Cells

29 pages, 813 KB

Open AccessReview

Extracellular Vesicles in Human Reproduction: Integrating Redox–Mitochondrial Signaling with Multi-Omics and AI-Driven Biomarker Discovery

by Sofoklis Stavros, Angeliki Gerede, Efthalia Moustakli, Athanasios Zikopoulos, Ioannis Tsakiridis, Christina Messini, Anastasios Potiris, Ismini Anagnostaki, Ioannis Arkoulis, Spyridon Topis, Themistoklis Dagklis and Dimitrios Loutradis

Cells 2026, 15(10), 955; https://doi.org/10.3390/cells15100955 - 21 May 2026

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Abstract

In the human reproductive system, extracellular vesicles (EVs) have been recognized as playing a vital role in mediating cell–cell communication. They are considered critical for embryo development, implantation, gamete interaction, and fertilization. The various cargoes carried by EVs, depending on the physiological and [...] Read more.

In the human reproductive system, extracellular vesicles (EVs) have been recognized as playing a vital role in mediating cell–cell communication. They are considered critical for embryo development, implantation, gamete interaction, and fertilization. The various cargoes carried by EVs, depending on the physiological and pathological state of the cell, include proteins, lipids, nucleic acids, and mitochondrial components. EVs are recognized as critical carriers of redox-related signals and mitochondrial components, linking oxidative stress (OS) to reproductive failure and influencing gamete quality and embryo competence. Although considerable progress has been made, research remains poorly integrated, despite individual omics technologies providing valuable molecular insights. The use of multi-omics technologies, including transcriptomics, proteomics, metabolomics, and microbiome analysis, has been proposed as a global approach to understanding the complexities associated with EVs and discovering new biomarkers associated with infertility. ML and AI have been proposed to identify predictive signatures linked to ART effectiveness and reproductive outcomes, with a strong capacity to handle high-dimensional data. The review aims to provide an overview of current knowledge on EV-mediated redox–mitochondrial signaling in human reproduction, while highlighting the importance of emerging multi-omics and AI technologies for EV-mediated biomarker development. The review discusses the promise of EVs in the development of minimally invasive diagnostic approaches and therapeutic interventions, as well as the challenges in the standardization, integration, and clinical translation of EV-mediated research. In addition, the review proposes integrating computational approaches to better understand molecular pathways involved in the development of next-generation precision medicine in human reproduction. Full article

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22 pages, 14622 KB

Open AccessArticle

The Trilineage Coexistence Observed During the Differentiation of Porcine EPSCs

by Lihua Zhao, Yanglin Chen, Xiyun Guo, Meng Zhou, Tianxu Guo, Junjun Ma, Manling Zhang, Linxin Cheng, Jinbo Yu, Yu Zhang, Guang Yang, Rongfeng Li and Xihe Li

Cells 2026, 15(10), 954; https://doi.org/10.3390/cells15100954 - 21 May 2026

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Abstract

The mammalian early embryo possesses totipotency and can be captured as extended pluripotent stem cells (EPSCs). The first two cell differentiations result in epiblast, primitive endoderm, and trophectoderm, with the trilineage coexisting in a unified uterine microenvironment. Nevertheless, the in vitro counterparts—primed PSCs, [...] Read more.

The mammalian early embryo possesses totipotency and can be captured as extended pluripotent stem cells (EPSCs). The first two cell differentiations result in epiblast, primitive endoderm, and trophectoderm, with the trilineage coexisting in a unified uterine microenvironment. Nevertheless, the in vitro counterparts—primed PSCs, trophoblast stem cells (TSCs), and extraembryonic endoderm (XEN) cells—require a distinct culture system. In this study, we successfully derived stable porcine EPSCs from fibroblasts at 35% efficiency, and interestingly observed that these EPSCs differentiated in parallel and gave rise to the transient coexistence (36–84 h) of trilineage cells when cultured in a single system (LCDM: hLIF, CHIR99021, DiM, and MiH). Then, XEN cells gradually predominated and eventually became the sole population in prolonged LCDM culture. However, TSCs and primed PSCs had to be differentiated from EPSCs under their respective culture system. EPSCs can differentiate into PGC-like cells independently of genetic modification and contribute to mouse neurula-stage embryos. Collectively, the trilineage coexistence phenomenon may provide novel insight into an early embryogenesis mechanism and strategy for porcine blastoid construction. Full article

(This article belongs to the Section Stem Cells)

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25 pages, 5611 KB

Open AccessArticle

Chemically Defined Medium Enables GDNF-Driven Early Neuronal-like Phenotype of Human Dental Pulp Stem Cells

by Maria-del-Carmen Silva-Lucero, Gustavo Lopez-Toledo, Víctor-Adrián Cortés-Morales, Juan-José Montesinos, Raúl Sampieri-Cabrera, David-E. García, Juan-Ramon Padilla-Mendoza, Obed-Ricardo Lora-Marin, Jesus-Adrian Buendia-Meraz, Fausto-Alejandro Jiménez-Orozco, Israel López-Reyes, Paul Mondragon-Teran and Maria-del-Carmen Cardenas-Aguayo

Cells 2026, 15(10), 953; https://doi.org/10.3390/cells15100953 - 21 May 2026

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Abstract

Background: Human dental pulp stem cells (hDPSCs) are a promising source of multipotent mesenchymal stem cells (MSCs) for regenerative neurology because of their inherent neurogenic potential. However, robust and reproducible protocols for driving their terminal neuronal maturation in a fully defined, xeno-free environment [...] Read more.

Background: Human dental pulp stem cells (hDPSCs) are a promising source of multipotent mesenchymal stem cells (MSCs) for regenerative neurology because of their inherent neurogenic potential. However, robust and reproducible protocols for driving their terminal neuronal maturation in a fully defined, xeno-free environment are lacking. Methods: hDPSCs were isolated from a donor tooth and characterized for mesenchymal (CD105, CD90, CD73, CD13) and stemness-associated markers (SOX2, Oct3/4 and Nanog). Cells were differentiated in a novel, fully chemically defined medium 1% ITS medium (ITS: Insulin, Transferrin, Selenium) supplemented with glial cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF). Neuronal commitment and partial maturation were assessed via immunofluorescence, Western blot, and RT-PCR for markers such as NeuN (Neuronal nuclei) and NF-M (Neurofilament medium chain), and functionally by whole-cell patch-clamp electrophysiology. Results: Although undifferentiated hDPSCs expressed neural progenitor markers (βIII-tubulin and Nestin), only GDNF treatment in a chemically defined medium significantly upregulated mature neuronal markers (NeuN and NF-M) and downregulated mesenchymal markers. Importantly, GDNF-treated cells exhibited key functional changes, including hyperpolarized resting membrane potentials, increased membrane capacitance, and elevated input resistance, which are electrophysiological hallmarks of neural precursor or early neuronal maturation, compared to control cells cultured in medium containing fetal bovine serum (FBS). Although action potentials were not elicited, this represents a significant advancement toward achieving a functional neuronal state. Conclusion: This study demonstrates that a fully chemically defined medium enables GDNF to drive hDPSCs beyond the neural progenitor state towards a partially mature neuronal phenotype. This defined medium protocol eliminates serum variability, enhances reproducibility, and provides a critical step towards standardizing hDPSC-derived neuronal cells for disease modeling and cell-based therapy. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Cell Therapy, Regenerative Medicine, and Tissue Engineering)

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18 pages, 15009 KB

Open AccessArticle

A Feedback Loop Driven by H3K18la and ASF1B via the LINC02732-miR-1291 Axis Promotes Hepatocellular Carcinoma Proliferation

by Jingya Yu, Lulu Xin, Ying Cui, Chunxin Fan, Yongheng Yang and Xiaolu Zhang

Cells 2026, 15(10), 952; https://doi.org/10.3390/cells15100952 - 21 May 2026

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Abstract

Histone lactylation acts as a master regulator in tumor development, but its role in a noncoding RNA (ncRNA) network remains unclear. This study aims to reveal the interaction between H3K18la and the lncRNA-miRNA-mRNA regulatory network in hepatocellular carcinoma (HCC). Transcriptome sequencing and ChIP [...] Read more.

Histone lactylation acts as a master regulator in tumor development, but its role in a noncoding RNA (ncRNA) network remains unclear. This study aims to reveal the interaction between H3K18la and the lncRNA-miRNA-mRNA regulatory network in hepatocellular carcinoma (HCC). Transcriptome sequencing and ChIP sequencing were performed in HCC and adjacent normal tissues. Cut&Run and qPCR were used to validate the H3K18la enrichment on LINC02732 and CD44 promoter. Dual luciferase reporter assay, qPCR and Western blotting were used to verify the LINC02732-miR-1291-ASF1B axis. Co-Immunoprecipitation was performed to validate ASF1B recruiting p300. CCK8 and mouse subcutaneous tumor formation were performed to demonstrate this axis promoting HCC. H3K18la enrichment on LINC02732 promoter elevates its expression in both HCC samples and cell lines, therefore enhancing ASF1B expression via sponging miR-1291. Moreover, ASF1B, a histone chaperone, promotes H3K18la by recruiting lactyltransferase p300, forming an ASF1B-H3K18la positive feedback loop. The axis upregulates CD44 expression and promotes HCC in vitro and in vivo. These findings demonstrated the influence of H3K18la on the LINC02732-miR-1291-ASF1B axis and the novel role of ASF1B in histone lactylation by recruiting p300, which together promoted HCC proliferation. Full article

(This article belongs to the Collection Targeting Signal Transduction Pathways and Non-coding RNAs as Potential Therapy in Cancer and Aging)

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31 pages, 804 KB

Open AccessReview

Is Recurrent Endometriosis a Reprogrammed Disease? Molecular Persistence Beyond Surgical Clearance

by Mario Palumbo, Luigi Della Corte, Maria Rotonda Conte, Giuseppe D’Angelo, Mario Ascione, Antonisia Pollio, Pierluigi Giampaolino and Giuseppe Bifulco

Cells 2026, 15(10), 951; https://doi.org/10.3390/cells15100951 - 21 May 2026

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Abstract

Background: Endometriosis is traditionally conceptualized as a localized gynecological disorder characterized by the presence of ectopic endometrial tissue. However, high recurrence rates following apparently complete surgical excision challenge this lesion-based paradigm and suggest the existence of underlying biological mechanisms that extend beyond residual [...] Read more.

Background: Endometriosis is traditionally conceptualized as a localized gynecological disorder characterized by the presence of ectopic endometrial tissue. However, high recurrence rates following apparently complete surgical excision challenge this lesion-based paradigm and suggest the existence of underlying biological mechanisms that extend beyond residual disease. Increasing evidence indicates that endometriotic cells exhibit persistent molecular alterations, including dysregulated gene expression, epigenetic modifications, and immune dysfunction, which may contribute to disease maintenance and recurrence. Objective: This study aims to critically examine whether endometriosis can be considered a molecularly reprogrammed disease, characterized by persistent cellular and microenvironmental alterations that are not reversed by surgical removal of visible lesions. Methods: A narrative review of the literature was conducted using PubMed, Scopus, and Web of Science databases including studies published from January 2016 to March 2026. Studies investigating molecular, genetic, epigenetic, and immunological mechanisms of endometriosis persistence and recurrence were included. Particular attention was given to pathways involved in cellular survival, inflammation, hormone resistance, and epigenetic regulation. Results: Endometriotic cells demonstrate stable alterations in gene expression profiles, including pathways related to estrogen signaling, progesterone resistance, inflammation, and cellular proliferation. Epigenetic mechanisms, such as aberrant DNA methylation and histone modifications, appear to sustain these changes over time, contributing to a form of “molecular memory.” In parallel, the peritoneal microenvironment is characterized by chronic inflammation, immune tolerance, and impaired clearance of ectopic cells. These factors collectively support lesion persistence and may explain recurrence even after complete surgical excision. Emerging evidence also highlights the role of systemic factors, including endocrine–immune interactions and microbiome-related pathways, reinforcing the concept of endometriosis as a systemic rather than purely localized condition. Conclusions: Endometriosis may be more accurately defined as a persistent, molecularly reprogrammed disease driven by stable alterations in cellular behavior and the surrounding microenvironment. This paradigm shift has important clinical implications, suggesting that surgical treatment alone may be insufficient and that future therapeutic strategies should target the underlying molecular and immunological mechanisms responsible for disease persistence. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Reproductive Biology and Fertility)

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21 pages, 3037 KB

Open AccessArticle

Dual Pathways Coupled to Oxytocin Molecular Signals in Cultured Astrocytes

by Elisa Farsetti, Sarah Amato, Monica Averna, Elena Gatta, Diego Guidolin, Marco Pedrazzi, Laura Lori, Matilde Gnecco, Guido Maura, Luigi F. Agnati, Manuela Marcoli and Chiara Cervetto

Cells 2026, 15(10), 950; https://doi.org/10.3390/cells15100950 - 21 May 2026

Viewed by 372

Abstract

Oxytocin’s capacity to affect the glial cell functions is increasingly recognized. We previously reported that oxytocin could cause both excitation and inhibition of Ca²⁺ signals and glutamate release in the processes of adult rodent astrocytes. Our purpose here was to investigate oxytocin [...] Read more.

Oxytocin’s capacity to affect the glial cell functions is increasingly recognized. We previously reported that oxytocin could cause both excitation and inhibition of Ca²⁺ signals and glutamate release in the processes of adult rodent astrocytes. Our purpose here was to investigate oxytocin receptor expression and oxytocin effects in astrocytes. In primary cortical astrocytes, we assessed the presence of oxytocin receptors by confocal imaging, and the effects of oxytocin receptor activation on intracellular Ca²⁺ signals and glutamate release. We found that oxytocin receptors are expressed in both the soma and processes of astrocytes; oxytocin at nanomolar concentrations could induce dual responses in astrocytes, namely facilitation and inhibition of Ca²⁺ signals and glutamate release; the oxytocin facilitatory and inhibitory effects were duplicated by the biased agonists carbetocin and atosiban, respectively; and the facilitatory and the inhibitory effect were dependent on activation of a G_q and a G_i pathway, respectively. It is concluded that oxytocin effects in astrocytes could duplicate the effects in processes prepared from astrocytes matured in neuron-astrocyte networks, substantiating the use of astrocytes to study astrocytic oxytocin molecular signaling. Full article

(This article belongs to the Special Issue Emerging Roles of Glial Cells in the Nervous System)

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20 pages, 6030 KB

Open AccessArticle

APN Inhibitor Bestatin Induces MM Cell Differentiation Through the CD79B/BTK/STAT3 Pathway

by Xiaoke Wang, Chunyan Fang, Shanyu Li, Huakai Zeng, Junyi Liu, Xinwei Duan, Xiaoyi Zhang, Wenyan Jiang and Xuejian Wang

Cells 2026, 15(10), 949; https://doi.org/10.3390/cells15100949 - 21 May 2026

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Abstract

Differentiation therapy holds significant potential for the treatment of multiple myeloma (MM). We previously identified that the aminopeptidase N (APN) inhibitor Bestatin promotes MM cell differentiation. Herein, we elucidate the underlying molecular mechanisms of this process. Utilizing MM1.S, U266, and RPMI-8226 cell lines, [...] Read more.

Differentiation therapy holds significant potential for the treatment of multiple myeloma (MM). We previously identified that the aminopeptidase N (APN) inhibitor Bestatin promotes MM cell differentiation. Herein, we elucidate the underlying molecular mechanisms of this process. Utilizing MM1.S, U266, and RPMI-8226 cell lines, a combination of CCK-8 assays, flow cytometry, Wright–Giemsa staining, Western blotting, qRT-PCR, ELISA, APN enzymatic activity analysis, SA-β-gal staining, and bioinformatic analyses revealed elevated APN expression across all cell types. Bestatin treatment induced MM cell differentiation in a concentration-dependent manner, which was accompanied by the upregulation of the differentiation marker CD49e, increased immunoglobulin light chain secretion, elevated cellular senescence, and a concomitant suppression of cell proliferation and APN enzymatic activity. Mechanistically, Bestatin exerts its effects by downregulating the CD79B/BTK signaling pathway, thereby activating the downstream transcription factor STAT3. Consistent with this axis, direct inhibition of CD79B/BTK alone was sufficient to induce differentiation, while blockade of STAT3 completely abrogated the differentiation-promoting effect of Bestatin. The APN-neutralizing antibody (WM15) yielded consistent results with Bestatin, further validating this regulatory axis. Furthermore, both the CD79B/BTK inhibitor Ibrutinib and the STAT3 agonist GCDA potentiated the cytotoxicity of the clinical MM drug Ixazomib. Bestatin itself synergized with Ixazomib and enhanced the anti-proliferative effect of IL-6. In summary, our findings establish that the APN inhibitor Bestatin induces MM cell differentiation via the CD79B/BTK-STAT3 signaling axis. Targeting this pathway represents a promising strategy to enhance the efficacy of Ixazomib, providing a compelling rationale for novel combination therapies in MM. Full article

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13 pages, 2117 KB

Open AccessArticle

Increased Osteoclast Activity Contributes to Bone Resorption and Osteopenia in a Rett Syndrome Mouse Model

by Nadeem Samee, Lou Belz, Nicolas Narboux-Nême, Jean-Christophe Roux, Nicolas Panayotis and Giovanni Levi

Cells 2026, 15(10), 948; https://doi.org/10.3390/cells15100948 - 21 May 2026

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Abstract

Rett syndrome is a severe neurodevelopmental disorder caused predominantly by loss-of-function mutations in the X-linked gene MECP2. In addition to a vast array of neurological and physiological impairments, patients also frequently develop severe osteopenia with increased fracture risk; however, the mechanisms underlying [...] Read more.

Rett syndrome is a severe neurodevelopmental disorder caused predominantly by loss-of-function mutations in the X-linked gene MECP2. In addition to a vast array of neurological and physiological impairments, patients also frequently develop severe osteopenia with increased fracture risk; however, the mechanisms underlying these skeletal defects are not completely understood. Previous work in Mecp2-null mouse models has suggested that osteopenia is mainly due to impaired osteoblast function and reduced bone formation. Here, we examined bone mass, microarchitecture, and remodeling parameters in a Mecp2-null mouse model during postnatal development, with a particular focus on osteoclast involvement. Microcomputed tomography and histomorphometric analyses showed reduced bone mineral density and trabecular bone volume, which are associated with increased trabecular separation and cortical thinning. These structural alterations were accompanied by increased osteoclast number per bone surface, elevated urinary deoxypyridinoline, and higher expression of osteoclast-associated genes, including Cathepsin K. Furthermore, gene expression analysis revealed an age-dependent shift in bone remodeling. At postnatal day 35, mutant mice showed reduced expression of Dlx5 and Dlx6, consistent with low bone turnover. By postnatal day 55, Rankl and Cathepsin K were markedly upregulated, suggesting an increase in osteoclast resorptive activity, while key osteoblast markers and the RANKL/OPG ratio did not change significantly. A potential cell-autonomous contribution of Mecp2 to osteoclast maturation is also suggested by the analysis of public transcriptomic datasets on human osteoclast differentiation. Together, our findings identify increased osteoclast activity as a significant contributor to Rett-associated osteopenia and suggest that skeletal pathology in Mecp2 deficiency progresses from an early low-turnover state to a later phase of increased osteoclast resorption. Full article

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20 pages, 16752 KB

Open AccessArticle

The Use of Single-Cell Mitochondrial DNA SNP Combinations for Distinguishing Organ-Specific Cell Types

by Shuai Wang, Xinyue Tu, Haozhe Zhu, Ce Gao, Jianan Gao, Jinsong Wei, Hui Shi and Jinrong Peng

Cells 2026, 15(10), 947; https://doi.org/10.3390/cells15100947 - 21 May 2026

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Abstract

Cell lineage relationship studies in developmental and regenerative biology have been greatly advanced using techniques such as fluorescent labeling driven by cell-type-specific promoters. Nevertheless, unbiased non-invasive tools for distinguishing cell lineages are inevitably desired. Mitochondrial DNA (mtDNA) exhibits wide-range single-nucleotide polymorphisms (SNPs) among [...] Read more.

Cell lineage relationship studies in developmental and regenerative biology have been greatly advanced using techniques such as fluorescent labeling driven by cell-type-specific promoters. Nevertheless, unbiased non-invasive tools for distinguishing cell lineages are inevitably desired. Mitochondrial DNA (mtDNA) exhibits wide-range single-nucleotide polymorphisms (SNPs) among individual cells. Here, we aim to distinguish cell types in organs/tissues of the same individual and in the regenerated liver based on the use of mtDNA SNPs. For this, two approaches—“Mitochondrial Alteration Enrichment and Sequencing” (MAESTER) and “mitochondrial single-cell assay for transposase-accessible chromatin with sequencing” (mtscATAC-seq)—were adopted to facilitate the detection of mtDNA SNPs in single cells. With MAESTER, we show that specific cell types in the liver and spleen of the same individual can be successfully defined using collective individual-specific markers composed of panels of unique mtDNA SNP combinations. For its application, we performed partial hepatectomy (PH) on a Krt19:Dre^ERT2/+;R26:Rox-ZsGreen-Stop-Rox-tdTomato/+ mouse harboring tdTomato-labeled cholangiocytes following tamoxifen injection and demonstrated that utilizing panels of unique mtDNA SNP combinations detected by mtscATAC-seq in the pre-PH cholangiocytes as markers can faithfully trace the cell fate in the post-PH liver samples. Hence, this approach may serve as an unbiased tool for investigating cell lineage relationships in relevant research areas such as liver regeneration. Full article

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19 pages, 1084 KB

Open AccessReview

Influence of Donor Obesity on Adipose-Derived Stem Cell Function and Therapeutic Efficacy

by Marva Khalid, Marvin L. Frommer, Jeries Abu-Hanna, Benjamin J. Langridge, Clara Calero Pages, Laura Awad and Peter E. M. Butler

Cells 2026, 15(10), 946; https://doi.org/10.3390/cells15100946 - 21 May 2026

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Abstract

Adipose-derived stem cells (ADSCs) are widely used in regenerative medicine and are considered key effectors underlying the therapeutic efficacy of autologous fat grafting for scarring and skin fibrosis, yet clinical outcomes remain variable. This review examines how obesity alters the adipose microenvironment through [...] Read more.

Adipose-derived stem cells (ADSCs) are widely used in regenerative medicine and are considered key effectors underlying the therapeutic efficacy of autologous fat grafting for scarring and skin fibrosis, yet clinical outcomes remain variable. This review examines how obesity alters the adipose microenvironment through chronic inflammation and metabolic dysfunction, resulting in epigenetic changes, mitochondrial impairment, oxidative stress, and premature cellular senescence in ADSCs. ADSCs from obese individuals exhibit reduced stemness, impaired differentiation, and a pro-inflammatory secretome with diminished regenerative capacity. While weight loss may partially reverse these effects, persistent epigenetic and functional memory limits full recovery. This review argues that donor metabolic status is a determinant of ADSC therapeutic potency and discusses key challenges and opportunities for improving regenerative outcomes. Full article

(This article belongs to the Special Issue Stem Cells in Action: Unlocking the Potential of Next-Generation Therapies)

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18 pages, 2079 KB

Open AccessArticle

The Impact of Surgical Trauma-Activated Platelet-Rich Fibrin on Mesenchymal Stromal Cells In Vitro

by René D. Verboket, Lea Usov, Isabell Bohl, Jonas Neijhoft, Marissa Penna-Martinez, Ingo Marzi and Dirk Henrich

Cells 2026, 15(10), 945; https://doi.org/10.3390/cells15100945 - 21 May 2026

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Abstract

Introduction: platelet-rich fibrin (PRF) is a second-generation platelet concentrate which is known for promoting cell migration, tissue repair, angiogenesis and bone formation. In contrast, the specific effects of trauma-activated PRF on mesenchymal stromal cells (MSC) are not yet fully understood. The present study [...] Read more.

Introduction: platelet-rich fibrin (PRF) is a second-generation platelet concentrate which is known for promoting cell migration, tissue repair, angiogenesis and bone formation. In contrast, the specific effects of trauma-activated PRF on mesenchymal stromal cells (MSC) are not yet fully understood. The present study investigates systemic effects of surgical trauma-activated PRF on MSCs in vitro, analyzing their metabolic activity, inflammatory responses, and regenerative capacity to optimize advanced treatment concepts for severe fractures and injuries. Material & Methods: PRF membranes (T-PRF from trauma patients, C-PRF from healthy controls) were generated. After co-incubation with MSC cells for 24, 72, and 120 h, further investigations of metabolic activity (MTT assay) and gene expression analyses were performed. Results: for MTT assay, results especially showed a significantly higher metabolic activity of T-PRF after 120 h. ELISA-results measuring cytokine levels (CXCL10, IL-6, VEGF, and IDO) exposed a frequent peak in T-PRF group at 72 h, declining slightly at 120 h. In the gene expression analyses, T-PRF exerted a comparatively stronger stimulating effect on MAPK14 and VEGFA after 24 h, while a decrease in gene expression for MAPK8, MAPK14, and RUNX2 was observed over time. Conclusion: surgical trauma-activated PRF seems to be a powerful inducer of early inflammatory and stress responses in MSCs with preserved angiogenic but limited osteogenic signaling. Therefore, a targeted balance between inflammatory activation and sustainable regeneration, as well as optimized preparation and possible combination with immunomodulatory approaches, appear to be crucial for the therapeutic success of PRF-based strategies. Full article

(This article belongs to the Special Issue The Challenges and Opportunities of Mesenchymal Stromal Cells in Regenerative Medicine)

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16 pages, 9732 KB

Open AccessArticle

Cryopreserved Mucosal Olfactory Ensheathing Cells Promote Functional Recovery After Dorsal Root Injury

by Kamile Minkelyte, Daqing Li, Ying Li and Ahmed Ibrahim

Cells 2026, 15(10), 944; https://doi.org/10.3390/cells15100944 - 20 May 2026

Viewed by 245

Abstract

Olfactory ensheathing cell (OEC) transplantation has been widely shown to support axonal regeneration, remyelination, and functional recovery after central nervous system injury; however, autologous approaches are limited by low cell yields from patient biopsies, which may be insufficient for large spinal cord lesions. [...] Read more.

Olfactory ensheathing cell (OEC) transplantation has been widely shown to support axonal regeneration, remyelination, and functional recovery after central nervous system injury; however, autologous approaches are limited by low cell yields from patient biopsies, which may be insufficient for large spinal cord lesions. This study evaluated whether cryopreservation could provide a scalable alternative by preserving the therapeutic potential of mucosa-derived OECs. Using a rat dorsal root injury model, cryopreserved mucosa-derived OECs (CmOECs) were thawed and assessed for viability, phenotype, and efficacy following transplantation. Although total viable cell yield was reduced compared with primary cultures, the relative proportion of OECs remained stable, and cells retained characteristic morphology and marker expression in vitro. In vivo, transplantation of CmOECs resulted in significant functional recovery in climbing and forepaw fault tasks compared with injured controls, with outcomes comparable to primary mucosal OEC transplantation. Immunohistochemical analysis confirmed the survival and integration of transplanted cells at the dorsal root entry zone, alongside evidence of axonal regeneration and astrocytic remodeling. These findings demonstrate that mucosa-derived OECs retain therapeutic efficacy following cryopreservation and support the development of standardized OEC biobanks as a scalable strategy for spinal cord repair. Full article

(This article belongs to the Collection Cell Biology of Spinal Cord Injury and Repair)

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21 pages, 1537 KB

Open AccessReview

Dual Roles of m⁶A Modification: Orchestrating Development and Abiotic Stress Resilience in Plants

by Yang Sun, Wen Qin, Yiting Gong, Yinqiao Jian, Fangling Jiang, Rosa M. Rivero, Ron Mittler, Zhen Wu and Rong Zhou

Cells 2026, 15(10), 943; https://doi.org/10.3390/cells15100943 - 20 May 2026

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Abstract

RNA N⁶-methyladenosine (m⁶A) is a prevalent epitranscriptomic modification that governs plant growth, development, and environmental adaptation. This review synthesizes recent advances in understanding the molecular mechanisms and biological functions of m⁶A in plants. The m⁶A [...] Read more.

RNA N⁶-methyladenosine (m⁶A) is a prevalent epitranscriptomic modification that governs plant growth, development, and environmental adaptation. This review synthesizes recent advances in understanding the molecular mechanisms and biological functions of m⁶A in plants. The m⁶A landscape is dynamically regulated by methyltransferases (writers), demethylases (erasers), and m⁶A-binding proteins (readers), which collectively influence mRNA stability, translation efficiency, alternative polyadenylation (APA), and chromatin crosstalk. Functionally, m⁶A integrates diverse developmental processes—including embryogenesis, organogenesis, flowering, fruit ripening, and leaf senescence—with abiotic stress responses such as salt, drought, cold, and heat. Notably, m⁶A modification exhibits remarkable species-, cultivar-, and tissue-specific plasticity, enabling precise spatiotemporal gene regulation. Recent breakthroughs have revealed bidirectional crosstalk between m⁶A and histone modifications, forming a multi-layered regulatory network, while emerging concepts including phase separation, RNA structure dynamics, and stress memory further expand the functional repertoire of m⁶A. Despite significant progress, plant epitranscriptomics remains mechanistically underexplored, with critical gaps persisting in our understanding of translation initiation mechanisms, upstream regulatory signals controlling writers/erasers activities, and the functional significance of individual m⁶A sites. This review provided systematic insights into the complexity and specificity of m⁶A regulation in plants, offering a theoretical foundation for future efforts to decipher and ultimately manipulate this epitranscriptional layer for crop improvement. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Abiotic Stress Tolerance in Plants)

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18 pages, 2193 KB

Open AccessArticle

Disruption of Fructose 1,6-Bisphosphatase 2 Proximity to MIC60 Correlates with Mitochondrial Ultrastructural Changes

by Łukasz Pietras, Marta Migocka-Patrzałek, Bartosz Budziak, Dariusz Rakus and Agnieszka Gizak

Cells 2026, 15(10), 942; https://doi.org/10.3390/cells15100942 - 20 May 2026

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Abstract

Fructose 1,6-bisphosphatase 2 (FBP2) is a multifunctional protein whose cellular functions depend on its oligomeric state. Forced FBP2 tetramerization has been linked to microtubule disruption and impaired mitochondrial trafficking, accompanied by abnormal mitochondrial morphology. Here, we identify MIC60 (mitofilin), a core element of [...] Read more.

Fructose 1,6-bisphosphatase 2 (FBP2) is a multifunctional protein whose cellular functions depend on its oligomeric state. Forced FBP2 tetramerization has been linked to microtubule disruption and impaired mitochondrial trafficking, accompanied by abnormal mitochondrial morphology. Here, we identify MIC60 (mitofilin), a core element of the mitochondrial contact site and cristae organizing system (MICOS), as a potential mediator of these effects. Using proximity ligation assay, protein crosslinking combined with mass spectrometry, and ultrastructural analysis, we demonstrate that FBP2 is in close proximity to MIC60 under basal conditions and this proximity is reduced upon FBP2 tetramerization or partial FBP2 depletion. Loss of this proximity coincides with marked remodeling of inner-membrane ultrastructure. These findings are consistent with a working model in which dimeric FBP2 contributes to the coordination of microtubule-dependent mitochondrial positioning with MICOS-linked intramitochondrial organization, providing a plausible mechanistic bridge between metabolic cues (AMP/NAD⁺) and mitochondrial structural integrity. Full article

(This article belongs to the Section Mitochondria)

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17 pages, 2421 KB

Open AccessReview

Plasminogen Activator Inhibitor-1 as a Therapeutic Target for Healthy Longevity, Immunosenescence, and Age-Related Disease: Translational Development of the Small-Molecule Inhibitor TM5614

by Mohamed Abdelhakim and Toshio Miyata

Cells 2026, 15(10), 941; https://doi.org/10.3390/cells15100941 - 20 May 2026

Viewed by 666

Abstract

Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, is the principal physiological inhibitor of tissue-type and urokinase-type plasminogen activators and a central regulator of fibrinolysis. Beyond its canonical hemostatic role, PAI-1 has emerged as a pleiotropic mediator of tissue remodeling, fibrosis, metabolic dysfunction, cancer [...] Read more.

Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, is the principal physiological inhibitor of tissue-type and urokinase-type plasminogen activators and a central regulator of fibrinolysis. Beyond its canonical hemostatic role, PAI-1 has emerged as a pleiotropic mediator of tissue remodeling, fibrosis, metabolic dysfunction, cancer progression, cellular senescence, and age-associated immune dysregulation. A central argument of this review is that PAI-1 should be understood not only as a downstream biomarker of aging-associated pathology, but also as an active effector linking senescence-associated secretory phenotype (SASP) signaling, chronic low-grade inflammation, impaired immune surveillance, fibrotic extracellular matrix remodeling, and a prothrombotic state. In this framework, PAI-1 may function as an immune-aging checkpoint: a molecular node through which senescent, stromal, malignant, and inflammatory cells reinforce immune evasion and tissue dysfunction. Structure-guided drug discovery has enabled the development of small-molecule PAI-1 inhibitors, including TM5275, TM5441, TM5509, and TM5614. Among these, TM5614 is an orally available investigational compound that has progressed to clinical evaluation. Preclinical studies support anti-thrombotic, anti-fibrotic, anti-inflammatory, anti-senescent, and tumor-microenvironment-modulating effects of PAI-1 inhibition, while early clinical studies have evaluated TM5614 in chronic myeloid leukemia, immune-checkpoint-refractory malignant melanoma, non-small-cell lung cancer, and COVID-19-associated pneumonia. This review summarizes the biology of PAI-1, expands the discussion of immunoaging, reviews representative preclinical and clinical data, compares available PAI-1 inhibitors, and discusses the translational opportunities and safety considerations for TM5614 and related compounds. Full article

(This article belongs to the Special Issue Targeting of Cancer Cells with Small Molecule Drugs)

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22 pages, 1985 KB

Open AccessReview

PPARα: Linking Cardiac Metabolism to Therapeutic Opportunities in Cardiovascular Diseases

by Maxime Roes, Claude Libert and Jolien Vandewalle

Cells 2026, 15(10), 940; https://doi.org/10.3390/cells15100940 - 20 May 2026

Viewed by 573

Abstract

Peroxisome proliferator-activated receptor alpha (PPARα) is a key transcriptional regulator of lipid metabolism, highly expressed in metabolically active organs such as the heart. In cardiomyocytes, where approximately 70% of energy is derived from fatty acid oxidation, PPARα plays a central role in maintaining [...] Read more.

Peroxisome proliferator-activated receptor alpha (PPARα) is a key transcriptional regulator of lipid metabolism, highly expressed in metabolically active organs such as the heart. In cardiomyocytes, where approximately 70% of energy is derived from fatty acid oxidation, PPARα plays a central role in maintaining metabolic homeostasis. Moreover, the transcription factor is implicated in postnatal maturation of the heart and immune modulation. Dysregulation of PPARα signaling has profound consequences for cardiac energy balance, particularly under stress conditions. Accordingly, its role has been extensively investigated in cardiovascular diseases, including ischemia/reperfusion, diabetic cardiomyopathy and sepsis-induced cardiomyopathy. Upon ischemia/reperfusion and sepsis, cardiac PPARα expression is typically downregulated, contributing to impaired fatty acid breakdown and reduced metabolic flexibility. In contrast, diabetic cardiomyopathy is characterized by sustained PPARα activation, promoting excessive fatty acid oxidation, lipid accumulation and lipotoxicity. These context-dependent effects highlight a complex role of PPARα in cardiac diseases. PPARα has emerged as a promising therapeutic target, as its modulation can alleviate cardiac injury in preclinical models. However, further research is required to validate its efficacy in human disease, improve cardiomyocyte-specific targeting strategies to minimize systemic side effects, and better define optimal timing of intervention, as inappropriate or prolonged modulation may lead to detrimental outcomes. Full article

(This article belongs to the Special Issue The Role of PPARs in Disease - Volume IV)

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26 pages, 850 KB

Open AccessReview

The Journey of Gene Therapy in Sickle Cell Disease: How Molecular Advances Meet Clinical Care

by Magalie Tardif, Manon Saby, Stéphanie Forté and Thomas Pincez

Cells 2026, 15(10), 939; https://doi.org/10.3390/cells15100939 - 20 May 2026

Viewed by 641

Abstract

Sickle cell disease (SCD) is a monogenic disorder responsible for recurrent vaso-occlusive crises, progressive organ damage, and shortened life expectancy. For decades, allogeneic hematopoietic stem cell transplantation from a matched sibling donor has been the only established cure, but its reach remains limited [...] Read more.

Sickle cell disease (SCD) is a monogenic disorder responsible for recurrent vaso-occlusive crises, progressive organ damage, and shortened life expectancy. For decades, allogeneic hematopoietic stem cell transplantation from a matched sibling donor has been the only established cure, but its reach remains limited by donor availability and transplant-related toxicity. The approval of two autologous gene therapy products in 2023, exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel), marked a turning point for the SCD population and the gene therapy field in general. This review proposes a molecular rationale for fetal hemoglobin reactivation and β-globin gene addition, describes the engineering of lentiviral and CRISPR-based platforms, and highlights the clinical evidence accumulated to date that demonstrated durable disease modification with acceptable short-term toxicity. We then assess the clinical positioning of gene therapy within the broader spectrum of curative options compared to current available treatments and address the financial, ethical and psychosocial barriers that limit access to gene therapy both within high-income countries and globally. Critical research priorities include long-term safety surveillance, comparative effectiveness studies, pediatric trials below 12 years, and validated patient-reported outcome instruments. Base editing, non-genotoxic conditioning, and in vivo delivery represent the most promising avenues to broaden access and reduce treatment burden. Full article

(This article belongs to the Special Issue Gene Editing Therapies for Hereditary Diseases)

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17 pages, 12568 KB

Open AccessArticle

Costunolide, a Sesquiterpene Lactone, Protects Against Platelet Activation and Thrombus Formation

by Joen-Rong Sheu, Kuan-Hung Lin, Ray-Jade Chen, Hao-Ping Chia, Ting-Yu Chen, Thanasekaran Jayakumar, Hsueh-Hsiao Wang, Hsien-Yu Peng, Jiun-Yi Li and Wan-Jung Lu

Cells 2026, 15(10), 938; https://doi.org/10.3390/cells15100938 - 20 May 2026

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Abstract

Background/Objectives: Circulating platelets mediate physiological hemostasis and are implicated in pathological thrombosis, which can cause vascular occlusion, leading to heart attacks or strokes. Costunolide is a sesquiterpene lactone extracted from Saussurea lappa. Although this lactone has multiple biological effects, including anti-inflammatory [...] Read more.

Background/Objectives: Circulating platelets mediate physiological hemostasis and are implicated in pathological thrombosis, which can cause vascular occlusion, leading to heart attacks or strokes. Costunolide is a sesquiterpene lactone extracted from Saussurea lappa. Although this lactone has multiple biological effects, including anti-inflammatory and antioxidant effects, that help slow the progression of atherosclerosis, its influence on platelet activation remains unclear. In this study, we examined the potential antiplatelet and antithrombotic effects of costunolide. Methods: We used platelet aggregation, flow cytometry, and Western blot analysis to examine its in vitro antiplatelet effects. Results: Our results indicated that costunolide inhibited platelet aggregation induced by collagen, but not by thrombin or the thromboxane A₂ analog U46619, suggesting that costunolide selectively inhibits collagen-induced platelet activation. Additionally, costunolide blocked collagen-mediated granule release, calcium mobilization, and glycoprotein IIb/IIIa (GPIIb/IIIa) activation. Costunolide also inhibited phospholipase Cγ2 (PLCγ2), pleckstrin (a downstream target of protein kinase C), Akt, and mitogen-activated protein kinase. Moreover, it prevented collagen/epinephrine-induced pulmonary thrombosis and increased the survival rate of mice. Furthermore, costunolide delayed thrombus formation in the mesenteric vessels while it did not significantly affect hemostasis, suggesting it exhibits antithrombotic activity without bleeding tendency. These findings indicate that costunolide can block PLCγ2-PKC, Akt, and MAPK signaling pathways and subsequent granule release, calcium mobilization, and GPIIb/IIIa activation, eventually impeding platelet activation, platelet aggregation, and thrombus formation. Conclusions: In conclusion, besides its multiple biological activities that are beneficial for slowing the progression of atherosclerosis, we also demonstrated the antiplatelet and antithrombotic activities of costunolide. These effects highlight the therapeutic potential of costunolide in the treatment of patients with cardiovascular disease, particularly stroke and heart attack. Full article

(This article belongs to the Section Cells of the Cardiovascular System)

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14 pages, 1288 KB

Open AccessReview

The Interplay Between Antioxidant and Chaperone Functions of α-Crystallin

by Krishna Sharma, Puttur Santhoshkumar and Tenzin Tender

Cells 2026, 15(10), 937; https://doi.org/10.3390/cells15100937 - 20 May 2026

Viewed by 444

Abstract

α-Crystallin, the predominant protein of the eye lens, possesses molecular chaperone activity and antioxidative properties, both of which are essential for maintaining lens transparency. Its chaperone function prevents the formation of light-scattering protein aggregates, while its antioxidative activity mitigates oxidative stress through both [...] Read more.

α-Crystallin, the predominant protein of the eye lens, possesses molecular chaperone activity and antioxidative properties, both of which are essential for maintaining lens transparency. Its chaperone function prevents the formation of light-scattering protein aggregates, while its antioxidative activity mitigates oxidative stress through both direct and indirect mechanisms. However, with aging, α-crystallin undergoes cumulative post-translational modifications and oxidative damage, leading to protein crosslinking and a decline in chaperone efficacy. Notably, α-crystallin exhibits free radical-scavenging activity comparable to that of serum albumin, a well-characterized antioxidant protein. In addition, its ability to bind redox-active metal ions and convert them into redox-inactive forms significantly reduces reactive oxygen species (ROS) generation in vivo. α-Crystallin also interacts with key proteins and signaling pathways involved in oxidative stress responses, further enhancing its multifunctional protective role. This review summarizes current evidence on the antioxidative properties of α-crystallin and their relationship to its chaperone function, highlighting its importance in lens homeostasis and age-related cataract formation. Full article

(This article belongs to the Special Issue Aging, Oxidative Stress, and Inflammation in Ocular Diseases)

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30 pages, 1817 KB

Open AccessReview

Structural and Signaling Mechanisms of Aortic Wall Failure in Heritable Thoracic Aortic Disease

by Norifumi Takeda, Hiroki Yagi, Takayuki Fujiwara, Hitomi Aono-Setoguchi, Ryo Inuzuka and Issei Komuro

Cells 2026, 15(10), 936; https://doi.org/10.3390/cells15100936 - 19 May 2026

Viewed by 530

Abstract

Heritable thoracic aortic diseases (HTAD) are inherited conditions that increase the risk of thoracic aortic aneurysms, dissections, and premature aortic rupture. Advances in human genetics and experimental models have transformed our understanding of these disorders from a phenotype-based classification system to a mechanism-based [...] Read more.

Heritable thoracic aortic diseases (HTAD) are inherited conditions that increase the risk of thoracic aortic aneurysms, dissections, and premature aortic rupture. Advances in human genetics and experimental models have transformed our understanding of these disorders from a phenotype-based classification system to a mechanism-based view involving extracellular matrix (ECM) architecture, transforming growth factor-β (TGFβ) signaling, and vascular smooth muscle cell contractility. Marfan syndrome, Loeys–Dietz syndrome, and nonsyndromic HTAD demonstrate how genetic mutations can disrupt the components that stabilize the aortic wall. These pathogenic mechanisms influence matrix organization, intracellular signaling, and the contractile machinery within the mechanically stressed proximal aorta. In this review, we summarize current mechanistic insights into the major forms of HTAD and discuss how new molecular and cellular concepts could influence surveillance, genetic counseling, and genotype-guided therapeutic strategies. Full article

(This article belongs to the Special Issue Vascular Biology: From Molecular Mechanisms to Precision Therapies)

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32 pages, 5466 KB

Open AccessReview

Plant-Derived Bioactive Ingredients for Osteoporosis and Bone Regeneration: Mechanisms, Pharmacology, and Delivery Strategies

by Changshun Li, Xin Zhang, Peiyu Tang, Mengying Li, Weijian Hu, Meng Zhou and Jiabin Xu

Cells 2026, 15(10), 935; https://doi.org/10.3390/cells15100935 - 19 May 2026

Viewed by 804

Abstract

Icariin (ICA), a prenylated flavonoid glycoside from Epimedium (Yin Yang Huo), exhibits multi-organ pharmacological effects and has emerged as a promising candidate for osteoporosis therapy and bone tissue regeneration because of its capacity to modulate diverse osteogenic, anti-inflammatory, and angiogenic signaling pathways. Preclinical [...] Read more.

Icariin (ICA), a prenylated flavonoid glycoside from Epimedium (Yin Yang Huo), exhibits multi-organ pharmacological effects and has emerged as a promising candidate for osteoporosis therapy and bone tissue regeneration because of its capacity to modulate diverse osteogenic, anti-inflammatory, and angiogenic signaling pathways. Preclinical studies in osteoporotic models suggest that ICA improves trabecular microarchitecture and increases bone mineral density. Mechanistically, ICA modulates bone remodeling bidirectionally: it promotes osteoblast differentiation and extracellular matrix mineralization via activation of pro-osteogenic pathways, including Wnt/β-catenin and PI3K/Akt signaling, while simultaneously inhibiting osteoclastogenesis and bone resorption by suppressing RANKL-mediated NF-κB activation, thus reestablishing remodeling equilibrium. Despite these benefits, clinical advancement is hindered by the suboptimal oral bioavailability of ICA, stemming from poor intestinal absorption and extensive first-pass metabolism. To address this, innovative delivery systems have been engineered to enhance localized bioavailability and sustain therapeutic efficacy, such as hydrogel depots, nanoparticle formulations, and 3D-printed scaffolds enabling precise, controlled release. In bone tissue engineering applications, ICA-incorporated biomaterials—either standalone or in combination with osteogenic factors or exosomes—foster a regenerative niche by mitigating inflammation and oxidative stress, while synergistically promoting osteogenesis and angiogenesis, thereby expediting bone defect healing and osseointegration. Overall, these mechanistic elucidations and delivery advancements underscore ICA’s potential as a translational candidate for osteoporosis treatment and bone regenerative therapies. This review aims to critically and systematically synthesize current evidence on ICA-mediated bone repair and regeneration, with a particular emphasis on the molecular regulation of osteogenic signaling, the restoration of bone-remodeling homeostasis, and delivery-system-enabled strategies that may facilitate translational application. Full article

(This article belongs to the Special Issue Natural Products and Their Derivatives Against Human Disease)

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13 pages, 1963 KB

Open AccessArticle

Exosomes Released by Cerebrolysin-Treated Cerebral Endothelial Cells Reverse Fibrin- or tPA-Impaired Endothelial Cell Permeability

by Hua Teng, Chao Li, Mingjin Wang, Jing Zhang, Yi Zhang, Michael Chopp and Zheng Gang Zhang

Cells 2026, 15(10), 934; https://doi.org/10.3390/cells15100934 - 19 May 2026

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Abstract

Cerebrolysin has a salutary effect on impaired cerebral endothelial cell (CEC) permeability. Using an in vitro endothelial permeability assay, the present study tested the hypothesis that exosomes released by Cerebrolysin-treated CECs (Cerebro-Exos) have a robust therapeutic effect on dysfunctional CECs. Stoichiometric analysis showed [...] Read more.

Cerebrolysin has a salutary effect on impaired cerebral endothelial cell (CEC) permeability. Using an in vitro endothelial permeability assay, the present study tested the hypothesis that exosomes released by Cerebrolysin-treated CECs (Cerebro-Exos) have a robust therapeutic effect on dysfunctional CECs. Stoichiometric analysis showed marked differences in cargo profiles between Cerebro-Exos and exosomes derived from CECs without Cerebrolysin treatment (Naïve-Exos), in which Cerebro-Exos were highly enriched with metabolic and tight junction related proteins compared to Naïve-Exos. Cerebro-Exos had a superior effect compared to Naïve-Exos on restoring CEC integrity impaired by fibrin and tissue plasminogen activator (tPA). Treatment of fibrin- and tPA-challenged CECs with Cerebro-Exos robustly reduced fibrin- and tPA-augmented proteins involved in inflammation and coagulation and substantially increased fibrin- and tPA-decreased proteins that are related to tight junctions and metabolism. Collectively, these data indicate that Cerebro-Exos have a broad effect on improvement of dysfunctional CECs, which is likely achieved by the alteration of CEC proteins. Full article

(This article belongs to the Section Cell Signaling)

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18 pages, 7014 KB

Open AccessArticle

Combined Effect of Metformin and miR-145/miR-23b Co-Transfection on Proliferation and Progression in 2D and 3D Epithelial Ovarian Cancer Models

by Matías Alfonso Rubio, Eduardo Velásquez, Sofia Antonucci, María José Sánchez and Carmen Romero

Cells 2026, 15(10), 933; https://doi.org/10.3390/cells15100933 - 19 May 2026

Viewed by 352

Abstract

Epithelial ovarian cancer (EOC) remains a lethal malignancy requiring novel therapeutic strategies due to high recurrence and chemoresistance. This study evaluated the combined antitumor effect of metformin and the co-transfection of tumor-suppressor microRNAs miR-145 and miR-23b in A2780 and OV90 EOC cell lines [...] Read more.

Epithelial ovarian cancer (EOC) remains a lethal malignancy requiring novel therapeutic strategies due to high recurrence and chemoresistance. This study evaluated the combined antitumor effect of metformin and the co-transfection of tumor-suppressor microRNAs miR-145 and miR-23b in A2780 and OV90 EOC cell lines using both 2D and 3D models. In monolayer cultures, our approach significantly reduced the expression of proliferation markers Ki-67 and c-MYC, and decreased cell migration and invasion in both cell lines compared to controls. In 3D spheroid models, the treatment reduced VEGF secretion and relative spheroid area in A2780 cells, significantly increasing cytotoxicity; however, OV90 spheroids exhibited marked resistance. Fluorescent miRNA tracking revealed that this resistance occurs despite successful intracellular delivery, indicating an intrinsic biological resistance conferred by the 3D microenvironment. Overall, these findings suggest that the combined administration of metformin and miRs effectively limits tumor progression, but also strongly underscore the importance of using complex 3D models to accurately evaluate therapeutic efficacy and intrinsic resistance mechanisms. Full article

(This article belongs to the Special Issue From Molecular Mechanisms to Treatment Progress of Ovarian Cancer)

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20 pages, 4600 KB

Open AccessReview

LRG1 as a Potential Therapeutic Target in Atherosclerosis: Mechanistic Basis and Current Evidence

by Jianan Wu, Xia Yi, Lanlan Wang, Kaixuan Yang, Minghuan Liu, Jiawei Song and Zenghui Yue

Cells 2026, 15(10), 932; https://doi.org/10.3390/cells15100932 - 19 May 2026

Viewed by 441

Abstract

Atherosclerosis (AS) is a chronic inflammatory disease of large arteries. It underlies many cardiovascular disorders, including coronary artery disease, myocardial infarction, stroke, and peripheral arterial disease. Current therapies have improved outcomes, especially lipid-lowering, antithrombotic, and anti-inflammatory treatments. Yet residual cardiovascular risk remains, and [...] Read more.

Atherosclerosis (AS) is a chronic inflammatory disease of large arteries. It underlies many cardiovascular disorders, including coronary artery disease, myocardial infarction, stroke, and peripheral arterial disease. Current therapies have improved outcomes, especially lipid-lowering, antithrombotic, and anti-inflammatory treatments. Yet residual cardiovascular risk remains, and new molecular targets are still needed. Leucine-rich α-2-glycoprotein 1 (LRG1) is an inflammation-inducible secreted glycoprotein. It has drawn attention because it is linked to pathological angiogenesis, vascular dysfunction, tissue remodeling, and fibrosis. Recent studies indicate that LRG1 is related to AS at several levels. These include circulating clinical associations, plaque localization, and experimental models. In AS, LRG1 may not simply act as a biomarker. It may promote macrophage pro-inflammatory polarization, disturb endothelial homeostasis, support abnormal angiogenesis, and influence extracellular matrix remodeling and plaque structural change. This review examines the biological features of LRG1 and the current evidence connecting it with AS. It also discusses possible mechanisms, therapeutic feasibility, and current limitations. Overall, LRG1 appears to be a promising but still incompletely validated candidate target in AS. Full article

(This article belongs to the Section Cells of the Cardiovascular System)

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14 pages, 2307 KB

Open AccessReview

Modelling the Neurobiology of ADHD Using Human iPSC Systems: A Multimodal Platform for Mechanistic Discovery

by Atefeh Namipashaki, Hanchen Yu, Mark A. Bellgrove and Ziarih Hawi

Cells 2026, 15(10), 931; https://doi.org/10.3390/cells15100931 - 19 May 2026

Viewed by 447

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common and highly heterogeneous neurodevelopmental condition with complex biological underpinnings. Despite substantial progress in identifying genetic and neurobiological correlates, the cellular mechanisms linking genetic variation to functional brain alterations remain poorly understood. Human induced pluripotent stem [...] Read more.

Attention deficit hyperactivity disorder (ADHD) is a common and highly heterogeneous neurodevelopmental condition with complex biological underpinnings. Despite substantial progress in identifying genetic and neurobiological correlates, the cellular mechanisms linking genetic variation to functional brain alterations remain poorly understood. Human induced pluripotent stem cell (iPSC) technology provides a powerful platform to investigate these mechanisms by enabling the generation of patient-specific neural cell types and the direct interrogation of molecular, cellular, and network-level phenotypes. In this review, we summarise the current understanding of the neurobiological mechanisms underlying ADHD, including dopaminergic dysregulation, delayed neurodevelopmental maturation, and excitatory/inhibitory imbalance. We then discuss how iPSC-based models, combined with genome engineering and advanced functional assays, can be used to dissect gene-specific effects, study neural circuit development, and establish scalable platforms for therapeutic discovery. Finally, we outline key methodological considerations for designing robust iPSC-based models of ADHD. Together, these approaches provide new opportunities to bridge genetic risk with cellular function and accelerate the development of mechanistically informed therapeutic strategies. Full article

(This article belongs to the Special Issue Human Pluripotent Stem Cells and Organoids: Current Trends and Future Perspectives)

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17 pages, 4989 KB

Open AccessReview

Split Reporter Systems in Viral Protein–Protein Interactions and Multimerization: Mechanisms and Applications

by Haseeb Ahmad, Faizan Masood, Uzair Iqbal, Mohamed Shaltout, Yunus Yukselten and Richard E. Sutton

Cells 2026, 15(10), 930; https://doi.org/10.3390/cells15100930 - 19 May 2026

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Abstract

Protein–protein interactions (PPIs) are fundamental to viral replication, regulating processes such as assembly, genome packaging, and virion maturation. Despite their biological importance, these interactions remain challenging to study and are relatively underexploited as therapeutic targets. Split reporter systems, based on protein-fragment complementation, provide [...] Read more.

Protein–protein interactions (PPIs) are fundamental to viral replication, regulating processes such as assembly, genome packaging, and virion maturation. Despite their biological importance, these interactions remain challenging to study and are relatively underexploited as therapeutic targets. Split reporter systems, based on protein-fragment complementation, provide quantitative platforms to measure PPIs by reconstituting reporter activity when interacting protein partners are brought into proximity. These systems can be applied in vitro and in live cells which enables detection of dynamic and multimeric interactions in physiologically relevant contexts. Major classes of split reporter systems include β-lactamase, alkaline phosphatase, luciferase-based platforms, green fluorescent protein, and horseradish peroxidase. Assay performance depends on factors such as fusion protein stability, expression levels, and reporter kinetics, which influence sensitivity, dynamic range, and reliability. These approaches have been applied to study viral protein interactions across diverse systems, including HIV-1 matrix and nucleocapsid proteins, flaviviral capsid proteins, hepatitis B virus core protein, and chikungunya virus capsid. Split reporter assays also enable high-throughput screening for small-molecule inhibitors that disrupt viral PPIs and multimerization. This provides a functional readout linked to viral replication. Despite the challenges that exist in assay optimization and protein stability, the sensitivity and versatility of these systems provide a framework to interrogate viral protein interactions and support the development of antiviral therapeutics.: Full article

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14 pages, 8039 KB

Open AccessCommunication

ZBTB4 Deficiency Exacerbates DSS-Induced Colitis Through Activating NF-κB Pathway

by Xinyi Peng, Genglin Guo, Songyu Li, Songyao Sun, Cong Ouyang and Jiajun Cui

Cells 2026, 15(10), 929; https://doi.org/10.3390/cells15100929 - 18 May 2026

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Abstract

Inflammatory bowel diseases, particularly ulcerative colitis (UC), are chronic relapsing inflammatory disorders with limited therapeutic options. The zinc-finger transcription factor ZBTB4 has been implicated in the initiation and progression of cancer, but its role in UC remains unknown. Here, we found that ZBTB4 [...] Read more.

Inflammatory bowel diseases, particularly ulcerative colitis (UC), are chronic relapsing inflammatory disorders with limited therapeutic options. The zinc-finger transcription factor ZBTB4 has been implicated in the initiation and progression of cancer, but its role in UC remains unknown. Here, we found that ZBTB4 deficiency exacerbates dextran sulfate sodium (DSS)-induced colitis in C57BL/6J male mice. Compared with the wild type, ZBTB4 deficiency increases weight loss, colon shortening and proinflammatory cytokine production. RNA-seq analysis revealed that ZBTB4 deficiency enhances Serpine1 expression and activates the NF-κB pathway. NF-κB inhibition by JSH-23 alleviated the effect of ZBTB4 deficiency on DSS-induced colitis. These results imply the protective role of ZBTB4 in UC. Through an integrated drug screening, we identified a natural sesquiterpene lactone, handelin, as a potential compound to enhance ZBTB4 expression in NCM460 cells. Handelin administration relieved colitis in wild-type mice but produced no effect in ZBTB4 knockout mice, demonstrating that its anti-colitic effect depends on ZBTB4 expression. Collectively, our results indicate the key role of ZBTB4 in UC and ZBTB4 agonists may serve as a novel approach for UC treatments. Full article

(This article belongs to the Topic Animal Models of Human Disease 3.0)

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53 pages, 1349 KB

Open AccessReview

Emerging Therapeutic Strategies for Neurodegenerative Diseases: A Comprehensive Review of Recent Advances and Future Directions

by Masood Sepehrimanesh, Sarah Victoria Melen, Fatima Yeasmin, Victor Adeleke Ojo, Francisca Walden, Humaira Urmee, Jenna Etheridge and Aruna Kumari Nasu

Cells 2026, 15(10), 928; https://doi.org/10.3390/cells15100928 - 18 May 2026

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Abstract

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the [...] Read more.

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies. Full article

(This article belongs to the Special Issue Mechanisms, Biomarkers, and Therapeutics of Neurodegeneration)

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22 pages, 3329 KB

Open AccessReview

Pleiotrophin in Mammary Gland Development and Breast Cancer: A Comprehensive Review of the Evidence

by Arianna S. Gholami, Ciara N. Walsh and Jean McBryan

Cells 2026, 15(10), 927; https://doi.org/10.3390/cells15100927 - 18 May 2026

Viewed by 292

Abstract

Pleiotrophin (PTN), a heparin-binding growth factor with potent mitogenic and angiogenic activity, has emerged as a key regulator of mammary gland biology and a potential driver of breast cancer progression. This review integrates current evidence on PTN’s roles from normal mammary development, where [...] Read more.

Pleiotrophin (PTN), a heparin-binding growth factor with potent mitogenic and angiogenic activity, has emerged as a key regulator of mammary gland biology and a potential driver of breast cancer progression. This review integrates current evidence on PTN’s roles from normal mammary development, where it can delay ductal outgrowth, to triple negative breast cancer, where it promotes lung metastasis and correlates with poor survival. Though frequently reported as being overexpressed in breast cancer, the published data indicates that PTN transcription is reduced in cancer relative to normal breast cells. By contrast, serum PTN protein levels have been shown by multiple studies to be elevated in breast cancer patients relative to healthy controls. We examine the expression and function of PTN at a cellular level and explore the interplay between PTN and the tumour microenvironment. We evaluate preclinical models, clinical correlations, and emerging biomarker data that position PTN as a candidate prognostic indicator and therapeutic target. Despite growing interest, significant gaps remain regarding context-specific signalling. By integrating developmental and oncogenic perspectives, this review highlights PTN as a pivotal but underexplored factor in mammary gland physiology and breast cancer and outlines future research directions needed to translate PTN-targeted strategies into clinical benefit. Full article

(This article belongs to the Special Issue Targeting Breast Cancer: Mechanisms of Resistance and Innovative Therapeutic Strategies)

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22 pages, 1479 KB

Open AccessReview

STIM1 GoF Mutants: Genotype–Phenotype Relationships Across the Stormorken/TAM/YPS Spectrum

by Lara Atzgerstorfer, Magdalena Prantl, Andrea Waldhauser, Isabella Derler and Marc Fahrner

Cells 2026, 15(10), 926; https://doi.org/10.3390/cells15100926 - 18 May 2026

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Abstract

Store-operated Calcium (Ca²⁺) entry (SOCE), mediated by stromal interaction molecule 1 (STIM1) and Orai1, is a central pathway controlling intracellular Ca²⁺ homeostasis. Gain-of-function (GoF) mutations in STIM1 cause a spectrum of clinically overlapping disorders historically classified as Stormorken Syndrome (STK), [...] Read more.

Store-operated Calcium (Ca²⁺) entry (SOCE), mediated by stromal interaction molecule 1 (STIM1) and Orai1, is a central pathway controlling intracellular Ca²⁺ homeostasis. Gain-of-function (GoF) mutations in STIM1 cause a spectrum of clinically overlapping disorders historically classified as Stormorken Syndrome (STK), tubular aggregate myopathy (TAM), and York Platelet Syndrome (YPS). However, increasing evidence indicates that these entities could represent a shared disease spectrum rather than distinct conditions. At the molecular level, STIM1 activation is governed by a series of autoinhibitory checkpoints that maintain the protein in a tightly controlled resting state. GoF mutations disrupt these regulatory constraints, leading to dysregulated SOCE activity that is frequently, but not uniformly, associated with constitutive channel activation depending on the specific mutation and cellular context. While many disease-associated variants localize to the EF hand, a highly conserved helix–loop–helix Ca²⁺ binding motif, and the CC1 (coiled-coil 1) domain involved in molecular regulation of STIM1 activation, an increasing number of mutations in the C-terminal region further expands the mechanistic and clinical spectrum. In this review, we summarize current concepts of molecular STIM1 activation and discuss how distinct mutations perturb specific regulatory elements of the protein. By systematically integrating published case reports into a comprehensive overview, including a mutation–phenotype correlation table, we highlight the remarkable variability in and incomplete penetrance of clinical manifestations. Full article

(This article belongs to the Special Issue Regulation of Ca²⁺ Signals in Human Disease)

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