synthesis rates, thereby balancing proteostasis. The natural flavonoid scutellarin (Scu), identified as an IDH1 agonist, elevates AKG to delay MSC senescence. In aged mice, Scu improves cognitive function, reduces osteoporosis and skin aging, and suppresses senescence-associated secretory phenotype. Our findings identify the AKG-IDH1-RPS23 axis as a regulator of stem cell senescence and we propose metabolic reprogramming strategies for anti-aging therapies.
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Materials Today Bio
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2025
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IF 10.2
Fei Sun,Yibo Shan,Shu Pan,Yi Lu,Zhiming Shen,Jianwei Zhu,Lei Yuan,Qi Wang,Wenxuan Chen,Hao Chen,Hongcan Shi
The success of tracheal transplantation depends on the rapid establishment of vascularization and epithelialization to support functional tissue formation. This study presents an innovative approach for in situ transplantation of a biomimetic tracheal graft, integrating microvascularization and epithelialization. First, endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) were isolated and purified from bone marrow, serving as seed cells for graft vascularization and epithelialization. Next, 3D printing was employed to create a bilayered tracheal graft using poly(ε-caprolactone) (PCL) and decellularized tracheal extracellular matrix (dtECM), which provided both optimal biomechanical properties and angiogenic potential. MSCs and EPCs were seeded on the inner and outer surfaces of the graft, respectively, and implanted in a long-segment in situ transplantation model. Six months post-transplantation, CT scans revealed a patent luminal space, bronchoscopy confirmed successful anastomosis, scanning electron microscopy showed abundant cilia on the inner graft surface, and α-SMA immunofluorescence demonstrated significant neovascularization. The PCL/dtECM graft exhibited excellent biomechanical properties, along with enhanced cell adhesion and proliferation. The combination of EPCs and MSCs effectively promoted both vascularization and epithelialization, ensuring successful graft integration and long-term survival of the experimental animals.
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Cellular and Molecular Bioengineering
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2025
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IF 5
Liu Junyu,Wang Hua,Zhang Caihua
Background Skin wound healing is a complex biological process involving cellular, molecular, and physiological events. Traditional treatments often fail to provide optimal outcomes, particularly for chronic wounds. Objectives This study aimed to develop a self-healing hydrogel loaded with Acteoside, a bioactive compound with antioxidant and anti-inflammatory properties, to enhance skin wound healing. Methods Using transcriptomic analysis, Rab31 was identified as a key target of Acteoside in regulating hair follicle stem cells (HFSCs). In vitro assays demonstrated that Acteoside promotes HFSC proliferation, migration, and differentiation by upregulating Rab31 expression. The self-healing hydrogel was prepared using quaternized chitosan derivatives, which exhibited excellent mechanical properties, antibacterial, and antioxidant activities. Results In vivo studies in a mouse model showed that Acteoside-loaded hydrogel significantly accelerated wound healing, promoting skin regeneration and improving wound closure. Conclusions This research highlights the potential of Acteoside-loaded self-healing hydrogels as an innovative therapeutic strategy for enhancing skin wound healing. By modulating HFSC activity, this hydrogel offers a promising solution for improving healing outcomes in challenging wound environments. Graphical Schematic representation of an injectable self-healing hydrogel loaded with the phenylethanoid compound acteoside for regulating the proliferation and differentiation of HFSCs to mediate the healing of skin wounds.
研究领域:
生物材料学
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分子生物学
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皮肤修复
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Biomaterials Advances
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2025
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IF 6
Yingjun Yang,Kai Wang,Xin Li,Shukai Ding,Miao Zhang,Siyuan Huang
Currently, in vitro fabrication of intra-tissue heterogeneity remains a critical challenge in development of adult stem cell based tissue engineering. Interestingly, as a typical structure in symmetry-breaking phase transitions, topological defects are extensively presented in biological substances. These topological defects are commonly observed within cell monolayer in vitro and demonstrated to be effective in induction of intra-tissue heterogeneity by regulating cell migration. Nevertheless, their impacts on the behavior of mesenchymal stem cells (MSCs) remain elusive. In this study, micro-grooved substrates were utilized to explore the role of topological defects in regulation of MSCs' self-organization and osteogenic differentiation. The results indicated that topological defects could induce the central aggregates of MSCs at central region of +1 and +1/2 topological defects by modulating centripetal migration. On the contrast, negatively charged topological were able to induce centrifugal migration and further inducing heterogeneous distribution of MSCs. Subsequently, these heterogeneously distributed MSCs were capable of inducing intra-tissue heterogeneity in terms of proliferation, stemness maintenance and osteogenic differentiation via regulatory morphogenesis.
研究领域:
细胞生物学
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组织工程学
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再生医学
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Xiao Xiao,Song Wang,Xin Zhang,Junyong Zheng,Dazhi Yang,Songlin Peng
The pollution issue of chlorinated paraffins has garnered widespread attention, with short-chain chlorinated paraffins (SCCPs) being comprehensively banned by the Stockholm Convention due to environmental contamination concerns. Currently, long-chain chlorinated paraffins (LCCPs) are widely used, necessitating an assessment of their toxicological impact. Bone marrow mesenchymal stem cells (MSCs) are a type of multipotent stem cell with self-renewal, immunoregulatory, and tissue repair capabilities, exhibiting important biological functions. In this study, MSCs were used as a model to evaluate the toxicological effects of LCCP. Initially, cell proliferation experiments were conducted to assess the impact of LCCP on MSC proliferation. The results indicated a significant reduction in cell proliferation capacity. Further work revealed that LCCP treatment induced cell senescence, as evidenced by Sa-β-gal staining and the evaluation of senescence markers, including p16, p21, and p53. Furthermore, LCCP treatment led to inflammation and oxidative stress, as analyzed by corresponding marker molecules, and ultimately resulted in cell death. Based on these findings, we investigated the molecular mechanisms underlying LCCP-induced MSC senescence. In summary, this paper is the first study to systematically investigate the toxicological effects of LCCPs on stem cells. The current study demonstrates that LCCP induces MSC senescence, highlighting its potential toxicity. This research lays the foundation for further elucidating the toxicology of LCCP. This finding suggests that the use of LCCPs should be strictly controlled under rigorous regulation.
研究领域:
毒理学
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细胞生物学
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环境科学
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JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Yang Jiao,Haixin Wang,Mingyu Zhao,Huiling Liu,Peng Shen,Gang Wu,Tim Forouzanfar,Franklin R. Tay,Li Miao,Hongchen Liu,Qian Liu
Bone regeneration is a dynamic, multistage process requiring the orchestrated interplay of cellular recruitment, immune modulation, and balanced osteoblast-osteoclast activity. To address this clinical challenge, we developed a nanocomposite hydrogel-based drug delivery system integrating gelatin methacrylate (GelMA) and silk fibroin methacrylate (SFMA) scaffolds containing mesoporous silica nanoparticles (MSNs) for spatiotemporally controlled co-delivery of stromal cell-derived factor-1α (SDF-1α) and osteoprotegerin (OPG). This dual-delivery platform enabled sustained and localized release of immunoregulatory and osteoprotective agents, achieving a synchronized modulation of the regenerative microenvironment. The MSNs functioned as an effective nanocarrier to preserve bioactivity and prolong release kinetics of bioactive factors, while the hydrogel matrix provided structural integrity and protease-responsive degradation matching bone repair dynamics. The system potentiated bone marrow mesenchymal stem cell (BMSC) recruitment, proliferation, and osteogenic differentiation, reprogrammed macrophage polarization toward pro-regenerative M2 phenotypes, and suppressed osteoclastogenesis. In vivo validation using a rat critical-sized femoral defect model revealed accelerated osseous regeneration. Mechanistically, transcriptomic profiling identified concerted PI3K/Akt-MAPK pathway activation. The immunomodulatory hydrogel reduced pro-inflammatory cytokines while elevating osteogenic factors. Crucially, the hydrogel restored osteoblast-osteoclast crosstalk balance, suppressing TRAP + osteoclast formation through OPG-mediated RANKL inhibition. Overall, this hydrogel-based delivery platform demonstrates a clinically translatable strategy for drug-enabled bone regeneration, with precise control over therapeutic release, spatial localization, and immuno-osteogenic coupling.
研究领域:
生物材料学
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再生医学
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骨科
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Journal of Materials Chemistry B
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2025
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IF 5.7
Jiuzhi Ma,Qi Feng,Zhipeng Sun,Manru Wang,Qiyuan Dai,Yue Huang,Xiaodong Cao,Qingtao Li
Bone defects have a broad impact, with over four million patients globally needing bone defect reconstruction every year due to various causes. Extracellular vesicle-functionalized scaffolds have recently emerged as a novel therapeutic approach for enhancing bone tissue regeneration. However, the clinical application of exosomes is limited by their low yield and rapid in vivo clearance. To address these challenges, we prepared nanovesicles (SCAPs-NVs) from stem cells of the apical papilla (SCAPs) using the extrusion method and loaded them into a tannic acid-Fe3+ network modified decellularized diaphragmatic tendon matrix. SCAPs can be abundantly obtained directly from extracted immature permanent teeth, are more readily available than other stem cells and also have the potential for multi-lineage differentiation. The strong interaction between tannic acid (TA) and the phospholipid bilayer of SCAPs-NVs enabled the controlled release of SCAPs-NVs. In our study, under the same conditions, the yield of SCAPs-NVs was approximately 23-fold higher than that of exosomes obtained by ultracentrifugation, highlighting the efficiency of the extrusion method. Moreover, MicroRNA sequencing of SCAPs-NVs reveals that they are enriched in angiogenic and osteogenic miRNAs. In vitro results showed that the composite scaffold loaded with SCAPs-NVs stimulated osteogenic differentiation of mesenchymal stem cells and promoted angiogenic activity of human umbilical vein endothelial cells. Micro-CT and histological evaluation confirmed the efficacy of the NVs-functionalized scaffold in promoting bone regeneration within a rat cranial defect model. This study provides novel insights into the therapeutic potential of nanovesicles, particularly SCAPs-NV, for clinical translation in bone regeneration.
研究领域:
生物材料学
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再生医学
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组织工程学
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Journal of Orthopaedic Surgery and Research
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2025
·Vol. 20
·期 1
·1-12
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IF 2.8
He Zhenhong,Zeng Shengqiang,Qin Bo,Liu Gang,Liu Huan,Bao Dingsu
ObjectiveTendon injury is a common and frequent disease in the field of sports medicine, and tendon repair after injury is a common clinical difficulty. Repair strategy based on tendon stem cells (TDSCs) therapy is considered a promising therapeutic option for the treatment of tendon injuries. Icariin (ICA) has been shown to be an effective herbal monomer for the treatment of tendon-bone healing and may be effective in the repair of tendon injuries.Methods In vitro, TDSCs isolated from C57 mice were treated with ICA (0.01–100 µM) to assess proliferation (CCK-8 assay) and tendonogenic differentiation (qRT-PCR). In vivo, 42 C57 mice with surgically induced patellar tendon defects were randomized into three groups (n = 14/group): (1) 20 mg/kg ICA, (2) 40 mg/kg ICA, and (3) control group (DMSO), administered intraperitoneally for 14 days. Half of each group (n = 7) underwent histopathological (hematoxylin-eosin staining, Masson staining) and molecular (qRT-PCR) analyses at 2 and 4 weeks post-surgery.Results In vitro, after 7 days of ICA intervention in TDSC, the expression of Mohawk (MKX), Scleraxis (SCX), fibromodulin (FMOD), and Tenomodulin (TNC) were higher in the ICA group than in the control group. In vivo, the expression of MKX, SCX, FMOD, and TNC was higher in the 20 mg/kg ICA group and 40 mg/kg ICA group than in the control group at 2 and 4 weeks after surgery. Histological evaluation revealed superior tendon repair in both ICA-treated groups compared to controls at both 2 and 4 weeks postoperative intervals. The 20 mg/kg ICA group demonstrated a significant enhancement in tissue continuity and collagen fiber organization, exhibiting greater defect filling, fewer interstitial gaps, and reduced vascular infiltration. In contrast, control specimens exhibited disorganized collagen architecture with prominent interstitial gaps. The 40 mg/kg ICA group showed intermediate repair outcomes between the 20 mg/kg ICA and control groups.Conclusion ICA can improve tendon injury repair by enhancing tendonogenic differentiation of TDSC.
研究领域:
运动医学
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再生医学
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药理学
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JOURNAL OF CELLULAR PHYSIOLOGY
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2024
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IF 4.5
Hairui Tian,Xingju Wang,Xiaoxiao Li,Weixiang Song,Jiaqi Mi,Kang Zou
In the orchestrated environment of the testicular niche, the equilibrium between self-renewal and differentiation of spermatogonial stem cells (SSCs) is meticulously maintained, ensuring a stable stem cell reserve and robust spermatogenesis. Within this milieu, extracellular vesicles, specifically exosomes, have emerged as critical conveyors of intercellular communication. Despite their recognized significance, the implications of testicular exosomes in modulating SSC fate remain incompletely characterized. Given the fundamental support and regulatory influence of Sertoli cells (SCs) on SSCs, we were compelled to explore the role of SC-derived exosomes (SC-EXOs) in the SSC-testicular niche. Our investigation hinged on the hypothesis that SC-EXOs, secreted by SCs from the testes of 5-day-old mice—a developmental juncture marking the onset of SSC differentiation—participate in the regulation of this process. We discovered that exposure to SC-EXOs resulted in an upsurge of PLZF, MVH, and STRA8 expression in SSC cultures, concomitant with a diminution of ID4 and GFRA1 levels. Intriguingly, obstructing exosomal communication in a SC-SSC coculture system with the exosome inhibitor GW4869 attenuated SSC differentiation, suggesting that SC-EXOs may modulate this process via paracrine signaling. Further scrutiny revealed the presence of miR-493-5p within SC-EXOs, which suppresses Gdnf mRNA in SCs to indirectly restrain SSC differentiation through the modulation of GDNF expression—an indication of autocrine regulation. Collectively, our findings illuminate the complex regulatory schema by which SC-EXOs affect SSC differentiation, offering novel perspectives and laying the groundwork for future preclinical and clinical investigations.
研究领域:
生殖生物学
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干细胞生物学
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分子生物学
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高影响因子
Stem Cell Research & Therapy
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2025
·Vol. 16
·期 1
·1-22
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IF 7.3
Shi Zhan,Lu Xiaowen,Fei Haiyi,Liu Xiu,Xu Shiqian,Lin Yuhan,Fang Ling,Jiang Lingling,Zhang Songying
Background Unexplained recurrent spontaneous abortion (URSA) is a distressing pregnancy disorder with no effective medical intervention. As a potential treatment for URSA, human umbilical cord mesenchymal stem cells (hucMSCs) undergo apoptosis and release apoptotic bodies (ABs) shortly after transplantation. However, the medical effects and the exact doses of ABs in the therapy for URSA remain unclear. Methods Staurosporine (STS) and ultraviolet (UV) induced apoptosis in hucMSCs. Differential centrifugation, transmission electron microscopy, immunofluorescent staining, and flow cytometry were used to isolate and characterize hucMSC-derived ABs (hucMSC-ABs), respectively. Two mouse abortion models (LPS-induced and CBA/J×DBA/2 immune-mediated) mimicked URSA. Flow cytometry, real-time quantitative PCR, immunofluorescence staining, and western blotting were used to analyze macrophage polarization and inflammatory pathways. Untargeted metabolomic analysis was used to detect the metabolic composition of hucMSC-ABs. RNA sequencing analysis was used to detect the transcriptome of macrophages (Macs). Dorsomorphin was used to inhibit the AMPK signaling pathway. Small interfering RNA (siRNA) was used to knock down Gys1 in raw246.7 macrophages. Results STS- and UV- induced hucMSC-ABs effectively alleviated abortion in both models, depended on Macs. However, excessive dosage of hucMSC-ABs induced pro-inflammatory Macs (pro-inflam Macs), worsening fetal loss. Appropriate doses suppressed the NF-κB pathway in Macs, while high doses activated it. Neither RNase nor trypsin fully abolished hucMSC-ABs’ regulatory effects on macrophage polarization. Metabolomics identified linoleamide and palmitic acid (PA) as the dominant hucMSC-AB metabolites (~ 1:1 ratio). RNA-seq revealed hucMSC-ABs modulated Nfkb1 and Gys1 in Macs, linked to linoleamide. Appropriate doses of the 1:1 mixture of linoleamide and PA induced anti-inflam Macs, while high dosages of the mixture induced pro-inflam Macs. Linoleamide alone activated AMPK, suppressed NF-κB via Gys1, and protected pregnancy, whereas PA induced pro-inflam Macs and promoted abortion. Conclusion Appropriate doses of hucMSC-ABs induce anti-inflam Macs in the uterus and prevent fetal loss, while high doses promote the polarization of pro-inflam Macs and lead to fetal loss. The effects of hucMSC-ABs in regulating Macs and treating URSA are related to different doses of linoleamide and PA on Macs. Linoleamide activates AMPK and suppresses NF-κB via Gys1. This study revealed the effect and mechanism of hucMSC-ABs intervention in fetal loss and provided a new idea for the treatment of URSA. Graphical abstract
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Nature Communications
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2025
·Vol. 16
·期 1
·1-21
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IF 15.7
Fang Wenzhuo,Du Xuan,Yang Ranxing,Liu Meng,Yang Ming,Jin Yangwang,Gao Guo,Fu Qiang,Wang Ying
Stress urinary incontinence (SUI) remains a significant clinical challenge due to the lack of strategies that simultaneously address muscle degeneration, neurogenic atrophy, and vascular deficits. Here, we report an innovative injectable system that combines a thermo-responsive poly(N-isopropylacrylamide)-COOH/leucine/decellularized extracellular matrix hydrogel with adipose-derived stem cells (ADSCs) pre-programmed by zeolitic imidazolate framework-8/polyethylene glycol 200@magnesium (ZIF-8/PEG200@Mg) nanoparticles. In vitro, programmed ADSCs exhibit enhanced neurogenic differentiation, while the hydrogels support robust myogenic activity and cell viability. In a female rat model of SUI—chosen to reflect the higher prevalence of SUI in women—the composite system leads to a marked improvement in leak point pressure (LPP) and restores urethral sphincter function. Mechanistic analyses reveals upregulation of muscle regeneration (e.g., Myoz1 , Smyd1 ) and neurogenesis/neuromuscular junction stabilization (NMJ) stabilization genes (e.g., Dok7 , Musk ), highlighting a coordinated multi-lineage regenerative process. This work establishes an integrated regeneration-plus-support injectable strategy, offering a regenerative medicine-based approach that surpasses conventional bulking or sling therapies for SUI.
研究领域:
泌尿生殖医学
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再生医学
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组织工程
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干细胞生物学
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神经肌肉生物学
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生物材料
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转化医学
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Materials Today Bio
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2025
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IF 10.2
Chen Wei,Xinyu Sun,Lijuan Gao,Yue Wang,Fantao Lin,Yao Du,Xiaoyu Zhao,Wei Gao,Jingkun Bai
Breast cancer stem cells (BCSCs) drive tumor formation and growth via self-renewal, differentiation, and high tumorigenic potential, and the persistence of BCSCs is an important cause of treatment failure in patients with breast cancer. In addition, the tumor microenvironment promotes the maintenance of BCSC stemness, inhibits immune cell activity, and forms an immune escape “barrier”. In this study, we developed an amphiphilic peptide nanocarrier system, PA/Pep1, with an RGD-targeting sequence. The delivery system simultaneously encapsulates the hydrophobic drugs paclitaxel (PTX) and all-trans retinoic acid (ATRA) and releases them in response to low pH in the tumor microenvironment. PA/Pep1 causes apoptosis in breast cancer cells, induces the differentiation of BCSCs and inhibits their expression, thus enhancing the killing effect of PTX. In breast cancer, PA/Pep1 effectively alleviates immune evasion by modulating transforming growth factor-β (TGF-β) and interleukin-6 (IL-6), thereby reducing the expression of programmed cell death-ligand 1 (PD-L1). Importantly, the transformation of the nanosystems into forms with high aspect ratios under acidic conditions effectively reduced drug efflux and extended the duration of drug action. In conclusion, the combination of stem cell therapy and immunotherapy, as well as the development of novel deformable amphiphilic peptide nanocarrier systems, provides new possibilities for breast cancer treatment.
研究领域:
生物医学
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肿瘤学
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免疫学
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药剂学
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高影响因子
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