Cells

14 pages, 4558 KB

Open AccessArticle

RGMa Nuclear Localization in Skeletal Muscle Cells Reveals a Novel Role in Cell Viability and Proliferation

by Cristhian David Andrade Alfaro, Julia Meireles Nogueira, Christhiam Douglas Caetano Ribeiro, Kirsty Ximena Noboa Carrasco, Ana Luísa Cremonese Lubiana, Ana Maria Alvarenga Fagundes, Natália Paloma Vieira de Souza, Victor Rodrigues Santos, Carolina Cattoni Koh, Walderez Ornelas Dutra and Erika Cristina Jorge

Cells 2026, 15(2), 161; https://doi.org/10.3390/cells15020161 - 15 Jan 2026

Abstract

The Repulsive Guidance Molecule a (RGMa) is a multifunctional GPI-anchored protein localized in the sarcolemma and sarcoplasm of the adult skeletal muscle cell. Our research group showed that RGMa overexpression can promote myoblast fusion and induce hypertrophic muscle fibers during in vitro differentiation. [...] Read more.

The Repulsive Guidance Molecule a (RGMa) is a multifunctional GPI-anchored protein localized in the sarcolemma and sarcoplasm of the adult skeletal muscle cell. Our research group showed that RGMa overexpression can promote myoblast fusion and induce hypertrophic muscle fibers during in vitro differentiation. Here, we report that RGMa is expressed in primary skeletal muscle cells cultured in vitro, showing a nuclear localization, revealed by immunostaining with an antibody targeting its C-terminal region (C-RGMa). While RGMa was detected in the nuclei, its canonical receptor, Neogenin, was predominantly found in the perinuclear region. Nuclear RGMa was absent in Neogenin-knockdown cells, suggesting that Neogenin mediates its nuclear transport. Functional assays suggested that RGMa promotes primary skeletal muscle cell viability and proliferation and supports their myogenic commitment. These findings reveal a previously unrecognized nuclear function of RGMa–Neogenin signaling and provide new insights into the regulation of skeletal muscle cell behavior in vitro. Full article

(This article belongs to the Special Issue Gene and Cellular Signaling Related to Muscle)

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25 pages, 3718 KB

Open AccessArticle

The WISP1/Src/MIF Axis Promotes the Malignant Phenotype of Non-Invasive MCF7 Breast Cancer Cells

by Maria-Elpida Christopoulou, Panagiota Karamitsou, Alexios Aletras and Spyros S. Skandalis

Cells 2026, 15(2), 160; https://doi.org/10.3390/cells15020160 - 15 Jan 2026

Abstract

Breast cancer is a heterogeneous disease that exists in multiple subtypes, some of which still lack targeted and effective therapy. A major challenge is to unravel their underlying molecular mechanisms and bring to light novel therapeutic targets. In this study, we investigated the [...] Read more.

Breast cancer is a heterogeneous disease that exists in multiple subtypes, some of which still lack targeted and effective therapy. A major challenge is to unravel their underlying molecular mechanisms and bring to light novel therapeutic targets. In this study, we investigated the role of WNT-inducible signaling pathway protein 1 (WISP1) matricellular protein in the acquirement of an invasive phenotype by breast cancer cells. To this aim, we treated non-invasive MCF7 cells with WISP1 and assessed the expression levels of macrophage migration inhibitory factor (MIF) and its cellular receptor CD74. Next, we examined the expression of epithelial-to-mesenchymal transition (EMT) markers as well as molecular effectors of the tumor microenvironment, such as CD44, the main hyaluronan receptor that also acts as a co-receptor for MIF, the hyaluronan oncogenic network, and specific matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). The results showed that WISP1 potently induces the expression of MIF cytokine and affects the expression of specific extracellular matrix molecules with established roles in the promotion of malignant properties. Notably, Src kinases and MIF are critically involved in these processes. Collectively, the present study demonstrates for first time a WISP1/Src/MIF axis as well as its ability to induce an invasive phenotype in MCF7 cells and highlights novel cellular and molecular processes involved in the epithelial-to-mesenchymal transition and the development of invasive breast cancer. This suggests that specific cues from the tumor microenvironment can activate a migratory/invasive phenotype in a subpopulation of cells residing within the heterogeneous breast tumor. Full article

(This article belongs to the Special Issue Emerging Targets and Therapeutic Potential Drugs in Tumor Progression and Therapeutic Resistance)

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19 pages, 2894 KB

Open AccessArticle

Inhibition of the JAK and MEK Pathways Limits Mitochondrial ROS Production in Human Saphenous Vein Smooth Muscle Cells

by Israel O. Bolanle, James P. Hobkirk, Mahmoud Loubani, Roger G. Sturmey and Timothy M. Palmer

Cells 2026, 15(2), 159; https://doi.org/10.3390/cells15020159 - 15 Jan 2026

Abstract

Activation of JAK/STAT and MAPK/ERK1,2 signalling pathways has been shown to increase the production of reactive oxygen species (ROS) in multiple cell types involved in cardiovascular diseases (CVDs), including vascular smooth muscle cells (VSMCs). However, these have not yet been studied in human [...] Read more.

Activation of JAK/STAT and MAPK/ERK1,2 signalling pathways has been shown to increase the production of reactive oxygen species (ROS) in multiple cell types involved in cardiovascular diseases (CVDs), including vascular smooth muscle cells (VSMCs). However, these have not yet been studied in human saphenous vein SMCs (HSVSMCs) responsible for the maladaptive remodelling leading to saphenous vein graft failure (VGF), to which patients with type 2 diabetes mellitus (T2DM) are more susceptible. Therefore, this study aimed to evaluate the contributions of the JAK/STAT and MAPK/ERK1,2 pathways towards production of mitochondrial ROS (mROS) in HSVSMCs from T2DM patients versus non-diabetic controls. HSVSMCs explanted from surplus HSV tissues from consenting patients undergoing coronary artery bypass graft surgery were stimulated in vitro with mitogenic stimuli known to be involved in neointimal hyperplasia (NIH) and VGF, which are known activators of the JAK/STAT and the MAPK/ERK1,2 signalling pathways. Flow cytometry was then used to analyse the production of mROS (superoxide) in MitoSOX-stained HSVSMCs. Additionally, we examined the effect of ruxolitinib and trametinib, selective inhibitors of JAK1/2 and MEK1/2 signalling pathways, respectively, on mROS levels in these cells. From our findings, mROS production was significantly higher in HSVSMCs from T2DM patients versus non-diabetic controls. Activation of either the JAK/STAT or MAPK/ERK1,2 signalling pathways did not significantly alter the production of mROS in HSVSMCs from both T2DM and non-diabetic patients. However, inhibition of JAK/STAT and MAPK/ERK1,2 signalling pathways with ruxolitinib and trametinib, respectively, resulted in a significant reduction in mROS in HSVSMCs from both T2DM and non-diabetic patients. Our findings demonstrate a JAK/STAT- and MAPK/ERK1,2-mediated production of mROS in HSVSMCs. Hence, they are potential targets for drug development to limit ROS production in ROS-driven proliferation and migration of HSVSMCs responsible for VGF. Full article

(This article belongs to the Special Issue The Role of Oxidative Stress in Cardiovascular Diseases—2nd Edition)

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31 pages, 793 KB

Open AccessReview

When Testosterone Fades: Leydig Cell Aging Shaped by Environmental Toxicants, Metabolic Dysfunction, and Testicular Niche Crosstalk

by Aris Kaltsas, Fotios Dimitriadis, Athanasios Zachariou, Sotirios Koukos, Michael Chrisofos and Nikolaos Sofikitis

Cells 2026, 15(2), 158; https://doi.org/10.3390/cells15020158 - 15 Jan 2026

Abstract

Declining Leydig cell steroidogenesis contributes to late-onset hypogonadism and to age-associated impairment of male reproductive health. Determinants of dysfunction extend beyond chronological aging. This review synthesizes recent experimental and translational evidence on cellular and molecular processes that compromise Leydig cell endocrine output and [...] Read more.

Declining Leydig cell steroidogenesis contributes to late-onset hypogonadism and to age-associated impairment of male reproductive health. Determinants of dysfunction extend beyond chronological aging. This review synthesizes recent experimental and translational evidence on cellular and molecular processes that compromise Leydig cell endocrine output and the interstitial niche that supports spermatogenesis. Evidence spanning environmental endocrine-disrupting chemicals (EDCs), obesity and metabolic dysfunction, and testicular aging is integrated with emphasis on oxidative stress, endoplasmic reticulum stress, mitochondrial dysregulation, apoptosis, disrupted autophagy and mitophagy, and senescence-associated remodeling. Across model systems, toxicant exposure and metabolic stress converge on impaired organelle quality control and altered redox signaling, with downstream loss of steroidogenic capacity and, in some settings, premature senescence within the Leydig compartment. Aging further reshapes the testicular microenvironment through inflammatory shifts and biomechanical remodeling and may erode stem and progenitor Leydig cell homeostasis, thereby constraining regenerative potential. Single-cell transcriptomic atlases advance the field by resolving Leydig cell heterogeneity, nominating subsets that appear more vulnerable to stress and aging, and mapping age-dependent rewiring of interstitial cell-to-cell communication with Sertoli cells, peritubular myoid cells, vascular cells, and immune cells. Many mechanistic insights derive from rodent in vivo studies and in vitro platforms that include immortalized Leydig cell lines, and validation in human tissue and human clinical cohorts remains uneven. Together, these findings frame mechanistically informed opportunities to preserve endogenous androgen production and fertility through exposure mitigation, metabolic optimization, fertility-preserving endocrine stimulation, and strategies that target inflammation, senescence, and regenerative capacity. Full article

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16 pages, 8167 KB

Open AccessArticle

Overwinter Syndrome in Grass Carp (Ctenopharyngodon idellus) Links Enteric Viral Proliferation to Mucosal Disruption via Multiomics Investigation

by Yang Feng, Yi Geng, Senyue Liu, Xiaoli Huang, Chengyan Mou, Han Zhao, Jian Zhou, Qiang Li and Yongqiang Deng

Cells 2026, 15(2), 157; https://doi.org/10.3390/cells15020157 - 15 Jan 2026

Abstract

Overwinter Syndrome (OWS) affects grass carp (Ctenopharyngodon idellus) aquaculture in China, causing high mortality and economic losses under low temperatures. Failure of antibiotic therapies shows limits of the ‘low–temperature–pathogen’ model and shifts focus to mucosal barrier dysfunction and host–microbiome interactions in [...] Read more.

Overwinter Syndrome (OWS) affects grass carp (Ctenopharyngodon idellus) aquaculture in China, causing high mortality and economic losses under low temperatures. Failure of antibiotic therapies shows limits of the ‘low–temperature–pathogen’ model and shifts focus to mucosal barrier dysfunction and host–microbiome interactions in OWS. We compared healthy and diseased grass carp collected from the same pond using histopathology, transcriptomics, proteomics, and metagenomics. This integrated approach was used to characterize intestinal structure, microbial composition, and host molecular responses at both taxonomic and functional levels. Results revealed a three-layer barrier failure in OWS fish: the physical barrier was compromised, with structural damage and reduced mucosal index; microbial dysbiosis featured increased richness without changes in diversity or evenness, and expansion of the virobiota, notably uncultured Caudovirales phage; and mucosal immune dysregulation indicated loss of local immune balance. Multi-omics integration identified downregulation of lysosome-related and glycosphingolipid biosynthesis pathways at transcript and protein levels, with disrupted nucleotide metabolism. Overall gut microbial richness, rather than individual taxa abundance, correlated most strongly with host gene changes linked to immunity, metabolism, and epithelial integrity. Although biological replicates were limited by natural outbreak sampling, matched high-depth multi-omics datasets provide exploratory insights into OWS-associated intestinal dysfunction. In summary, OWS entails a cold-triggered breakdown of intestinal barrier integrity and immune homeostasis. This breakdown is driven by a global restructuring of the gut microbiome, which is marked by increased richness, viral expansion, and functional shifts, ultimately resulting in altered host–microbe crosstalk. This ecological perspective informs future mechanistic and applied studies for disease prevention. Full article

(This article belongs to the Section Cell Microenvironment)

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27 pages, 917 KB

Open AccessReview

Chronic In Vivo CRISPR-Cas Genome Editing: Challenges, Long-Term Safety, and Outlook

by Caroline Bao, Catherine I. Channell, Yi Hsuan Tseng, Johnathan Bailey, Naeem Sbaiti, Aykut Demirkol and Stephen H. Tsang

Cells 2026, 15(2), 156; https://doi.org/10.3390/cells15020156 - 15 Jan 2026

Abstract

CRISPR/Cas systems have transformed molecular medicine, yet the field still lacks principled guidance on when transient editing suffices versus when sustained exposure through in vivo viral delivery is necessary and how to keep prolonged exposure safe. Notably, EDIT-101 was designed for a permanent [...] Read more.

CRISPR/Cas systems have transformed molecular medicine, yet the field still lacks principled guidance on when transient editing suffices versus when sustained exposure through in vivo viral delivery is necessary and how to keep prolonged exposure safe. Notably, EDIT-101 was designed for a permanent edit in post-mitotic photoreceptors with lifelong Cas9 persistence. This review addresses this gap by defining the biological and therapeutic conditions that drive benefit from extended Cas activity while minimizing risk. We will (i) examine relationships between expression window and efficacy across Cas9/Cas12/Cas13 modalities, (ii) identify genome-wide off-target liabilities alongside orthogonal assays, and (iii) discuss controllable, self-limiting, and recallable editor platforms. By separating durable edits from persistent nuclease exposure, and by providing validated control levers, this work establishes a generalizable framework for safe, higher-efficacy CRISPR medicines. Furthermore, we highlight key studies in cell lines, murine models, non-human primates, and humans that examine the long-term effects of sustained expression of CRISPR/Cas systems and discuss the safety and efficacy of such approaches. Current evidence demonstrates promising therapeutic outcomes with manageable safety profiles, although there is a need for continued monitoring as CRISPR/Cas therapies are increasingly applied in clinical contexts and therapies are developed for broader clinical applications. Full article

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18 pages, 2713 KB

Open AccessArticle

The Putative E3 Ubiquitin Ligase TEX1 Is Required for Nuclear Biology and Developmental Progression of Plasmodium berghei in the Liver

by Melanie Schmid, Raphael Golomingi, Blandine Franke-Fayard, Reto Caldelari, Ruth Rehmann, Magali Roques and Volker T. Heussler

Cells 2026, 15(2), 155; https://doi.org/10.3390/cells15020155 - 15 Jan 2026

Abstract

Malaria remains a major global health burden, and the emergence of resistance to blood stage antimalarials underscores the need for new interventions targeting earlier stages of the parasite’s life cycle. The pre-erythrocytic liver stage represents a critical bottleneck and an attractive target for [...] Read more.

Malaria remains a major global health burden, and the emergence of resistance to blood stage antimalarials underscores the need for new interventions targeting earlier stages of the parasite’s life cycle. The pre-erythrocytic liver stage represents a critical bottleneck and an attractive target for chemotherapeutic and prophylactic interventions. In this study, we functionally characterized the putative E3 ubiquitin ligase Trophozoite Exported Protein 1 (TEX1; PBANKA_0102200) in Plasmodium berghei using gene knockout, tagging, and imaging approaches across the mosquito and liver stages. TEX1 knockout parasites (PbTEX1-KO) showed impaired development during mosquito-stage transitions, with significant reductions in ookinete formation, oocyst numbers, and sporozoites reaching the salivary glands. In hepatic stages, TEX1-KO parasites displayed reduced growth, abnormal nuclear division, and impaired liver stage maturation, ultimately leading to a dramatic decline in detached cell formation and blood stage infectivity. Endogenous C-terminal tagging of TEX1 with GFP and 3×HA revealed a discrete subnuclear localization pattern, indicating a critical role in DNA synthesis and/or mitotic regulation. Our findings reveal that TEX1 is required for nuclear replication and division and successful development in both the mosquito and liver stages of Plasmodium. Given its pivotal role and nuclear localization during hepatic schizogony, TEX1 represents a promising target for the development of liver stage antimalarial interventions. Full article

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

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15 pages, 1077 KB

Open AccessArticle

Long Non-Coding RNA MALAT1 Regulates HMOX1 in Sickle Cell Disease-Associated Pulmonary Hypertension

by Viranuj Sueblinvong, Sarah S. Chang, Jing Ma, David R. Archer, Solomon Ofori-Acquah, Roy L. Sutliff, Changwon Park, C. Michael Hart, Benjamin T. Kopp and Bum-Yong Kang

Cells 2026, 15(2), 154; https://doi.org/10.3390/cells15020154 - 15 Jan 2026

Abstract

Pulmonary hypertension (PH) causes morbidity and mortality in sickle cell disease (SCD). The release of heme during hemolysis triggers endothelial dysfunction and contributes to PH. Long non-coding RNAs (lncRNAs) may play a pivotal role in endothelial dysfunction and PH pathogenesis. This study assessed [...] Read more.

Pulmonary hypertension (PH) causes morbidity and mortality in sickle cell disease (SCD). The release of heme during hemolysis triggers endothelial dysfunction and contributes to PH. Long non-coding RNAs (lncRNAs) may play a pivotal role in endothelial dysfunction and PH pathogenesis. This study assessed the regulatory role of the lncRNA–heme oxygenase-1 (HMOX1) axis in SCD-associated PH pathogenesis. Total RNAs were isolated from the lungs of 15–17-week-old sickle cell (SS) mice and littermate controls (AA) mice and subjected to lncRNA expression profiling using the Arrystar™ lncRNA array. Volcano plot filtering was used to screen for differentially expressed lncRNAs and mRNAs with statistical significance (fold change > 1.8, p < 0.05). A total of 3915 lncRNAs were upregulated and a total of 3545 lncRNAs were downregulated in the lungs of SS mice compared to AA mice. To validate differentially expressed lncRNAs, six upregulated lncRNAs and six downregulated lncRNAs were selected for quantitative PCR. MALAT1 expression was significantly upregulated in the lungs of SS mice and in hemin-treated human pulmonary artery endothelial cells (HPAECs), suggesting that hemolysis induces MALAT1. Functional studies revealed that MALAT1 depletion increased, while MALAT1 overexpression decreased, the endothelial dysfunction markers endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM1), indicating a protective role of MALAT1 in maintaining endothelial homeostasis. In vivo, adenoviral MALAT1 overexpression attenuated PH, right ventricular hypertrophy (RVH), vascular remodeling, and reduced ET-1 and VCAM1 expression in SS mice. Given that HMOX1 protects endothelial cells during hemolysis, we observed that HMOX1 expression and activity were elevated in SS mouse lungs and hemin-treated HPAECs. HMOX1 knockdown enhanced ET-1 and VCAM1 expression, confirming its endothelial-protective function. Importantly, MALAT1 overexpression increased HMOX1 expression and activity, whereas MALAT1 knockdown reduced HMOX1 levels and mRNA stability. Collectively, these findings identify MALAT1 as a protective regulator that mitigates endothelial dysfunction, vascular remodeling, and PH in SCD, at least in part through the induction of HMOX1. These results suggest that SCD modulates the MALAT1–HMOX1 axis, and further characterization of MALAT1 function may provide new insights into SCD-associated endothelial dysfunction and PH pathogenesis, as well as identify novel therapeutic targets. Full article

(This article belongs to the Special Issue Sickle Cell Disease: Pathogenesis, Diagnosis and Treatment)

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37 pages, 2633 KB

Open AccessReview

Organ-Specific Regulation of Systemic Aging: Focus on the Brain, Skeletal Muscle, and Gut

by Jie Fu, Chengrui Liu, Yulin Shu, Yuxin Jiang, Ping Li and Kai Yao

Cells 2026, 15(2), 153; https://doi.org/10.3390/cells15020153 - 14 Jan 2026

Abstract

As global population aging accelerates, the growing burden of age-related diseases is driving a shift in medical research from single-disease treatment to interventions targeting the aging process itself. Organ-specific interventions have emerged as a promising strategy to modulate systemic aging. Among organs, the [...] Read more.

As global population aging accelerates, the growing burden of age-related diseases is driving a shift in medical research from single-disease treatment to interventions targeting the aging process itself. Organ-specific interventions have emerged as a promising strategy to modulate systemic aging. Among organs, the brain, muscle, and gut have attracted particular attention due to their central roles in neural regulation, metabolic homeostasis, and immune balance. In this review, we focus on these three key organs, systematically summarizing their roles and regulatory mechanisms in organismal aging and discussing how exercise influences the aging process by affecting these organs. Crucially, we propose a novel “local-to-global” regulatory model, positing that preserving homeostasis in these specific tissues is sufficient to orchestrate systemic anti-aging effects. This work represents a conceptual advance by providing the theoretical rationale to move beyond non-specific systemic treatments toward precise, organ-targeted interventions. Full article

17 pages, 7354 KB

Open AccessArticle

Adrenomedullin-RAMP2 Enhances Lung Endothelial Cell Homeostasis Under Shear Stress

by Yongdae Yoon, Sean R. Duffy, Shannon E. Kirk, Kamoltip Promnares, Pratap Karki, Anna A. Birukova, Konstantin G. Birukov and Yifan Yuan

Cells 2026, 15(2), 152; https://doi.org/10.3390/cells15020152 - 14 Jan 2026

Abstract

Analysis of pulmonary vascular dysfunction in various lung pathologies remains challenging due to the lack of functional ex vivo models. Paracrine signaling in the lung plays a critical role in regulating endothelial maturation and vascular homeostasis. Previously, we employed single-cell RNA-sequencing (scRNAseq) to [...] Read more.

Analysis of pulmonary vascular dysfunction in various lung pathologies remains challenging due to the lack of functional ex vivo models. Paracrine signaling in the lung plays a critical role in regulating endothelial maturation and vascular homeostasis. Previously, we employed single-cell RNA-sequencing (scRNAseq) to systematically map ligand–receptor (L/R) interactions within the lung vascular niche. However, the functional impact of these ligands on endothelial biology remained unknown. Here, we systematically evaluated selected ligands in vitro to assess their effects on endothelial barrier integrity, anti-inflammatory responses, and phenotypic maturation. Among the top soluble ligands, we found that adrenomedulin (ADM) exhibited superior barrier enhancing effect on human pulmonary endothelial cell monolayers, as evidenced by electrical cell impedance sensing (ECIS) and XperT assays. ADM also exhibited anti-inflammatory properties, decreasing ICAM1 and increasing IkBa expression in a dose-dependent manner. Perfusion is commonly used in bioengineered vascular model systems. Shear stress (15 dynes/cm²) alone increased endothelial characteristics, including homeostatic markers such as CDH5, NOS3, TEK, and S1PR1. ADM treatment maintained the enhanced level of these markers under shear stress and further improved anti-coagulation by increasing THBD and decreasing F3 expression and synergistically enhanced the expression of the native lung aerocyte capillary endothelial marker EDNRB. This effect was completely attenuated by a blockade of ADM receptor, RAMP2. Together, these findings identify ADM/RAMP2 signaling as a key paracrine pathway that enhances vascular barrier integrity, anti-inflammatory phenotype, and endothelial homeostasis, providing a framework for improving the physiological relevance of engineered vascular models. Full article

(This article belongs to the Collection The Endothelial Cell in Lung Inflammation)

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26 pages, 6754 KB

Open AccessArticle

Akhirin Functions as an Innate Immune Barrier to Preserve Neurogenic Niche Homeostasis During Mouse Brain Development

by Mikiko Kudo, Tenta Ohkubo, Taichi Sugawara, Takashi Irie, Jun Hatakeyama, Shigehiko Tamura, Kenji Shimamura, Tomohiko Wakayama, Naoki Matsuo, Kinichi Nakashima, Takahiro Masuda and Kunimasa Ohta

Cells 2026, 15(2), 151; https://doi.org/10.3390/cells15020151 - 14 Jan 2026

Abstract

Neurogenesis is tightly regulated by complex interactions among neural stem and progenitor cells (NSCs/NPCs), blood vessels, microglia, and extracellular matrix components within the neurogenic niche. In the embryonic brain, NSCs reside along the ventricular surface, where cerebrospinal fluid (CSF) directly regulates their proliferation. [...] Read more.

Neurogenesis is tightly regulated by complex interactions among neural stem and progenitor cells (NSCs/NPCs), blood vessels, microglia, and extracellular matrix components within the neurogenic niche. In the embryonic brain, NSCs reside along the ventricular surface, where cerebrospinal fluid (CSF) directly regulates their proliferation. Here, we identify Akhirin (AKH) as a critical regulator that preserves the integrity of the NSC niche during mouse brain development. At embryonic day 14.5, AKH is secreted and enriched at the apical surface of choroid plexus epithelial cells and the ventricular lining. Loss of AKH leads to increases the inflammatory cytokine expression in the CSF and disrupts NSC niche homeostasis. Furthermore, AKH is cleaved upon inflammatory stimulation, and its LCCL domain directly binds bacteria, thereby preventing their spread. These findings reveal that AKH functions as a protective barrier molecule within the developing neurogenic niche, providing immune protection and preserving NSC niche homeostasis during periods when the innate immune defenses are still immature. Full article

(This article belongs to the Section Stem Cells)

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19 pages, 352 KB

Open AccessReview

Ketones in Cardiovascular Health and Disease: An Updated Review

by Sanjiv Shrestha, Isis Harrison, Aminat Dosunmu and Ping Song

Cells 2026, 15(2), 150; https://doi.org/10.3390/cells15020150 - 14 Jan 2026

Abstract

Ketones are metabolites primarily produced by the liver and are utilized by various organs outside of the liver. Recent advances have demonstrated that ketones serve not only as alternative energy sources but also as signaling molecules. Research indicates that ketones can influence cancer [...] Read more.

Ketones are metabolites primarily produced by the liver and are utilized by various organs outside of the liver. Recent advances have demonstrated that ketones serve not only as alternative energy sources but also as signaling molecules. Research indicates that ketones can influence cancer development and metastasis, cardiac metabolic and structural remodeling, physical performance, vascular function, inflammation, and the aging process. Emerging evidence from preclinical and early-phase clinical studies suggests that strategies such as ketone salts, ketone esters, and the ketogenic diet may offer therapeutic benefits for conditions like heart failure, acute cardiac injury, diabetic cardiomyopathy, vascular complications, atherosclerosis, hypertension, and aortic aneurysm. This literature review updates the current understanding of ketone metabolism and its contributions to cardiovascular health and diseases. We highlight the underlying molecular mechanism with post-translational modification known as β-hydroxybutyrylation, which affects the fate and function of target proteins. Additionally, we discuss the therapeutic challenges associated with ketone therapy, the potential of using ketone levels as biomarkers for cardiovascular diseases, as well as gender- and age-specific differences in ketone treatment. Finally, we explore future research directions and what is needed to translate these new insights into cardiovascular medicine. Full article

(This article belongs to the Special Issue New Insights into Therapeutic Targets for Cardiovascular Diseases)

20 pages, 740 KB

Open AccessReview

Mitochondrial Metabolic Checkpoints in Human Fertility: Reactive Oxygen Species as Gatekeepers of Gamete Competence

by Sofoklis Stavros, Nikolaos Thomakos, Efthalia Moustakli, Nikoleta Daponte, Dimos Sioutis, Nikolaos Kathopoulis, Athanasios Zikopoulos, Ismini Anagnostaki, Chrysi Christodoulaki, Themos Grigoriadis, Ekaterini Domali and Anastasios Potiris

Cells 2026, 15(2), 149; https://doi.org/10.3390/cells15020149 - 14 Jan 2026

Abstract

Crucial regulators of gamete metabolism and signaling, mitochondria synchronize energy generation with redox equilibrium and developmental proficiency. Once thought of as hazardous byproducts, reactive oxygen species (ROS) are now understood to be vital signaling molecules that provide a “redox window of competence” that [...] Read more.

Crucial regulators of gamete metabolism and signaling, mitochondria synchronize energy generation with redox equilibrium and developmental proficiency. Once thought of as hazardous byproducts, reactive oxygen species (ROS) are now understood to be vital signaling molecules that provide a “redox window of competence” that is required for oocyte maturation, sperm capacitation, and early embryo development. This review presents the idea of mitochondrial metabolic checkpoints, which are phases that govern gamete quality and fertilization potential by interacting with cellular signaling, redox balance, and mitochondrial activity. Recent research shows that oocytes may sustain a nearly ROS-free metabolic state by blocking specific respiratory-chain components, highlighting the importance of mitochondrial remodeling in gamete competence. Evidence from in vitro and in vivo studies shows that ROS act as dynamic gatekeepers at critical points in oogenesis, spermatogenesis, fertilization, and early embryogenesis. However, assisted reproductive technologies (ARTs) may inadvertently disrupt this redox–metabolic equilibrium. Potential translational benefits can be obtained via targeted techniques that optimize mitochondrial function, such as modifying oxygen tension, employing mitochondria-directed antioxidants like MitoQ and SS-31, and supplementing with nutraceuticals like melatonin, CoQ10, and resveratrol. Understanding ROS-mediated checkpoints forms the basis for developing biomarkers of gamete competence and precision therapies to improve ART outcomes. By highlighting mitochondria as both metabolic sensors and redox regulators, this review links fundamental mitochondrial biology to clinical reproductive medicine. Full article

(This article belongs to the Collection Feature Papers in Mitochondria)

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19 pages, 963 KB

Open AccessReview

Impact of Menopause and Associated Hormonal Changes on Spine Health in Older Females: A Review

by Julia Chagas, Gabrielle Gilmer, Gwendolyn Sowa and Nam Vo

Cells 2026, 15(2), 148; https://doi.org/10.3390/cells15020148 - 14 Jan 2026

Abstract

Low back pain (LBP) represents a major societal and economic burden, with annual costs in the United States estimated at $90–134.5 billion. LBP disproportionately impacts postmenopausal women relative to age-matched men, suggesting a role for sex-specific biological factors. Although the mechanisms underlying this [...] Read more.

Low back pain (LBP) represents a major societal and economic burden, with annual costs in the United States estimated at $90–134.5 billion. LBP disproportionately impacts postmenopausal women relative to age-matched men, suggesting a role for sex-specific biological factors. Although the mechanisms underlying this disparity are not fully understood, hormonal imbalance during menopause may contribute to LBP pathophysiology. This narrative review aimed to elucidate the impact of menopause on LBP, with emphasis on hormonal effects on spinal tissues and systemic processes. A literature search was conducted, followed by screening of titles, abstracts, and full texts of original clinical studies, preclinical research using human or animal samples, and relevant reviews. Rigour and reproducibility were evaluated using the ARRIVE Guidelines and the Modified Downs & Black Checklist. Evidence indicates that menopause is associated with changes in intervertebral discs, facet joint, ligamentum flavum, skeletal muscle, sympathetic innervation, and systemic systems such as the gut microbiome. However, most findings are correlational rather than causal. Evidence supporting hormone replacement therapy for LBP remains inconclusive, whereas exercise and other treatments, including parathyroid hormones, show more consistent benefits. Future studies should focus on causal mechanisms and adhere to rigour guidelines to improve translational potential. Full article

(This article belongs to the Special Issue Novel Insights into Mechanism and Treatment of Degenerative Disc Disease)

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22 pages, 9987 KB

Open AccessArticle

Network Hypoactivity in ALG13-CDG: Disrupted Developmental Pathways and E/I Imbalance as Early Drivers of Neurological Features in CDG

by Rameen Shah, Rohit Budhhraja, Silvia Radenkovic, Graeme Preston, Alexia Tyler King, Sahar Sabry, Charlotte Bleukx, Ibrahim Shammas, Lyndsay Young, Jisha Chandran, Seul Kee Byeon, Ronald Hrstka, Doughlas Y. Smith IV, Nathan P. Staff, Richard Drake, Steven A. Sloan, Akhilesh Pandey, Eva Morava and Tamas Kozicz

Cells 2026, 15(2), 147; https://doi.org/10.3390/cells15020147 - 14 Jan 2026

Abstract

Background: ALG13-CDG is an X-linked N-linked glycosylation disorder caused by pathogenic variants in the glycosyltransferase ALG13, leading to severe neurological manifestations. Despite the clear CNS involvement, the impact of ALG13 dysfunction on human brain glycosylation and neurodevelopment remains unknown. We hypothesize that ALG13-CDG [...] Read more.

Background: ALG13-CDG is an X-linked N-linked glycosylation disorder caused by pathogenic variants in the glycosyltransferase ALG13, leading to severe neurological manifestations. Despite the clear CNS involvement, the impact of ALG13 dysfunction on human brain glycosylation and neurodevelopment remains unknown. We hypothesize that ALG13-CDG causes brain-specific hypoglycosylation that disrupts neurodevelopmental pathways and contributes directly to cortical network dysfunction. Methods: We generated iPSC-derived human cortical organoids (hCOs) from individuals with ALG13-CDG to define the impact of hypoglycosylation on cortical development and function. Electrophysiological activity was assessed using MEA recordings and integrated with multiomic profiling, including scRNA-seq, proteomics, glycoproteomics, N-glycan imaging, lipidomics, and metabolomics. X-inactivation status was evaluated in both iPSCs and hCOs. Results: ALG13-CDG hCOs showed reduced glycosylation of proteins involved in ECM organization, neuronal migration, lipid metabolism, calcium homeostasis, and neuronal excitability. These pathway disruptions were supported by proteomic and scRNA-seq data and included altered intercellular communication. Trajectory analyses revealed mistimed neuronal maturation with early inhibitory and delayed excitatory development, indicating an E/I imbalance. MEA recordings demonstrated early network hypoactivity with reduced firing rates, immature burst structure, and shortened axonal projections, while transcriptomic and proteomic signatures suggested emerging hyperexcitability. Altered lipid and GlcNAc metabolism, along with skewed X-inactivation, were also observed. Conclusions: Our study reveals that ALG13-CDG is a disorder of brain-specific hypoglycosylation that disrupts key neurodevelopmental pathways and destabilizes cortical network function. Through integrated multiomic and functional analyses, we identify early network hypoactivity, mistimed neuronal maturation, and evolving E/I imbalance that progresses to compensatory hyperexcitability, providing a mechanistic basis for seizure vulnerability. These findings redefine ALG13-CDG as disorders of cortical network instability, offering a new framework for targeted therapeutic intervention. Full article

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18 pages, 1992 KB

Open AccessReview

Peptide Arrays as Tools for Unraveling Tumor Microenvironments and Drug Discovery in Oncology

by Anna Grab, Christoph Reißfelder and Alexander Nesterov-Mueller

Cells 2026, 15(2), 146; https://doi.org/10.3390/cells15020146 - 14 Jan 2026

Abstract

Peptide arrays represent a powerful tool for investigating a wide application field for biomedical questions. This review summarizes recent applications of peptide chips in oncology, with a focus on tumor microenvironment, metastasis, and drug mechanism of action for various cancer types. These high-throughput [...] Read more.

Peptide arrays represent a powerful tool for investigating a wide application field for biomedical questions. This review summarizes recent applications of peptide chips in oncology, with a focus on tumor microenvironment, metastasis, and drug mechanism of action for various cancer types. These high-throughput platforms enable the simultaneous screening of thousands of peptides. We report on recent achievements in peptide array technology for tumor microenvironments, an enhanced ability to decipher complex cancer-related signaling pathways, and characterization of cell-adhesion-mediating peptides. Furthermore, we highlight the applications in high-throughput drug screenings for development of immune therapies, e.g., the development of novel neoantigen therapies of glioblastoma. Moreover, epigenetic profiling using peptide arrays has uncovered new therapeutic targets across various cancer types with clinical impact. In conclusion, we discuss artificial intelligence-driven peptide array analysis as a tool to determine tumor origin and metastatic state, potentially transforming diagnostic approaches. These innovations promise to accelerate the development of precision cancer approaches. Full article

(This article belongs to the Special Issue Cancer Cell Signaling, Autophagy and Tumorigenesis)

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33 pages, 4569 KB

Open AccessArticle

Heterotypic 3D Model of Breast Cancer Based on Tumor, Stromal and Endothelial Cells: Cytokines Interaction in the Tumor Microenvironment

by Anastasia Leonteva, Alina Kazakova, Ekaterina Berezutskaya, Anna Ilyina, David Sergeevichev, Sergey Vladimirov, Maria Bogachek, Igor Vakhrushev, Pavel Makarevich, Vladimir Richter and Anna Nushtaeva

Cells 2026, 15(2), 145; https://doi.org/10.3390/cells15020145 - 14 Jan 2026

Abstract

The recreation of the tumor microenvironment remains a significant challenge in the development of experimental cancer models. The present study constitutes an investigation into the interconnection between tumor, endothelial and stromal cells in heterotypic breast cancer spheroids. The generation of models was achieved [...] Read more.

The recreation of the tumor microenvironment remains a significant challenge in the development of experimental cancer models. The present study constitutes an investigation into the interconnection between tumor, endothelial and stromal cells in heterotypic breast cancer spheroids. The generation of models was achieved through the utilization of MCF7, MDA-MB-231, and SK-BR-3 tumor cell lines, in conjunction with endothelial TIME-RFP cells and either cancer-associated (BrC4f) or normal (BN120f) fibroblasts, within ultra-low attachment plates. It was established that stromal cells, most notably fibroblasts, were conducive to the aggregation of tumor cells into spheroids and the formation of pseudovessels in close proximity to fibroblast bands. In contrast to the more aggressive tumor models MDA-MB-231 and SK-BR-3, microenvironment cells do not influence the migration ability of MCF7 tumor cells. Heterotypic spheroids incorporating CAFs demonstrated a more aggressive and immunosuppressive phenotype. Multiplex immunoassay analysis of cytokines, followed by STRING cluster analysis, was used to identify key processes including angiogenesis, invasion, stem cell maintenance, and immunosuppression. Furthermore, a cluster of cytokines (LIF, SDF-1, HGF, SCGFb) was identified as potentially involved in the regulation of PD-L1 expression by tumor cells. This finding reveals a potential mechanism of immune evasion and suggests new avenues for therapeutic investigation. Full article

(This article belongs to the Special Issue Cell-to-Cell Crosstalk as a Target of Therapies)

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23 pages, 1633 KB

Open AccessReview

TRPC3 and TRPC6: Multimodal Cation-Conducting Channels Regulating Cardiovascular Contractility and Remodeling

by Takuro Numaga-Tomita and Motohiro Nishida

Cells 2026, 15(2), 144; https://doi.org/10.3390/cells15020144 - 14 Jan 2026

Abstract

Transient receptor potential canonical (TRPC) channels function as multimodal cation channels that integrate chemical and mechanical cues to regulate cellular signaling. Among them, TRPC3 and TRPC6 have been studied primarily in the context of cardiovascular and renal physiology, and their roles in other [...] Read more.

Transient receptor potential canonical (TRPC) channels function as multimodal cation channels that integrate chemical and mechanical cues to regulate cellular signaling. Among them, TRPC3 and TRPC6 have been studied primarily in the context of cardiovascular and renal physiology, and their roles in other organ systems are now increasingly recognized. Although these channels are known to be activated downstream of phospholipase C (PLC) signaling, especially 1,2-diacylglycerol (DAG) production, their precise modes of activation under native physiological conditions remain incompletely understood. Recent structural and functional studies have greatly advanced our understanding of their primary activation by DAG. This review summarizes how decades of physiological analyses have revealed multiple modes of TRPC3 and TRPC6 channel activation beyond DAG gating, providing a broader perspective on their diverse regulatory mechanisms. This review also highlights recent progress in elucidating the channel properties, activation mechanisms, and the physiological as well as pathophysiological roles of TRPC3 and TRPC6 in cardiovascular contractility and remodeling, and discusses the remaining challenges that will lead to the establishment of TRPC3 and TRPC6 as validated therapeutic targets. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels and Health and Disease)

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22 pages, 2780 KB

Open AccessReview

Hippo Signaling in the Lung: A Tale of Two Effectors—Yap Drives Airway Fate and Taz Drives Alveolar Differentiation

by Rachel Warren and Stijn P. J. De Langhe

Cells 2026, 15(2), 143; https://doi.org/10.3390/cells15020143 - 13 Jan 2026

Abstract

The mammalian lung operates under a biological paradox, requiring architectural fragility for gas exchange while maintaining robust regenerative plasticity to withstand injury. The Hippo signaling pathway has emerged as a central “rheostat” in orchestrating these opposing needs, yet the distinct roles of its [...] Read more.

The mammalian lung operates under a biological paradox, requiring architectural fragility for gas exchange while maintaining robust regenerative plasticity to withstand injury. The Hippo signaling pathway has emerged as a central “rheostat” in orchestrating these opposing needs, yet the distinct roles of its downstream effectors remain underappreciated. This review synthesizes recent genetic and mechanobiological advances to propose a “Tale of Two Effectors” model, arguing for the functional non-redundancy of YAP and TAZ. We posit that YAP functions to drive airway progenitor expansion, mechanical force generation, and maladaptive remodeling. Conversely, TAZ—regulated uniquely via transcriptional mechanisms and mechanotransduction—acts as an obligate driver of alveolar differentiation and adaptive repair through an NKX2-1 feed-forward loop. Furthermore, we introduce the “See-Saw” model of tissue fitness, where mesenchymal niche collapse releases the mechanical brake on the epithelium, triggering the bronchiolization characteristic of pulmonary fibrosis. Finally, we extend this framework to malignancy, illustrating how Small Cell Lung Cancer (SCLC) subtypes mirror these developmental and regenerative states. This integrated framework offers new therapeutic distinct targets for modulating tissue fitness and resolving fibrosis. Full article

(This article belongs to the Special Issue Mechanisms of Lung Growth and Regeneration)

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