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301. Activating PIK3CA mutations in adipose-derived stem cells drive mutant-like phenotypes of wild-type cells in macrodactyly.

作者: Xiao Zhang.;Yating Yin.;Zhibo Wang.;Yongkang Jiang.;Aiping Yu.;Xinyi Dai.;Xiaoli Wang.;Xuesong Guo.;Hailei Mao.;Bin Wang.
来源: Cell Death Dis. 2025年16卷1期477页
Macrodactyly is a congenital overgrowth disorder characterized by pathological adipose proliferation due to PIK3CA mutations in adipose-derived stem cells (ADSCs). Due to the somatic mosaicism, the affected tissues comprise a mixture of mutant and wild-type cells. However, how PIK3CA mutated ADSCs influence adjacent wild-type cells in macrodactyly remains poorly understood. In this study, we utilized coculture systems to investigate the effects of macrodactylous adipose-derived stem cells (Mac-ADSCs) on normal ADSCs, fibroblasts (FBs), and vascular endothelial cells (VECs). Our study demonstrated that activating PIK3CA mutations in Mac-ADSCs promotes the proliferation, migration, invasion, adipogenesis, and angiogenesis of wild-type ADSCs, FBs and VECs. Furthermore, using RNA sequencing and cytokine arrays, we revealed that these effects are primarily mediated by various secreted paracrine cytokines. These findings demonstrated that activating PIK3CA mutation alters the paracrine characteristics of Mac-ADSCs and reshapes the microenvironment of macrodactyly, driving adjacent wild-type cells to exhibit mutant-like phenotypes. Targeting PIK3CA with BYL-719 could influence the progression of macrodactyly by inhibiting the paracrine signaling of Mac-ADSCs.

302. Single-cell transcriptomics reveals BMP4-BMPR2 signaling promotes radiation resistance in hematopoietic stem cells following injury.

作者: Yanhua Li.;Yunxing Li.;Bowen Zhang.;Jiahui Zhao.;Jinhua Qin.;Siao Jiang.;Yunqiao Li.;Yanzhou Chen.;Jisheng Li.;Keyi Chen.;Yang Lv.;Tao Fan.;Zuyin Yu.;Hao Lu.;Cheng Quan.;Yiming Lu.;Xuetao Pei.;Gangqiao Zhou.
来源: Nat Commun. 2025年16卷1期5470页
High doses of ionizing radiation (IR) cause severe damage to the hematopoietic system. However, the heterogeneity of hematopoietic stem and progenitor cells (HSPCs) in response to IR stress remains largely uncharacterized. Here, we present a dynamic single cell transcriptomic landscape and elucidate the complex crosstalk between HSPCs and the bone marrow (BM) microenvironment during IR-induced regeneration process. We reveal that BMP4 signaling in HSPCs confers IR resistance, and a single administration of BMP4 or SB4 can rescue mice from the IR-induced mortality. Furthermore, we identify BMPR2+ HSCs as a radiation resistant subset, displaying distinct epigenetic landscapes from BMPR2- HSCs under radiation stress. BMPR2+ HSCs sustain a strong self-renewal capacity primarily by reducing the H3K27me3 modification on the Nrf2 gene in response to radiation stress. In Nrf2 knockout mice, we demonstrate that Nrf2 is a critical downstream functional gene for BMP4-BMPR2 signaling on HSCs to resist IR-induced damage. Collectively, we provide insights into the molecular intricacies underlying HSPC heterogeneity and BM niche after radiation exposure, and we uncover that BMP4-BMPR2 signaling may serve as a promising target for developing innovative and effective intervention strategies to mitigate IR-induced hematopoietic injury.

303. circGIGYF1 inhibits stemness and metastasis in colorectal cancer by promoting WWP2-HOXD13 interaction to regulate β-catenin signalling.

作者: Bin Zhao.;Jiacheng Li.;Zunxian Wang.;Hairui Zhou.;Zhuoxin Cheng.;Shuxia Ma.
来源: Commun Biol. 2025年8卷1期975页
Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies worldwide, with cancer stemness and metastasis being critical factors contributing to poor prognosis. While circular RNAs are emerging as important regulators in cancer progression, the role of circGIGYF1 in CRC development is poorly understood. Here, we found that downregulated circGIGYF1 is linked to poor survival rate in CRC patients. circGIGYF1 inhibits CRC stemness, epithelial-mesenchymal transition, and metastatic potential both in vitro and in vivo. Mechanistically, circGIGYF1 promotes the interaction between WWP2 and HOXD13, enhancing HOXD13 ubiquitination and subsequent degradation. This degradation prevented HOXD13 from binding to the CTNNB1 promoter, thereby suppressing Wnt/β-catenin signalling pathway activation. Importantly, circGIGYF1 overexpression or HOXD13 knockdown significantly reduces tumor growth and liver metastasis in mouse models. These findings reveal a circGIGYF1/WWP2/HOXD13/β-catenin regulatory axis in CRC progression and highlight circGIGYF1 as a potential therapeutic target for developing strategies to combat CRC metastasis and recurrence.

304. Liver developmental microenvironment promotes iHSC generation from human iPSCs.

作者: Di Ye.;Min Ding.;Yu-Mu Song.;Heng-Xing Meng.;Wen-Hao Chen.;Jian-Yun Ge.;Yun-Wen Zheng.
来源: Sci Rep. 2025年15卷1期22338页
Hepatic stellate cells (HSCs) are liver-specific mesenchymal cells that play a crucial role in liver formation and regeneration, as well as in different pathological diseases. However, the limited source of primary HSCs (pHSCs) and the suboptimal functionality of induced HSCs (iHSCs) by existing methods restrict their application in biomedical modeling. We developed a de novo differentiation method to generate iHSCs under simulated liver microenvironment in vitro, thereby enhancing the function of the differentiated cells. These iHSCs exhibited key HSC functions, including the expression of α-smooth muscle actin, collagen, and the capability to store Vitamin A. RNA sequencing further revealed that the present iHSCs converged more closely to pHSCs with very similar transcriptional profile compared to the established conventional induction. Additionally, the novel HSC-specific marker genes, FBLN5, NID2, and SVEP1 were identified by RNA sequencing and gene expression assay. In conclusion, our novel differentiation approach enables the generation of iHSCs with phenotypic and functional traits similar to those of pHSCs. The generation of highly functional iHSCs may make it more feasible to accurately simulate the liver-specific multicellular microenvironments, thus providing new perspectives on the modeling of physiological regenerative processes and disease progression in the liver, as well as useful tools for creating of new therapeutic strategies.

305. Nascent actin dynamics and the disruption of calcium dynamics by actin arrest in developing neural cell networks.

作者: Sylvester J Gates.;Phillip H Alvarez.;Kate M O'Neill.;Kan Cao.;Wolfgang Losert.
来源: Commun Biol. 2025年8卷1期978页
Waves and oscillations are key to information flow and processing in the brain. Recent work shows that, in addition to electrical activity, biomechanical signaling can also be excitable and support self-sustaining oscillations and waves. Here, we measured the biomechanical dynamics of actin polymerization in neural precursor cells (NPC) during their differentiation into populations of neurons and astrocytes. Using fluorescence-based live-cell imaging, we analyzed the dynamics of actin and calcium signals. The size and localization of actin dynamics adjusts to match functional needs throughout differentiation, enabling the initiation and elongation of processes and, ultimately, the formation of synaptic and perisynaptic structures. Throughout differentiation, actin remains dynamic in the soma, with many cells showing notable rhythmic character. Arrest of actin dynamics increases the slower time scale (likely astrocytic) calcium dynamics by 1) decreasing the duration and increasing the frequency of calcium spikes and 2) decreasing the time-delay cross-correlations in the networks. These results are consistent with the transition from an overdamped system to a spontaneously oscillating system and suggest that dynamic actin may dampen calcium signals. We conclude that mechanochemical interventions can impact calcium signaling and, thus, information flow in the brain.

306. Angiogenic and Immunomodulatory effects of embryonic stem cell derived mesenchymal stem cells in a murine model of ischemic hindlimb.

作者: Do Jung Kim.;Young-Nam Youn.;Ji Min Kim.;Sang-Hyun Lim.
来源: Sci Rep. 2025年15卷1期20397页
In critical limb-threatening ischemia (CLTI), failed revascularization and pharmacotherapy substantially increase amputation and mortality risks. Mesenchymal stem cells (MSCs) are a promising therapeutic option for CLTI. This study evaluated the therapeutic effects of embryonic stem cell-derived MSCs (E-MSCs) on inflammation and angiogenesis under ischemic conditions across different E-MSC doses. Hindlimb ischemia was induced in 85 BALB/c nude mice by cauterizing the femoral and branched arteries. The mice were divided into five groups: non-ischemia (G1); saline-treated ischemia (G2); and ischemia treated with E-MSCs at low, medium, and high doses (G3-G5). Therapeutic effects were assessed using the rotarod test, blood perfusion ratio, and histological and cytokine analyses. G1 exhibited normal blood perfusion and motor function, whereas E-MSC-treated groups (G3-G5) demonstrated improved perfusion compared to G2. Although the medium-dose group (G4) showed numerically greater recovery, differences between G3, G4, and G5 were not statistically significant, suggesting no dose-response. All E-MSC-treated groups exhibited reduced inflammation and increases in motor function and angiogenic factors. Histological analysis revealed enhanced myofiber regeneration, reduced inflammatory infiltration, and diminished collagen deposition in the ischemic muscle of G3-G5. These changes were observed across all dose groups without significant dose-dependent differences. These results suggest E-MSCs enhance blood perfusion and modulate inflammation and angiogenesis in ischemic limbs, regardless of dose. These findings support the therapeutic potential of E-MSCs in CLTI, although further investigation is needed to optimize dosing and elucidate the mechanisms involved.

307. Functional immune reconstitution after allogeneic hematopoietic stem cell transplantation in myeloablative and non-myeloablative conditioned patients.

作者: Patrick Terrence Brooks.;Lia Minculescu.;Rebecca Svanberg Teglgaard.;Hans Jakob Hartling.;Jose Antonio Salado-Jimena.;Lone Smidstrup Friis.;Brian Kornblit.;Ida Schjødt.;Søren Lykke Petersen.;Niels Smedegaard Andersen.;Susanne Dam Nielsen.;Jens Lundgren.;Hanne Vibeke Marquart.;Lars Klingen Gjaerde.;Henrik Sengeløv.;Sisse Rye Ostrowski.
来源: Sci Rep. 2025年15卷1期21029页
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a treatment modality for several hematological and immune-driven diseases. A conditioning regimen precedes transplantation. These comprise myeloablative (MA) conditioning consisting of chemotherapeutics often in combination with high-dose total body irradiation (TBI), while non-myeloablative (NMA) conditioning regimens use reduced dosage of chemotherapy and TBI allowing allo-HCT to patients who would otherwise not be eligible for treatment. While cellular immune reconstitution in allo-HCT patients has been well studied, differences between MA and NMA conditioned patients including the functional status of the immune system post-transplantation remains unclear. Seventy-seven patients undergoing allo-HCT were included in the main study, only including patients receiving peripheral blood stem cell grafts, no ATG treatment and no other GVHD prophylaxis than tacrolimus + methotrexate or cyclosporine + MMF + sirolimus (median age 59; IQR: 48-65). The cohort consisted of 34 patients receiving MA conditioning and 43 NMA conditioned patients. As a proxy for post-transplantation immune function, we analyzed stimulated cytokine release patterns in whole-blood samples from MA and NMA patients before and after transplantation alongside major immune cell phenotypes and T cell chimerism on day 28 after transplantation. Notably, among patients receiving grafts from peripheral blood apheresis, MA patients exhibited higher T cell counts, and elevated CD3/CD28-stimulated cytokine release compared to NMA patients. Assessment of associations between cytokine release and immune cell concentration associations indicated that variation in T cell or other immune cell concentrations between the cohorts could not account for differences in CD3/CD28-stimulated cytokine release. Meanwhile, LPS- and R848-stimulated cytokine release was associated with innate immune cell subtypes. A secondary study amongst MA conditioned patients further revealed that those who received fludarabine and treosulfan (n = 35) had higher T cell concentration and stimulated immune function compared to patients receiving more intense MA regimens (n = 15). These findings highlight the complex impact conditioning has on immune function after allo-HCT. Further analyses of T cell compartments and myeloid/lymphoid innate cells are needed to further understand the functional differences observed between conditioning groups and the potential impact on clinical outcomes.

308. miR-210 locus deletion disrupts cellular homeostasis: an integrated genetic study.

作者: Mihai Bogdan Preda.;Evelyn Gabriela Nastase-Rusu.;Carmen Alexandra Neculachi.;Xiaoling Zhong.;Christine Voellenkle.;Nathalie M Mazure.;Ovidiu Balacescu.;Cristina Ivan.;Xiao-Wei Zheng.;Mihaela Gherghiceanu.;Kevin Lebrigand.;Maya Simionescu.;Fabio Martelli.;Bernard Mari.;Sergiu-Bogdan Catrina.;Alexandrina Burlacu.;Mircea Ivan.
来源: Sci Rep. 2025年15卷1期22659页
MiR-210 is widely recognized as the quintessential hypoxia-responsive miRNA and is thought to fine-tune various facets of cellular homeostasis. We hereby present an integrative appraisal of the phenotypic and molecular repercussions of disrupting the corresponding locus in human and mouse cells using multiple genetic strategies. In brief, MIR210 deletion led to decreased cellular fitness and suboptimal responses to several stress types. Transcriptomic comparisons via different profiling platforms, performed independently by members of this collaboration, revealed consistent deregulation of neighboring genes, in locus-disrupted cells. Interestingly, the anticipated enrichment of miR-210 targets failed to materialize in unbiased analyses. Our results point to the biological significance of unrecognized regulatory elements that overlap miRNA genes and should serve as a note of caution for studies based on the genetic disruption of such loci.

309. Novel kinetic and developmental transcriptomic pan-stress responses by embryonic stem cells.

作者: Aditi Singh.;Ximena Lu Ruden.;Wen Tang.;Awoniyi Olumide Awonuga.;Douglas Mark Ruden.;Steven James Korzeniewski.;Elizabeth Ella Puscheck.;Hao Feng.;Daniel Allen Rappolee.
来源: Sci Rep. 2025年15卷1期21291页
Embryo development is highly susceptible to environmental stressors, contributing significantly to early miscarriages in 70% of human embryos (Cross et al. in Science 266:1508-1518, 1994, Macklon et al. in Hum Reprod Update 8:333-343, 2002). Yet the underlying mechanisms remain poorly understood. Here, we employ mouse embryonic stem cells (ESC) as a model to identify shared "pan-stress" markers for responses to diverse environmental insults implicated in miscarriage (Puscheck et al. in Birth Defects Res 114:1014-1036, 2022, Puscheck et al., in: Leese HJ, Brison DR (eds) Cell Signaling During Mammalian Early Embryo Development, Springer, New York, 2015 ). ESC were exposed to control stimuli and diverse stressors at previously characterized risk levels for growth, mimicking miscarriage risk exposures, then subjected to transcriptomic analysis via RNA sequencing. Surprisingly, we identify a large, substantial set of significantly-changing genes-termed pan-stress genes that also exhibited concordant changes in directionality compared to initial stemness. These genes show significant differential expression across stress conditions, distinguishing weak and strong stressors. Notably, ninety-four genes display significant expression changes under four weaker stressors and normal differentiation conditions, while a twenty-one/ninety-four gene subset exhibits shared significance with the inclusion of two stronger stimuli. Importantly, all identified pan-stress genes, the set of ninety-four and subset of twenty-one, exhibit 100% concordant, highly nonrandom directional changes from the initial stemness. Transcription and secreted factors that might mediate nonrandom concordant stress response were identified. These findings characterize a robust pan-stress response in ESC, suggesting potential biomarkers for miscarriage prediction and testing of underlying mechanisms.

310. High glucose inhibits proliferation, migration, and osteogenic differentiation of human placenta-derived mesenchymal stem cells.

作者: Supawadee Duangprom.;Pakpoom Kheolamai.;Chairat Tantrawatpan.;Sirikul Manochantr.
来源: Sci Rep. 2025年15卷1期22512页
Chronic hyperglycemia is recognized as an important contributor to chronic inflammation, oxidative stress, and organ dysfunction that causes serious complications in diabetes and aging. This study investigates the effects of elevated glucose levels on human placenta-derived mesenchymal stem cells (hP-MSCs), especially since these cells hold a promise for tissue engineering and regenerative medicine due to their multipotency and self-renewal capabilities. hP-MSCs were treated with 10-40 mM D-glucose to study the effects of high glucose on hP-MSCs functions. hP-MSCs viability and proliferation were determined by using thiazolyl blue tetrazolium bromide (MTT), cell cycle analysis, and senescence assays. The migration and osteogenic differentiation capacity were also determined by migration assay, alkaline phosphatase (ALP) activity assay, and Alizarin Red S staining. Quantitative real-time RT-PCR, Western blot, and Nanostring® nCounter assay were performed to study the effect of high glucose on the expression levels of genes involved in various aspects of hP-MSCs functions. The results demonstrated that high glucose significantly inhibited proliferation and cell cycle progression of hP-MSCs at the G1/S phase and induced replicative senescence in hP-MSCs possibly by decreasing the expression of proliferation-promoting genes, CCND1 and LMNB1, and increasing the expression of several senescence-associated proteins, p16, p21, and p53. Furthermore, high glucose also inhibited the migration and osteogenic differentiation of hP-MSCs, possibly by suppressing the expression of SDF1, CXCR4, RUNX2, OSX, OCN, and COL1A. The additional Nanostring analysis also showed that high glucose significantly affects multiple genes involved in inflammation, DNA repair, autophagy, and oxidative stress response in hP-MSCs. This study provides significant insights into the wide-ranging effects of high glucose on the expression of the hP-MSCs genes that affect various aspects of its function, including proliferation, viability, senescence, oxidative stress response, and DNA repair, highlighting its implications for regenerative medicine in the context of diabetes and metabolic disorders.

311. A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model.

作者: Sulagna Mukherjee.;Matthew J Wolan.;Mary K Scott.;Victoria A Riley.;Aidan M Sokolov.;David M Feliciano.
来源: Sci Rep. 2025年15卷1期20367页
Neural stem cells (NSCs) of the ventricular-subventricular zone (V-SVZ) generate diverse cell types including striatal glia during the neonatal period. NSC progeny uncouple stem cell-related mRNA transcripts from being translated during differentiation. We previously demonstrated that Tsc2 inactivation, which occurs in the neurodevelopmental disorder Tuberous Sclerosis Complex (TSC), prevents this from happening. Loss of Tsc2 causes hyperactivation of the protein kinase mechanistic target of rapamycin complex 1 (mTORC1), altered translation, retention of stemness in striatal glia, and the production of misplaced cytomegalic neurons having hypertrophic dendrite arbors. These phenotypes model characteristics of TSC hamartomas called subependymal giant cell astrocytomas (SEGAs). mTORC1 inhibitors called rapamycin analogs (rapalogs) are currently used to treat TSC and to assess the role of mTORC1 in regulating TSC-related phenotypes. Rapalogs are useful for treating SEGAs. However, they require lifelong application, have untoward side effects, and resistance may occur. They also incompletely inhibit mTORC1 and have limited efficacy. Rapalink-1 is a bitopic inhibitor that links rapamycin to a second-generation mTOR ATP competitive inhibitor, MLN0128. Here we explored the effect of Rapalink-1 on a TSC hamartoma model. The model is created by neonatal electroporation of mice having conditional Tsc2 genes. Prolonged Rapalink-1 treatment could be achieved with 1.5 or 3.0 mg/Kg injected intraperitoneally every five days. Rapalink-1 inhibited the mTORC1 pathway, decreased cell size, reduced neuron dendrite arbors, and reduced hamartoma size. In conclusion, these results demonstrate that cellular phenotypes in a TSC SEGA model are reversed by Rapalink-1 which may be useful to resolve TSC brain hamartomas.

312. A comparative study of the effectivity of MSC-based, NP-based and combined therapies in an experimental model of NaIO3-induced retinal degeneration.

作者: Katerina Palacka.;Barbora Hermankova.;Tereza Cervena.;Pavel Rossner.;Vladimir Holan.;Eliska Javorkova.
来源: Sci Rep. 2025年15卷1期22281页
Mesenchymal stem cells (MSCs) represent the promising options for retinal therapy and combined therapy with nanoparticles (NPs) could currently provide increased immunoregulatory and neuroprotective effects. Therefore, we tested the effect of silver (Ag)NPs on the properties of MSCs in an experimental model of chronic retinal degeneration. The results showed that simultaneous administration had no effect on the survival of MSCs, but a less effective local regulation of Iba-1 expression compared to MSC- or AgNP-only treated groups was observed. In addition, MSCs applied alone or in combination with AgNPs and sorted from the degenerated retina had increased expression of genes for retinal markers (rhodopsin, S-antigen, recoverin), and for TGF-β and IGF-1. These effects were confirmed also on protein level by increased production of IGF-1 and proportion of rhodopsin+ MSCs. Nevertheless, the increased expression of the gene for GDNF was observed only in the MSCs combined with AgNPs. Regarding the immune response, the application of MSCs with AgNPs triggered increased expression of the IL-6 gene in the CD45 cells separated from the retina. In conclusion, applications of MSCs or AgNPs, as a single therapy, were able to modulate the inflammation. However, the combined applications decreased the immunomodulatory effects of MSCs or AgNPs.

313. Molybdenum facilitates PDLSC-based bone regeneration through the JAK/STAT3 signaling pathway.

作者: Jing Xia.;Jue Yu.;Wenwen Shi.;Yan Liu.
来源: Sci Rep. 2025年15卷1期22204页
Bone regeneration is a critical area of research in the treatment of bone defects within clinical practice. Molybdenum (Mo) is an essential trace element for many organisms, which plays a vital role in various cellular activities, such as maintaining energy metabolism and promoting cell proliferation. However, whether Mo regulates the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and promotes bone tissue regeneration remains unknown. This study confirmed the nourishing effect of Mo on the osteogenic differentiation of PDLSCs, as evidenced by higher expression of osteogenic-related markers (OCN, BSP, OSX and RUNX2), ALP activity and mineralization ability. Moreover, through constructing compound material GelMA + PDLSC, we proved that Mo promoted PDLSC-based bone regeneration quantity and quality in rat calvarial defects. Finally, we revealed the underlying mechanism that the JAK/STAT3 signaling pathway actively participated in the Mo-enhanced osteogenic differentiation of PDLSCs. The inhibition of STAT3 diminished the benefit of Mo. Overall, our study found that Mo facilitated PDLSC-based bone regeneration through the JAK/STAT3 signaling pathway, which may shed new light on clinical bone regeneration therapeutic strategies.

314. The novel amino-artemisinin derivative WHN-11 disrupts mitochondria and protein homeostasis, and induces autophagy and apoptosis in cancer cells.

作者: Deborah Kajewole.;Ho Ning Wong.;Alexander von Kriegsheim.;Richard K Haynes.;Jo-Anne de la Mare.;Adrienne Lesley Edkins.
来源: Sci Rep. 2025年15卷1期21604页
Semi-synthetic derivatives of artemisinin exhibit anti-cancer activity in vitro and in vivo in addition to anti-malarial activity. Here, we report the anti-cancer and anti-cancer stem cell potential of novel C-10 substituted amino-artemisinin derivatives. Of these, the 4'-trifluoromethylarylurea piperazinyl derivative WHN-11 demonstrated cytotoxic activity at high nanomolar concentrations across a range of cancer cell lines. WHN-11 reduced short- and long-term survival of triple-negative breast cancer (TNBC) cells, a highly aggressive breast cancer subtype that currently lacks standardized targeted treatments. Mechanistically, WHN-11 induced a stress response and increased proteasome-mediated turnover of ubiquitinated proteins. WHN-11 promoted mitochondrial depolarization and fission, suppressing the expression of anti-apoptotic B-cell lymphoma extra-large (Bcl-xL) protein and ATP synthesis, thereby decreasing cellular energy production, and inducing apoptosis. WHN-11 treatment also increased autophagosomes, acidic vesicular organelles and lipid droplets. Activation or inhibition of autophagy synergized with the activity of WHN-11 in promoting cellular toxicity, as did increasing cellular dependence on oxidative phosphorylation. Unexpectedly, the effects of WHN-11 appear independent of substantial reactive oxygen species (ROS) production. Taken together, these data suggest that amino-artemisinins related to WHN-11 are promising candidates for anti-TNBC therapies targeting the mitochondria alone or in combination with autophagy modulators.

315. The interplay between endoplasmic reticulum stress and inflammation in multiple sclerosis.

作者: Zhila Maghbooli.;Forough Azam Sayahpour.;Tarlan Varzandi.;Mahya Rouhollahi Masoumi.;Mohammad Ali Sahraian.
来源: Sci Rep. 2025年15卷1期22916页
Endoplasmic reticulum (ER) stress is one of the hallmarks of neurodegenerative diseases. This study aimed to investigate the role of ER stress in interaction with inflammatory markers in patients with multiple sclerosis (MS). The participants in the current study were recruited in two age and sex-matched groups: 44 recently diagnosed MS patients and 53 control subjects. Differential gene expression of C/EBP homologous protein (CHOP), 78-kDa glucose-regulated protein (GRP78), and circulating levels of interleukin (IL)-1β and tumor necrosis factor (TNF-α) were assessed in MS patients and controls. The results showed that serum levels of TNF-α were significantly higher in MS patients than in the control group (p = 0.01), but not IL-1β serum levels. As for ER stress markers, there were no changes in CHOP expression levels in MS patients compared to the control group (p = 0.2). In contrast, GRP78 showed significant upregulation in MS patients compared to the control group (p = 0.0001). This study showed that the interaction between GRP78 and TNF-α influences the risk of MS (beta = 1.43, 95%CI:1.09-1.87, p = 0.01). Our data suggest that the interaction between TNF-α and GRP78 may modulate ER stress in MS patients.

316. Fabrication and validation of an affordable DIY coaxial 3D extrusion bioprinter.

作者: M Jergitsch.;R Soiunov.;F Selinger.;M Frauenlob.;L M Delgado.;S Perez-Amodio.;R A Perez.;M A Mateos-Timoneda.
来源: Sci Rep. 2025年15卷1期22978页
3D bioprinting has emerged as a promising technology in tissue engineering, allowing for the precise fabrication of complex structures to mimic native tissues. Coaxial bioprinting enhances the complexity of printed structures by extruding multiple materials in concentric layers. However, costly commercial systems and a lack of Do-it-Yourself (DIY) guides for coaxial 3D bioprinting limit the wider adoption of this technology. This study presents a detailed description of modifying a commercial 3D printer to a coaxial 3D bioprinting system that simultaneously drives two syringe pump extruders connected to a coaxial nozzle. The system was validated using a soft alginate-gelatin hydrogel core and a load-bearing methylcellulose-based (MC) hydrogel shell. Shape fidelity of the 3D printed structures was evaluated for core-shell extrusion ratio, coaxial nozzle configuration, and in-situ crosslinking of the hydrogel core. Employing optimized printing settings allowed the fabrication of complex scaffold structures with a gradual transition between the extrusion of core and shell material. Mesenchymal stem cells (MSCs) encapsulated in varying alginate concentrations were printed, maintaining shape fidelity and high cell viability. In conclusion, we developed a cost-effective DIY coaxial 3D bioprinter capable of extruding soft cell-laden hydrogels that are not printable by conventional extrusion bioprinting. This printer presents an easy to build and modify platform to encourage a wider audience to utilize and tailor coaxial bioprinting for their specific requirements.

317. Dynamic changes in BDNF, VEGF, and GDNF after transplanting human protein-based scaffolds with Wharton's Jelly MSCs in a rat brain injury model.

作者: Wioletta Lech.;Marta Kot.;Marlena Welniak-Kaminska.;Monika Drabik.;Leonora Buzanska.;Marzena Zychowicz.
来源: Sci Rep. 2025年15卷1期22625页
Stroke poses a considerable challenge for regenerative medicine due to the complex and multidimensional specificity of the central nervous system, and cell therapy is one of the currently considered treatments. The aim of this study was to determine the pro-regenerative outcome after transplantation of preconditioned and scaffold-encapsulated mesenchymal stem/stromal cells isolated from Wharton's Jelly (WJ-MSCs) in an experimental rat model of brain injury. For this purpose, WJ-MSCs cultured at different oxygen concentrations (21% O2 or 5% O2) were transplanted into the injured rat brain in saline or hydrogel scaffolds derived from human platelet lysate or fibrinogen. Using magnetic resonance imaging, we observed the signal of labelled WJ-MSCs at injection site at different time-points after transplantation. By diffusion-weighted imaging we detected the signal at the lesion site only after WJ-MSCs transplantation. Furthermore, cell transplantation resulted in a significant decrease in the extent of brain damage and dynamic change in the expression of investigated rat trophic factors (BDNF, GDNF, VEGF-A) in the brain and cerebrospinal fluid. The highest increase in this expression was observed after transplantation of physioxia-preconditioned and scaffold-encapsulated cells. The results demonstrated the regenerative effect of WJ-MSCs, which was enhanced by their transplantation within human protein-based hydrogel scaffolds in the rat model of brain injury.

318. Surface-elastic hydrogels delay senescence via the modulation of redox homeostasis and cytoskeletal tension.

作者: Thasaneeya Kuboki.;Satoru Kidoaki.
来源: Sci Rep. 2025年15卷1期20460页
The Bone marrow-derived mesenchymal stem cells (MSCs) are widely used in clinical applications owing to their therapeutic properties. However, in vitro expansion of MSCs in tissue culture dishes induces aging, which reduces their quality through an undefined mechanism. This study delineates the role of substrate stiffness as a potential modulator to delay MSC aging by elucidating the senescence progression of preconditioned and serially passaged MSCs on engineered stiffness-tunable gelatinous hydrogels. We demonstrated that mechanoactivation of MSCs increased their radical-scavenging capacity, maintained redox homeostasis, restored actin dynamics, and maintained their therapeutic properties. The hydrogels alleviated hydrogen peroxide-induced oxidative stress, linking mechanical signaling to redox balance and senescence. These hydrogels restored actin remodeling, highlighting the importance of cytoskeletal tension and dynamics in cellular senescence. We established a new culture method to maintain the stemness, proliferation, motility, and osteogenic differentiation potential of MSCs by serially passaging the cells on stepwise surface-elastic gels. Evidence points toward the complex interplay between mechanical memories and actin dynamics and their implications for autophagic activity in the delaying of senescent MSCs via hydrogels. Our findings suggest that mechanoregulation of culture substrates finely tunes the balance between cellular stress, redox homeostasis, and cytoskeletal dynamics to delay the progression of MSC senescence.

319. Maintenance of pluripotency and osteogenic differentiation of human mesenchymal stem cells on acrylate-based substrates exhibiting gelatin or heparin grafting.

作者: María Noel Tamaño-Machiavello.;Juan Carlos Marín Payá.;Silvia Flores.;Lourdes Cordón.;Amparo Sempere.;Roser Sabater I Serra.;José Luis Gómez Ribelles.
来源: Sci Rep. 2025年15卷1期22821页
This study investigated the in vitro biological behaviour of human mesenchymal stem cells grown on acrylate-based substrates functionalized with biomolecules that play a significant role in the extracellular matrix, specifically gelatin (derived from collagen) and heparin. Synthetic supports were synthesised by free radical polymerization in the form of flat films, prepared by solvent casting, and microspheres, produced via an oil-in-water emulsion, with gelatin or heparin grafted onto theirs surface. The viability and proliferation of primary cells obtained from bone marrow aspirates were analysed in 2D monolayer environments, and in 3D environments using microspheres. In addition, the gene expression of osteogenic and chondrogenic markers was studied in cells expanded in basal medium before reaching confluence in both 2D and 3D environments, to assess the influence of the grafted biomolecules and dimensionality on the early commitment of MSCs. Significant changes were induced by the interaction of cells with the grafted biomolecules, which suggested the commitment of the human bone marrow mesenchymal stem cells (hBMMSCs) to specific lineages and loss of multipotency. The culture was continued in basal or osteogenic medium for up to 21 days in 2D environments after confluence, revealing significant differences between the functionalised supports and either the non-functionalised substrates and standard polystyrene culture wells (tissue culture plastic, TCP). These findings highlight the potential of this approach to advance bone tissue engineering applications and contribute to the development of innovative and effective bone regeneration strategies.

320. 3D collagen nanofiber scaffold with adipose derived stem cells for functional adipose tissue regeneration.

作者: Liping Zhang.;Yueguang Xue.;Delu Mu.;Siyi Chen.;Guangmin Wu.;Zitong Yang.;Yizhu Chen.;Hu Xu.;Li Zhu.;Jiandong Wang.
来源: Sci Rep. 2025年15卷1期21802页
Adipose tissue engineering offers a promising approach for breast reconstruction, yet achieving efficient adipose regeneration remains challenging due to poor cell survival and tissue integration. Hence, we developed a three-dimensional (3D) electrospun collagen nanofiber scaffold integrated with adipose-derived mesenchymal stem cells (ADSCs), designed to enhance adipose tissue regeneration by providing a biomimetic extracellular matrix environment. The incorporation of collagen nanofibers enhances cell adhesion and extracellular matrix remodeling, further promoting adipogenic differentiation. Compared to conventional two-dimensional (2D) culture, ADSCs seeded on the scaffold exhibit significantly improved viability and lipid accumulation. In vivo implantation in a rat model demonstrated that the COL-ADSCs composite scaffold increased subcutaneous fat thickness from 2.69 ± 0.10 mm to 3.37 ± 0.11 mm over four weeks, while also promoting collagen remodeling and angiogenesis, as confirmed by CD31-positive staining. Despite these promising outcomes, this study is limited to a small animal model, and further validation in large animal models and clinical settings is necessary. These findings indicate that the COL-ADSCs composite scaffold provides a biomimetic microenvironment that supports ADSC adhesion, differentiation, and tissue remodeling, highlighting its potential as a clinically applicable biomaterial for breast reconstruction.
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