Cells

25 pages, 31027 KiB

Open AccessArticle

The Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) 3 Regulates the Myogenic Differentiation of Yunan Black Pig Muscle Satellite Cells (MuSCs) In Vitro via Iron Homeostasis and the PI3K/AKT Pathway

by Wei Zhang, Minying Zhang, Jiaqing Zhang, Sujuan Chen, Keke Zhang, Xuejing Xie, Chaofan Guo, Jiyuan Shen, Xiaojian Zhang, Huarun Sun, Liya Guo, Yuliang Wen, Lei Wang and Jianhe Hu

Cells 2025, 14(9), 656; https://doi.org/10.3390/cells14090656 (registering DOI) - 29 Apr 2025

Abstract

The myogenic differentiation of muscle satellite cells (MuSCs) is an important biological process that plays a key role in the regeneration and repair of skeletal muscles. However, the mechanisms regulating myoblast myogenesis require further investigation. In this study, we found that STEAP3 is [...] Read more.

The myogenic differentiation of muscle satellite cells (MuSCs) is an important biological process that plays a key role in the regeneration and repair of skeletal muscles. However, the mechanisms regulating myoblast myogenesis require further investigation. In this study, we found that STEAP3 is involved in myogenic differentiation based on the Yunan black pig MuSCs model in vitro using cell transfection and other methods. Furthermore, the expression of myogenic differentiation marker genes MyoG and MyoD and the number of myotubes formed by the differentiation of cells from the si-STEAP3 treated group were significantly decreased but increased in the STEAP3 overexpression group compared to that in the control group. STEAP3 played a role in iron ion metabolism, affecting myogenic differentiation via the uptake of iron ions and enhancing IRP-IRE homeostasis. STEAP3 also activated the PI3K/AKT pathway, thus promoting myoblast differentiation of Yunan black pig MuSCs. The results of this study showed that STEAP3 overexpression increased intracellular iron ion content and activated the homeostatic IRP-IRE system to regulate intracellular iron ion metabolism. Full article

(This article belongs to the Section Cell Signaling)

32 pages, 5875 KiB

Open AccessArticle

Enhanced Expression of Mitochondrial Magmas Protein in Ovarian Carcinomas: Magmas Inhibition Facilitates Antitumour Effects, Signifying a Novel Approach for Ovarian Cancer Treatment

by Ali Raza, Ashfaqul Hoque, Rodney Luwor, Ruth M. Escalona, Jason Kelly, Revati Sharma, Fadi Charchar, Simon Chu, Mary K. Short, Paul T. Jubinsky, George Kannourakis and Nuzhat Ahmed

Cells 2025, 14(9), 655; https://doi.org/10.3390/cells14090655 (registering DOI) - 29 Apr 2025

Abstract

Mitochondrial-associated granulocyte macrophage colony-stimulating factor (Magmas) is a unique protein located in the inner membrane of mitochondria, with an active role in scavenging reactive oxygen species (ROS) in cellular systems. Ovarian cancer (OC), one of the deadliest gynaecological cancers, is characterised by genomic [...] Read more.

Mitochondrial-associated granulocyte macrophage colony-stimulating factor (Magmas) is a unique protein located in the inner membrane of mitochondria, with an active role in scavenging reactive oxygen species (ROS) in cellular systems. Ovarian cancer (OC), one of the deadliest gynaecological cancers, is characterised by genomic instability, affected by ROS production in the tumour microenvironment. This manuscript discusses the role of Magmas and efficacy of its novel small molecule inhibitor BT#9 in OC progression, metastasis, and chemoresistance. Magmas expression levels were significantly elevated in high-grade human OC compared to benign tumours by immunohistochemistry. The inhibition of Magmas by BT#9 enhanced ROS production and reduced mitochondrial membrane permeability, basal respiration, mitochondrial ATP production, and cellular functions, such as the proliferation and migration of OC cell lines in vitro. Oral administration of BT#9 in vivo significantly reduced tumour growth and spread and enhanced the survival of mice without having any effect on the peritoneal organs. These data suggest that Magmas is functionally important for OC growth and spread by affecting ROS levels and that the inhibition of Magmas activity by BT#9 may provide novel clinical benefits for patients with this malignancy. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism in Cancer Stem Cells (CSCs))

20 pages, 445 KiB

Open AccessArticle

Gene Expression of Extracellular Matrix Proteins, MMPs, and TIMPs in Post-Operative Tissues of Chronic Rhinosinusitis Patients

by Zygimantas Vaitkus, Astra Vitkauskiene, Liutauras Labanauskas, Justinas Vaitkus, Povilas Lozovskis, Saulius Vaitkus and Ieva Janulaityte

Cells 2025, 14(9), 654; https://doi.org/10.3390/cells14090654 (registering DOI) - 29 Apr 2025

Abstract

Chronic rhinosinusitis (CRS) is a persistent inflammatory condition of the sinus mucosa characterized by significant tissue remodeling. This study aimed to evaluate the gene expression of extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) in post-operative tissues of [...] Read more.

Chronic rhinosinusitis (CRS) is a persistent inflammatory condition of the sinus mucosa characterized by significant tissue remodeling. This study aimed to evaluate the gene expression of extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) in post-operative tissues of CRS patients. A total of 30 patients diagnosed with CRS, divided into CRSwNP (with nasal polyps) and CRSsNP (without nasal polyps) groups, were compared with a control group of 10 individuals undergoing nasal surgeries for non-CRS conditions. Gene expression analysis was conducted using quantitative real-time PCR, and plasma cytokine levels were measured via ELISA. Results indicated significantly higher expression of collagen I, collagen III, fibronectin, vimentin, periostin, and tenascin C in CRS tissues, especially in CRSsNP patients. Conversely, elastin expression was markedly lower. MMP-2, MMP-9, TIMP-1, and TIMP-2 expression was significantly altered, with CRSsNP showing lower levels compared to CRSwNP and controls. TGF-β1 expression was elevated in both CRS groups, particularly in CRSsNP, highlighting its role in fibrosis and ECM remodeling. Additionally, increased plasma concentrations of TSLP and TGF-β1 suggest epithelial activation and immune dysregulation in CRS. These findings underscore distinct remodeling profiles in CRS endotypes, emphasizing the need for targeted therapeutic strategies based on molecular phenotyping. Understanding ECM dysregulation and inflammatory pathways in CRS may lead to improved, individualized treatment approaches. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Treating Fibrosis)

17 pages, 955 KiB

Open AccessReview

Targeted Redox Regulation α-Ketoglutarate Dehydrogenase Complex for the Treatment of Human Diseases

by Ryan J. Mailloux

Cells 2025, 14(9), 653; https://doi.org/10.3390/cells14090653 (registering DOI) - 29 Apr 2025

Abstract

α-ketoglutarate dehydrogenase complex (KGDHc) is a crucial enzyme in the tricarboxylic acid (TCA) cycle that intersects monosaccharides, amino acids, and fatty acid catabolism with oxidative phosphorylation (OxPhos). A key feature of KGDHc is its ability to sense changes in the redox environment through [...] Read more.

α-ketoglutarate dehydrogenase complex (KGDHc) is a crucial enzyme in the tricarboxylic acid (TCA) cycle that intersects monosaccharides, amino acids, and fatty acid catabolism with oxidative phosphorylation (OxPhos). A key feature of KGDHc is its ability to sense changes in the redox environment through the reversible oxidation of the vicinal lipoic acid thiols of its dihydrolipoamide succinyltransferase (DLST; E2) subunit, which controls its activity and, by extension, OxPhos. This characteristic inculcates KGDHc with redox regulatory properties for the modulation of metabolism and mediating of intra- and intercellular signals. The innate capacity of KGDHc to participate in the regulation of cell redox homeodynamics also occurs through the production of mitochondrial hydrogen peroxide (mtH₂O₂), which is generated by the dihydrolipoamide dehydrogenase (DLD; E3) downstream from the E2 subunit. Reversible covalent redox modification of the E2 subunit controls this mtH₂O₂ production by KGDHc, which not only protects from oxidative distress but also modulates oxidative eustress pathways. The importance of KGDHc in modulating redox homeodynamics is underscored by the pathogenesis of neurological and metabolic disorders that occur due to the hyper-generation of mtH₂O₂ by this enzyme complex. This also implies that the targeted redox modification of the E2 subunit could be a potential therapeutic strategy for limiting the oxidative distress triggered by KGDHc mtH₂O₂hyper-generation. In this short article, I will discuss recent findings demonstrating KGDHc is a potent mtH₂O₂source that can trigger the manifestation of several neurological and metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), inflammation, and cancer, and the targeted redox modification of the E2 subunit could alleviate these syndromes. Full article

(This article belongs to the Special Issue Charming Micro-Insights into Health and Diseases)

25 pages, 6761 KiB

Open AccessArticle

Dopamine Receptor D3 Induces Transient, mTORC1-Dependent Autophagy That Becomes Persistent, AMPK-Mediated, and Neuroprotective in Experimental Models of Huntington’s Disease

by Diego Luis-Ravelo, Felipe Fumagallo-Reading, Alejandro Febles-Casquero, Jonathan Lopez-Fernandez, Daniel J. Marcellino and Tomas Gonzalez-Hernandez

Cells 2025, 14(9), 652; https://doi.org/10.3390/cells14090652 (registering DOI) - 29 Apr 2025

Abstract

Huntington disease’s (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine region (PolyQ) within the huntingtin protein (HTT). Mutated huntingtin (mHTT) is cytotoxic, particularly for striatal medium spiny neurons (MSNs), whose degeneration is the hallmark of HD. Autophagy inducers currently [...] Read more.

Huntington disease’s (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine region (PolyQ) within the huntingtin protein (HTT). Mutated huntingtin (mHTT) is cytotoxic, particularly for striatal medium spiny neurons (MSNs), whose degeneration is the hallmark of HD. Autophagy inducers currently available promote the clearance of toxic proteins. However, due to their low selectivity and the possibility that prolonged autophagy hampers essential processes in unaffected cells, researchers have questioned their benefits in neurodegenerative diseases. Since MSNs express dopamine receptors D2 (DRD2) and D3 (DRD3) and DRD2/DRD3 agonists may activate autophagy, here, we explored how healthy and mHTT-challenged cells respond to prolonged DRD2/DRD3 agonist treatment. Autophagy activation and its effects on mHTT/polyQ clearance were studied in R6/1 mice (a genetic model of HD), their wild-type littermates, and DRD2- and DRD3-HEK cells expressing a pathogenic (Q74) and a non-pathogenic (Q23) polyQ fragment of mHTT treated with the DRD2/DRD3 agonist pramipexole. Two forms of DRD3-mediated autophagy were found: a transient mTORC1-dependent in WT mice and Q23-DRD3-HEK cells and a persistent AMPK-ULK1-activated in R6/1 mice and Q74-DRD3-HEK cells. This also promoted a robust clearance of soluble mHTT/polyQ and neuroprotection in striatal neurons and DRD3-HEK cells. The findings indicate that DRD3-induced autophagy may be a safe, disease-modifying intervention in HD patients. Full article

(This article belongs to the Special Issue Molecular Therapeutic Advances for Neurodegenerative Diseases)

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20 pages, 38507 KiB

Open AccessArticle

Multipotent Mesenchymal Stem Cell Therapy for Vascular Dementia

by Eun-Young Kim, Ki-Sung Hong, Dong-Hun Lee, Eun Chae Lee, Hyung-Min Chung, Se-Pill Park, Man Ryul Lee and Jae Sang Oh

Cells 2025, 14(9), 651; https://doi.org/10.3390/cells14090651 (registering DOI) - 29 Apr 2025

Abstract

Vascular dementia (VD), characterized by cognitive decline and behavioral disorders, has seen a rapid increase in prevalence in recent years. However, effective treatments for VD remain unavailable. Due to its regenerative potential, stem cell therapy has garnered attention as a promising approach for [...] Read more.

Vascular dementia (VD), characterized by cognitive decline and behavioral disorders, has seen a rapid increase in prevalence in recent years. However, effective treatments for VD remain unavailable. Due to its regenerative potential, stem cell therapy has garnered attention as a promising approach for VD treatment, yet it has shown limited effects on cognitive and behavioral impairments caused by the disease. To address this limitation, this study aimed to develop a novel treatment using human embryonic stem cell-derived multipotent mesenchymal stem cells (MMSCs). The therapeutic efficacy of MMSCs was evaluated using a vascular dementia mouse model induced by bilateral carotid artery stenosis (BCAS). The effects of MMSCs were assessed through behavioral tests and postmortem brain tissue analysis, including mRNA expression analysis and hematoxylin and eosin (H&E) staining. MMSCs treatment significantly improved both working memory and long-term memory. Histological analysis revealed enhanced angiogenesis, preservation of blood–brain barrier integrity, and improved hippocampal organization. Furthermore, MMSCs treatment reduced the expression of Rock1/2, indicating suppression of neuroinflammatory and apoptotic pathways. These findings suggest that MMSCs offer a sustainable and effective therapeutic approach for vascular dementia. Full article

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21 pages, 1275 KiB

Open AccessReview

Inflammation in Schizophrenia: The Role of Disordered Oscillatory Mechanisms

by Lucinda J. Speers and David K. Bilkey

Cells 2025, 14(9), 650; https://doi.org/10.3390/cells14090650 (registering DOI) - 29 Apr 2025

Abstract

Schizophrenia is a chronic, debilitating disorder with diverse symptomatology, including disorganised cognition and behaviour. Despite considerable research effort, we have only a limited understanding of the underlying brain dysfunction. A significant proportion of individuals with schizophrenia exhibit high levels of inflammation, and inflammation [...] Read more.

Schizophrenia is a chronic, debilitating disorder with diverse symptomatology, including disorganised cognition and behaviour. Despite considerable research effort, we have only a limited understanding of the underlying brain dysfunction. A significant proportion of individuals with schizophrenia exhibit high levels of inflammation, and inflammation associated with maternal immune system activation is a risk factor for the disorder. In this review, we outline the potential role of inflammation in the disorder, with a particular focus on how cytokine release might affect the development and function of GABAergic interneurons. One consequence of this change in inhibitory control is a disruption in oscillatory processes in the brain. These changes disrupt the spatial and temporal synchrony of neural activity in the brain, which, by disturbing representations of time and space, may underlie some of the disorganisation symptoms observed in the disorder. Full article

(This article belongs to the Special Issue Inflammatory Pathways in Psychiatric Disorders)

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18 pages, 8189 KiB

Open AccessArticle

Study on γδT-Cell Degranulation at Maternal–Fetal Interface via iKIR–HLA-C Axis

by Diana Manchorova, Marina Alexandrova, Antonia Terzieva, Ivaylo Vangelov, Ljubomir Djerov, Iana Hristova, Gil Mor and Tanya Dimova

Cells 2025, 14(9), 649; https://doi.org/10.3390/cells14090649 (registering DOI) - 29 Apr 2025

Abstract

Maternal–fetal tolerance mechanisms are crucial during human pregnancy to prevent the immune rejection of the embryo. A well-known mechanism blocking NK-cell cytotoxicity is the interaction of their inhibitory killer-cell immunoglobulin-like receptors (iKIR) with HLA-C molecules on the target cells. In this study, we [...] Read more.

Maternal–fetal tolerance mechanisms are crucial during human pregnancy to prevent the immune rejection of the embryo. A well-known mechanism blocking NK-cell cytotoxicity is the interaction of their inhibitory killer-cell immunoglobulin-like receptors (iKIR) with HLA-C molecules on the target cells. In this study, we aimed to investigate the expression of iKIRs (KIR2DL1 and KIR2DL2/3) on the matched decidual and peripheral γδT cells and the localization of HLA-C ligands throughout human pregnancy. The degranulation of γδT cells of pregnant and non-pregnant women in the presence of trophoblast cells was evaluated as well. Our results showed a higher proportion of iKIR-positive γδT cells at the maternal–fetal interface early in human pregnancy compared to the paired blood of pregnant women and full-term pregnancy decidua. In accordance, HLA-C was intensively expressed by the intermediate cytotrophoblasts and decidua-invading extravillous trophoblasts (EVTs) in early but not late pregnancy. Decidual γδT cells during early pregnancy showed higher spontaneous degranulation compared to their blood pairs, but neither decidual nor peripheral γδ T cells increased their degranulation in the presence of Sw71 EVT-like cells. The latter were unable to suppress the higher cytotoxicity of γδT cells, suggesting a complex regulatory landscape beyond NK-like activity inhibition. Full article

(This article belongs to the Section Cellular Immunology)

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21 pages, 1147 KiB

Open AccessReview

B Cell Lineage in the Human Endometrium: Physiological and Pathological Implications

by Kotaro Kitaya

Cells 2025, 14(9), 648; https://doi.org/10.3390/cells14090648 (registering DOI) - 29 Apr 2025

Abstract

Immunocompetent cells of B lineage function in the humoral immunity system in the adaptive immune responses. B cells differentiate into plasmacytes upon antigen-induced activation and produce different subclasses of immunoglobulins/antibodies. Secreted immunoglobulins not only interact with pathogens to inactivate and neutralize them, but [...] Read more.

Immunocompetent cells of B lineage function in the humoral immunity system in the adaptive immune responses. B cells differentiate into plasmacytes upon antigen-induced activation and produce different subclasses of immunoglobulins/antibodies. Secreted immunoglobulins not only interact with pathogens to inactivate and neutralize them, but also involve the complement system to exert antibacterial activities and trigger opsonization. Endometrium is a mucosal tissue that lines the mammalian uterus and is indispensable for the establishment of a successful pregnancy. The lymphocytes of B cell lineage are a minority in the human cycling endometrium. Human endometrial B cells have therefore been understudied so far. However, the disorders of the female reproductive tract, including chronic endometritis and endometriosis, have highlighted the importance of further research on the endometrial B cell lineage. This review aims to revisit lymphopoiesis, maturation, commitment, and survival of B cells, shedding light on their physiological and pathological implications in the human endometrium. Full article

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22 pages, 4136 KiB

Open AccessArticle

Collapsin Response Mediator Protein 2 (CRMP2) Modulates Mitochondrial Oxidative Metabolism in Knock-In AD Mouse Model

by Tatiana Brustovetsky, Rajesh Khanna and Nickolay Brustovetsky

Cells 2025, 14(9), 647; https://doi.org/10.3390/cells14090647 (registering DOI) - 29 Apr 2025

Abstract

We explored how the phosphorylation state of collapsin response mediator protein 2 (CRMP2) influences mitochondrial functions in cultured cortical neurons and cortical synaptic mitochondria isolated from APP-SAA KI mice, a knock-in APP mouse model of Alzheimer’s disease (AD). CRMP2 phosphorylation was increased at [...] Read more.

We explored how the phosphorylation state of collapsin response mediator protein 2 (CRMP2) influences mitochondrial functions in cultured cortical neurons and cortical synaptic mitochondria isolated from APP-SAA KI mice, a knock-in APP mouse model of Alzheimer’s disease (AD). CRMP2 phosphorylation was increased at Thr 509/514 and Ser 522 in brain cortical lysates and cultured neurons from AD mice. The basal and maximal respiration of AD neurons were decreased. Mitochondria were hyperpolarized and superoxide anion production was increased in neurons from AD mice. In isolated synaptic AD mitochondria, ADP-stimulated and DNP-stimulated respiration were decreased, whereas ADP-induced mitochondrial depolarization was reduced and prolonged. We found that CRMP2 binds to the adenine nucleotide translocase (ANT) in a phosphorylation-dependent manner. The increased CRMP2 phosphorylation in AD mice correlated with CRMP2 dissociation from the ANT and decreased ANT activity in AD mitochondria. On the other hand, recombinant CRMP2 (rCRMP2), added to the ANT-reconstituted proteoliposomes, increased ANT activity. A small molecule (S)-lacosamide ((S)-LCM), which binds to CRMP2 and suppresses CRMP2 phosphorylation by Cdk5 and GSK-3β, prevented CRMP2 hyperphosphorylation, rescued CRMP2 binding to the ANT, improved ANT activity, and restored the mitochondrial membrane potential and respiratory responses to ADP and 2,4-dinitrophenol. Thus, our study highlights an important role for CRMP2 in regulating the mitochondrial oxidative metabolism in AD by modulating the ANT activity in a phosphorylation-dependent manner. Full article

(This article belongs to the Special Issue Mitochondria at the Crossroad of Health and Disease—Second Edition)

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22 pages, 14956 KiB

Open AccessArticle

Isolation and Characterization of Mouse Choroidal Melanocytes and Their Proinflammatory Characteristics

by Yong-Seok Song, SunYoung Park, Debra Fisk, Christine M. Sorenson and Nader Sheibani

Cells 2025, 14(9), 646; https://doi.org/10.3390/cells14090646 (registering DOI) - 28 Apr 2025

Abstract

Melanocytes are a major cellular component of the choroid which aids in the maintenance of choroidal integrity and vision. Unfortunately, our knowledge regarding the cell autonomous melanocyte function, in preserving choroidal health and the ocular pathologies associated with choroidal dysfunction, remain largely unknown. [...] Read more.

Melanocytes are a major cellular component of the choroid which aids in the maintenance of choroidal integrity and vision. Unfortunately, our knowledge regarding the cell autonomous melanocyte function, in preserving choroidal health and the ocular pathologies associated with choroidal dysfunction, remain largely unknown. The ability to culture melanocytes has advanced our knowledge regarding the origin and function of these cells in choroidal homeostasis and vision. However, the culture of murine choroid melanocytes has not been previously reported. Here, we describe a method for the isolation of melanocytes from the mouse choroid, as well as the delineation of many of their cellular characteristics, including the expression of various cell-specific markers, cell adhesion molecules, melanogenic capacity, and inflammatory responses to various extracellular stressors. Unraveling the molecular mechanisms that regulate melanocyte functions will advance our understanding of their role in choroidal homeostasis and how alterations in these functions impact ocular diseases that compromise vision. Full article

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21 pages, 12541 KiB

Open AccessArticle

ATIP1 Is a Suppressor of Cardiac Hypertrophy and Modulates AT2-Dependent Signaling in Cardiac Myocytes

by Tobias Fischer, Sina Gredy, Nadine Scheel, Peter M. Benz, Benjamin Fissler, Melanie Ullrich, Marco Abeßer, Adam G. Rokita, Jochen Reichle, Lars S. Maier, Oliver Ritter, Hideo A. Baba and Kai Schuh

Cells 2025, 14(9), 645; https://doi.org/10.3390/cells14090645 (registering DOI) - 28 Apr 2025

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Abstract

So far, the molecular functions of the angiotensin-type-2 receptor (AT2) interacting protein (ATIP1) have remained unclear, although expression studies have revealed high levels of ATIP1 in the heart. To unravel its physiological function, we investigated ATIP1-KO mice. They develop a spontaneous cardiac hypertrophy [...] Read more.

So far, the molecular functions of the angiotensin-type-2 receptor (AT2) interacting protein (ATIP1) have remained unclear, although expression studies have revealed high levels of ATIP1 in the heart. To unravel its physiological function, we investigated ATIP1-KO mice. They develop a spontaneous cardiac hypertrophy with a significantly increased heart/bodyweight ratio, enlarged cardiomyocyte diameters, and augmented myocardial fibrosis. Hemodynamic measurements revealed an increased ejection fraction (EF) in untreated ATIP1-KO mice, and reduced end-systolic and end-diastolic volumes (ESV and EDV), which, in sum, reflect a compensated concentric cardiac hypertrophy. Importantly, no significant differences in blood pressure (BP) were observed. Chronic angiotensin II (AngII) infusion resulted in increases in BP and EF in ATIP1-KO and WT mice. Reductions in ESV and EDV occurred in both ATIP1-KO and WT but to a lesser extent in ATIP1-KOs. Isolated cardiomyocytes exhibited a significantly increased contractility in ATIP1-KO and accelerated Ca²⁺ decay. AngII treatment resulted in increased fractional shortening in WT but decreased shortening in ATIP1-KO, accompanied by accelerated cell relaxation in WT but absent effects on relaxation in ATIP1-KO cells. The AT2 agonist CGP42112A increased shortening in WT cardiomyocytes but, again, did not affect shortening in ATIP1-KO cells. Relaxation was accelerated by CGP42112A in WT but was unaffected in ATIP1-KO cells. We show that ATIP1 deficiency results in spontaneous cardiac hypertrophy in vivo and that ATIP1 is a downstream signal in the AT2 pathway regulating cell contractility. We hypothesize that the latter effect is because of a disinhibition of the AT1 pathway by impaired AT2 signaling. Full article

(This article belongs to the Special Issue The Cell Biology of Heart Disease)

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23 pages, 7879 KiB

Open AccessArticle

Nardostachys jatamansi Extract and Nardosinone Exert Neuroprotective Effects by Suppressing Glucose Metabolic Reprogramming and Modulating T Cell Infiltration

by Congyan Duan, Weifang Lin, Mingjie Zhang, Bianxia Xue, Wangjie Sun, Yang Jin, Xiaoxu Zhang, Hong Guo, Qing Yuan, Mingyu Yu, Qi Liu, Naixuan Wang, Hong Wang, Honghua Wu and Shaoxia Wang

Cells 2025, 14(9), 644; https://doi.org/10.3390/cells14090644 (registering DOI) - 28 Apr 2025

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Abstract

Background: Nardostachys jatamansi DC. (Gansong), a widely utilized herb in traditional Chinese medicine, has been historically employed in the management of various neuropsychiatric disorders. Nardosinone (Nar), a sesquiterpenoid compound, has been identified as one of the principal bioactive constituents of N. jatamansi. [...] Read more.

Background: Nardostachys jatamansi DC. (Gansong), a widely utilized herb in traditional Chinese medicine, has been historically employed in the management of various neuropsychiatric disorders. Nardosinone (Nar), a sesquiterpenoid compound, has been identified as one of the principal bioactive constituents of N. jatamansi. This study investigated the effects of ethyl acetate extract (NJ-1A) from N. jatamansi and its active constituent nardosinone on neuroinflammatory mediator release, glucose metabolic reprogramming, and T cell migration using both in vitro and in vivo experimental models. Methods: Lipopolysaccharide(LPS)-induced BV-2 microglial cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced male C57BL/6N mouse chronic model of Parkinson’s disease were applied. Results: Both NJ-1A and Nar could significantly suppress LPS-induced production of M1 pro-inflammatory factors or markers in microglia and could inhibit the glycolytic process and promote oxidative phosphorylation via the AKT/mTOR signaling pathway. Furthermore, they exhibited the capacity to attenuate chemokine release from activated microglia, consequently reducing T cell migration. In vivo experiments revealed that NJ-1A and Nar effectively inhibited microglial activation, diminished T cell infiltration, and mitigated the loss of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra of MPTP-induced mice. Conclusions: NJ-1A and nardosinone exert neuroprotective effects through the modulation of microglial polarization states, regulation of metabolic reprogramming, and suppression of T cell infiltration. Full article

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

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18 pages, 4154 KiB

Open AccessArticle

Survival and Axonal Regeneration of Retinal Ganglion Cells in a Mouse Optic Nerve Crush Model After a Cell-Based Intravitreal Co-Administration of Ciliary Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor at Different Post-Lesion Time Points

by Yue Hu, Lynn Michelle Grodzki and Udo Bartsch

Cells 2025, 14(9), 643; https://doi.org/10.3390/cells14090643 (registering DOI) - 28 Apr 2025

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Abstract

We recently showed, in a mouse optic nerve crush model, that a sustained cell-based intravitreal administration of ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) synergistically slowed the lesion-induced degeneration of retinal ganglion cells (RGCs), resulting in the presence of [...] Read more.

We recently showed, in a mouse optic nerve crush model, that a sustained cell-based intravitreal administration of ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) synergistically slowed the lesion-induced degeneration of retinal ganglion cells (RGCs), resulting in the presence of approximately 35% viable RGCs eight months after the lesion. However, the combinatorial neuroprotective treatment was initiated shortly after the lesion. To mimic a more clinically relevant situation, we co-administered both factors either three or five days after an intraorbital nerve crush when approximately 35% or 57% of the RGCs were degenerated, respectively. Analyses of the retinas at different time points after the lesion consistently revealed the presence of significantly more surviving RGCs in retinas co-treated with CNTF and GDNF than in retinas treated with either factor alone. For example, when the neurotrophic factors were administered five days after the nerve crush and the animals were analyzed two months after the lesion, retinas co-treated with CNTF and GDNF contained approximately 40% of the RGCs present at the start of treatment. In comparison, monotherapy with either CNTF or GDNF protected only about 15% or 10% of the RGCs present at baseline, respectively. The number of regenerating axons in the distal nerve stumps was similar in CNTF- and CNTF/GDNF-treated animals, despite the significantly higher number of rescued RGCs in the latter group. These findings have potential implications for studies aimed at developing neuroprotective treatments for optic neuropathies such as glaucoma. Full article

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23 pages, 2766 KiB

Open AccessArticle

Prolactin Mediates Distinct Time Course Regulation of Tyrosine Hydroxylase Phosphorylation and Gene Expression in Tuberoinfundibular Dopaminergic Neurons of Female Rats

by Philip J. Jensik and Lydia A. Arbogast

Cells 2025, 14(9), 642; https://doi.org/10.3390/cells14090642 (registering DOI) - 27 Apr 2025

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Abstract

Prolactin (PRL) regulates its own secretion by short-loop feedback to tuberoinfundibular dopaminergic (TIDA) neurons. PRL-induced cellular mechanisms in the regulation of tyrosine hydroxylase (TH) are not completely understood. The objectives were to (1) examine PRL-induced, time-dependent hypothalamic changes in JAK2-STAT5B signaling, TH activity, [...] Read more.

Prolactin (PRL) regulates its own secretion by short-loop feedback to tuberoinfundibular dopaminergic (TIDA) neurons. PRL-induced cellular mechanisms in the regulation of tyrosine hydroxylase (TH) are not completely understood. The objectives were to (1) examine PRL-induced, time-dependent hypothalamic changes in JAK2-STAT5B signaling, TH activity, TH phosphorylation state and Th mRNA levels, and (2) evaluate direct influences of PRLR-STAT5B signaling on Th promoter activity. Ovariectomized rats were administered ovine PRL. JAK2 and STAT5 phosphorylation in the mediobasal hypothalamus peaked at 15 and 30–60 min, respectively. TH Ser40 phosphorylation in the median eminence was increased between 2 and 72 h, correlating with increased dihydroxyphenylalanine (DOPA) accumulation. Th mRNA levels in TIDA neurons were unchanged up to 72 h but elevated by 7 days. PRL did not alter Th promoter activity in CAD cells, and STAT5B did not bind three putative Gamma Interferon Activation Sites (GAS) elements. We conclude that PRL initiates an integrated cascade of cellular mechanisms in TIDA neurons, including JAK2-STAT5B activation, TH Ser40 phosphorylation coupled to increased TH activity, followed by a delayed rise in Th gene expression. PRL-induced changes in Th gene expression are not the result of STAT5-mediated transactivation but likely result from enduring changes in TIDA neuronal activity. Full article

(This article belongs to the Special Issue Select Topics in Molecular and Cellular Mechanisms of Mammalian Reproduction)

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14 pages, 2632 KiB

Open AccessArticle

Impact of Chronic Cold Water Immersion and Vitamin D3 Supplementation on the Hippocampal Metabolism and Oxidative Stress in Rats

by Daria Korewo-Labelle, Mateusz Jakub Karnia, Dorota Myślińska and Jan Jacek Kaczor

Cells 2025, 14(9), 641; https://doi.org/10.3390/cells14090641 (registering DOI) - 26 Apr 2025

Viewed by 165

Abstract

Chronic cold exposure is a stressor that may adversely affect the hippocampal structure and cognitive function. Critical for memory formation and learning processes, the hippocampus is particularly susceptible to hypothalamic–pituitary–adrenal (HPA) axis activity and elevated glucocorticoid levels. Vitamin D plays a complex role [...] Read more.

Chronic cold exposure is a stressor that may adversely affect the hippocampal structure and cognitive function. Critical for memory formation and learning processes, the hippocampus is particularly susceptible to hypothalamic–pituitary–adrenal (HPA) axis activity and elevated glucocorticoid levels. Vitamin D plays a complex role in regulating mitochondrial function and may provide neuroprotection. This study aimed to investigate the effects of chronic cold exposure on proteins associated with signaling pathways, mitochondrial function, and oxidative stress in the hippocampus of rats and to evaluate the neuroprotective potential of vitamin D3 supplementation. Male Wistar rats (n = 26) were assigned to four groups: control (CON; n = 4), sham stress (WW; n = 6), chronic cold water immersion (CCWI) (CW group; n = 8), and CCWI with 600 IU/kg/day vitamin D3 (VD3) supplementation (CW + D group; n = 8). Exposure to CCWI significantly reduced the hippocampal mass of rats, an effect not reversed by vitamin D3 supplementation. However, vitamin D3 improved mitochondrial function and exhibited antioxidant effects, partially reducing markers of protein and lipid free radicals damage in neural tissue. Our findings demonstrate the antioxidant properties of VD3 and its potential role in mitigating hippocampal damage during prolonged cold exposure, although its neuroprotective effects remain limited. Full article

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31 pages, 1825 KiB

Open AccessReview

Epigenetic Control of Alveolar Macrophages: Impact on Lung Health and Disease

by Nirmal Parajuli, Kalpana Subedi, Xzaviar Kaymar Solone, Aimin Jiang, Li Zhou and Qing-Sheng Mi

Cells 2025, 14(9), 640; https://doi.org/10.3390/cells14090640 - 25 Apr 2025

Viewed by 330

Abstract

Alveolar macrophages (AMs) are immune cells located in the alveoli—the tiny air sacs in the lungs where gas exchange occurs. Their functions are regulated by various epigenetic mechanisms, which are essential for both healthy lung function and disease development. In the lung’s microenvironment, [...] Read more.

Alveolar macrophages (AMs) are immune cells located in the alveoli—the tiny air sacs in the lungs where gas exchange occurs. Their functions are regulated by various epigenetic mechanisms, which are essential for both healthy lung function and disease development. In the lung’s microenvironment, AMs play critical roles in immune surveillance, pathogen clearance, and tissue repair. This review examines how epigenetic regulation influences AM functions and their involvement in lung diseases. Key mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs, regulate gene expression in response to environmental signals. In healthy lungs, these modifications enable AMs to quickly respond to inhaled threats. However, when these processes malfunction, they could contribute to diseases such as pulmonary fibrosis, COPD, and pulmonary hypertension. By exploring how epigenetic changes affect AM polarization, plasticity, and immune responses, we can gain deeper insights into their role in lung diseases and open new avenues for treating and preventing respiratory conditions. Ultimately, understanding the epigenetic mechanisms within AMs enhances our knowledge of lung immunology and offers potential for innovative interventions to restore lung health and prevent respiratory diseases. Full article

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20 pages, 1696 KiB

Open AccessReview

Role of IgG4 Antibodies in Human Health and Disease

by Li-li Shi, Peng Xiong, Minglin Yang, Ozge Ardicli, Stephan Raphael Schneider, Anders Boutrup Funch, Ayca Kiykim, Juan Lopez, Cezmi A. Akdis and Mübeccel Akdis

Cells 2025, 14(9), 639; https://doi.org/10.3390/cells14090639 - 25 Apr 2025

Viewed by 298

Abstract

Immunoglobulin G4 (IgG4), a unique subclass of IgG antibodies, plays diverse roles in human health and disease. Its distinct features, such as Fab-arm exchange and specific mutations, confer reduced effector functions compared to other IgG subclasses. In health, IgG4 responses contribute to immune [...] Read more.

Immunoglobulin G4 (IgG4), a unique subclass of IgG antibodies, plays diverse roles in human health and disease. Its distinct features, such as Fab-arm exchange and specific mutations, confer reduced effector functions compared to other IgG subclasses. In health, IgG4 responses contribute to immune tolerance, particularly in the context of allergen-specific immunotherapy (AIT), where they can mediate tolerance to environmental antigens, inhibit IgE-dependent mast cell degranulation, and compete with IgE for allergen binding. This helps in attenuating allergic symptoms and is associated with increased levels of allergen-specific IgG4. However, in disease scenarios, the role of IgG4 is complex. IgG4 lacks complement fixation and, thus, shows a reduced ability to activate immune effector pathways, it was initially thought to be protective against autoimmune diseases. However, emerging evidence suggests that it can contribute to pathology. For instance, IgG4 autoantibodies against specific antigens can aggravate conditions in certain autoimmune disorders. In some cancers, it may play a role in immune evasion, with higher levels correlating with poor patient survival, albeit in others, its exact function remains elusive. Overall, understanding the precise role of IgG4 in various physiological and pathological conditions is crucial for developing targeted therapeutic strategies and improving patient outcomes. Full article

(This article belongs to the Special Issue The Role of IgE and IgG Antibodies in Allergic Reactions: Cellular Mechanisms and Biological Implications)

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18 pages, 2137 KiB

Open AccessArticle

Complex Metabolomic Changes in a Combined Defect of Glycosylation and Oxidative Phosphorylation in a Patient with Pathogenic Variants in PGM1 and NDUFA13

by Silvia Radenkovic, Isabelle Adant, Matthew J. Bird, Johannes V. Swinnen, David Cassiman, Tamas Kozicz, Sarah C. Gruenert, Bart Ghesquière and Eva Morava

Cells 2025, 14(9), 638; https://doi.org/10.3390/cells14090638 - 25 Apr 2025

Viewed by 167

Abstract

Inherited metabolic disorders (IMDs) are genetic disorders that occur in as many as 1:2500 births worldwide. Nevertheless, they are quite rare individually and even more rare is the co-occurrence of two IMDs in one individual. To better understand the metabolic cross-talk between glycosylation [...] Read more.

Inherited metabolic disorders (IMDs) are genetic disorders that occur in as many as 1:2500 births worldwide. Nevertheless, they are quite rare individually and even more rare is the co-occurrence of two IMDs in one individual. To better understand the metabolic cross-talk between glycosylation changes and deficient energy metabolism, and its potential effect on outcomes, we evaluated patient fibroblasts with likely pathogenic variants in PGM1 and pathogenic variants in NDUFA13 derived from a patient who passed away at 16 years of age. The patient presented with characteristic of PGM1-CDG including bifid uvula, muscle involvement, abnormal glycosylation in blood, and elevated liver transaminases. In addition, hearing loss, seizures, elevated plasma and CSF lactate and a Leigh-like MRI brain pattern were present, which are commonly associated with Leigh syndrome. PGM1-CDG has been reported in about 70 individuals, while NDUFA13 deficiency has so far only been reported in 13 patients. As abundant energy is essential for glycosylation, and both PGM1 and NDUFA13 are linked to energy metabolism, we sought to better understand the underlying biochemical cause of the patient’s clinical presentation. To do so, we performed extensive investigations including tracer metabolomics, lipidomics and enzymatic studies on the patient’s fibroblasts. We found a profound depletion of UDP-hexoses, consistent with PGM1-CDG. Complex I enzyme activity and mitochondrial function were also impaired, corroborating complex I deficiency and Leigh syndrome. Further, lipidomics analysis showed similarities with both PGM1-CDG and OXPHOS-deficient patients. Based on our results, the patient was diagnosed with both PGM1-CDG and Leigh syndrome. In summary, we present the first case of combined CDG and Leigh syndrome, caused by (likely) pathogenic variants in PGM1 and NDUFA13, and underline the importance of considering the synergistic effects of multiple disease-causing variants in patients with complex clinical presentation, leading to the patient’s early demise. Full article

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27 pages, 13370 KiB

Open AccessArticle

Cytokine Profile Analysis During Sialodacryoadenitis Virus and Mouse Hepatitis Virus JHM Strain Infection in Primary Mixed Microglia and Astrocyte Culture—Preliminary Research

by Michalina Bartak, Weronika D. Krahel, Karolina Gregorczyk-Zboroch, Marcin Chodkowski, Adrian Valentin Potârniche, Ewa Długosz, Małgorzata Krzyżowska and Joanna Cymerys

Cells 2025, 14(9), 637; https://doi.org/10.3390/cells14090637 - 25 Apr 2025

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Abstract

The Coronaviridae family has again demonstrated the potential for significant neurological complications in humans during the recent pandemic. In patients, these symptoms persist throughout the infection, often lasting for months. The consequences of most of these post-infection symptoms might be linked with abnormal [...] Read more.

The Coronaviridae family has again demonstrated the potential for significant neurological complications in humans during the recent pandemic. In patients, these symptoms persist throughout the infection, often lasting for months. The consequences of most of these post-infection symptoms might be linked with abnormal cytokine production and reactive oxygen species (ROS) expression, resulting in neuron damage. We investigated the effect of infection with the Mouse Hepatitis Virus (MHV) JHM strain and Sialodacryoadenitis Virus (SDAV) on a primary microglia and astrocyte culture by analysing ROS production, cytokine and chemokine expression, and cell death during one month post infection. For this purpose, confocal microscopy, flow cytometry, and a high-throughput Luminex ProcartaPlex immunopanel for 48 cytokines and chemokines were utilised. The replication of MHV-JHM and SDAV in microglia and astrocytes has increased the production of pro-inflammatory cytokines and inhibited the production of anti-inflammatory cytokines. The cytokine expression induced by the two viruses differed, as did their detection after infection. SDAV infection resulted in a much broader cytokine response compared to that of MHV-JHM. Both viruses significantly increased ROS levels and induced apoptosis in a small percentage of the cells, but without necrosis. Full article

(This article belongs to the Special Issue Advances in the Study of Neuroinflammation)

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33 pages, 2532 KiB

Open AccessReview

Quitting Your Day Job in Response to Stress: Cell Survival and Cell Death Require Secondary Cytoplasmic Roles of Cyclin C and Med13

by Justin R. Bauer, Tamaraty L. Robinson, Randy Strich and Katrina F. Cooper

Cells 2025, 14(9), 636; https://doi.org/10.3390/cells14090636 - 25 Apr 2025

Viewed by 307

Abstract

Following unfavorable environmental cues, cells reprogram pathways that govern transcription, translation, and protein degradation systems. This reprogramming is essential to restore homeostasis or commit to cell death. This review focuses on the secondary roles of two nuclear transcriptional regulators, cyclin C and Med13, [...] Read more.

Following unfavorable environmental cues, cells reprogram pathways that govern transcription, translation, and protein degradation systems. This reprogramming is essential to restore homeostasis or commit to cell death. This review focuses on the secondary roles of two nuclear transcriptional regulators, cyclin C and Med13, which play key roles in this decision process. Both proteins are members of the Mediator kinase module (MKM) of the Mediator complex, which, under normal physiological conditions, positively and negatively regulates a subset of stress response genes. However, cyclin C and Med13 translocate to the cytoplasm following cell death or cell survival cues, interacting with a host of cell death and cell survival proteins, respectively. In the cytoplasm, cyclin C is required for stress-induced mitochondrial hyperfission and promotes regulated cell death pathways. Cytoplasmic Med13 stimulates the stress-induced assembly of processing bodies (P-bodies) and is required for the autophagic degradation of a subset of P-body assembly factors by cargo hitchhiking autophagy. This review focuses on these secondary, a.k.a. “night jobs” of cyclin C and Med13, outlining the importance of these secondary functions in maintaining cellular homeostasis following stress. Full article

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

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21 pages, 3496 KiB

Open AccessReview

Multimodality in the Collicular Pathway: Towards Compensatory Visual Processes

by Dario Rusciano and Paola Bagnoli

Cells 2025, 14(9), 635; https://doi.org/10.3390/cells14090635 - 25 Apr 2025

Viewed by 182

Abstract

The integration of multisensory inputs plays a crucial role in shaping perception and behavior, particularly in the visual system. The collicular pathway, encompassing the optic tectum in non-mammalian vertebrates and the superior colliculus (SC) in mammals, is a key hub for integrating sensory [...] Read more.

The integration of multisensory inputs plays a crucial role in shaping perception and behavior, particularly in the visual system. The collicular pathway, encompassing the optic tectum in non-mammalian vertebrates and the superior colliculus (SC) in mammals, is a key hub for integrating sensory information and mediating adaptive motor responses. Comparative studies across species reveal evolutionary adaptations that enhance sensory processing and contribute to compensatory mechanisms following neuronal injury. The present review outlines the structure and function of the multisensory visual pathways, emphasizing the retinocollicular projections, and their multisensory integration, which depends on synaptic convergence of afferents conveying information from different sensory modalities. The cellular mechanisms underlying multimodal integration remain to be fully clarified, and further investigations are needed to clarify the link between neuronal activity in response to multisensory stimulation and behavioral response involving motor activity. By exploring the interplay between fundamental neuroscience and translational applications, we aim to address multisensory integration as a pivotal target for its potential role in visual rehabilitation strategies. Full article

(This article belongs to the Section Tissues and Organs)

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13 pages, 4774 KiB

Open AccessArticle

A Novel Allelic Variant of OsAGPL2 Influences Rice Eating and Cooking Quality

by Yuqing Dan, Fudeng Huang, Junfeng Xu, Yong He, Ruixiao Peng, Chunshou Li, Jiayu Song, Yuanyuan Hao and Zhihong Tian

Cells 2025, 14(9), 634; https://doi.org/10.3390/cells14090634 - 25 Apr 2025

Viewed by 193

Abstract

Starch biosynthesis is crucial in determining rice quality during rice endosperm development. This study obtained a stable inheritable white-core endosperm mutant, h5, by treating the japonica rice variety Nipponbare with MNU (N-methyl-N-nitro-sourea). The mutated gene is an allele of OsAGPL2, which [...] Read more.

Starch biosynthesis is crucial in determining rice quality during rice endosperm development. This study obtained a stable inheritable white-core endosperm mutant, h5, by treating the japonica rice variety Nipponbare with MNU (N-methyl-N-nitro-sourea). The mutated gene is an allele of OsAGPL2, which encodes the large subunit of ADP-glucose pyrophosphorylase (AGPase), a key and rate-limiting enzyme in the rice starch biosynthesis pathway. A G-C mutation in the third exon of OsAGPL2 led to impaired starch synthesis, significantly reduced amylose content (AC) and gel consistency (GC), and a marked decrease in AGPase activity. The haplotype analysis revealed that an SNP in the 3′UTR and two SNPs in the 5′UTR of OsAGPL2 were associated with significant differences in AC and GC among rice resources. These SNPs can be utilized to design molecular markers for breeding programs to improve rice quality. This study elucidates the impact of OsAGPL2 on the eating and cooking quality of rice. It identifies superior haplotypes, providing a theoretical foundation and molecular markers for accumulating minor-effect genes to enhance rice quality. Full article

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16 pages, 5043 KiB

Open AccessArticle

Adaptive Optics-Transscleral Flood Illumination Imaging of Retinal Pigment Epithelium in Dry Age-Related Macular Degeneration

by Laura Kowalczuk, Rémy Dornier, Aurélie Navarro, Fanny Jeunet, Christophe Moser, Francine Behar-Cohen and Irmela Mantel

Cells 2025, 14(9), 633; https://doi.org/10.3390/cells14090633 - 24 Apr 2025

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Abstract

Adaptive optics-transscleral flood illumination (AO-TFI) is a novel imaging technique with potential for detecting retinal pigment epithelium (RPE) changes in dry age-related macular degeneration (AMD). This single-center prospective study evaluated its ability to visualize pathological features in AMD. AO-TFI images were acquired using [...] Read more.

Adaptive optics-transscleral flood illumination (AO-TFI) is a novel imaging technique with potential for detecting retinal pigment epithelium (RPE) changes in dry age-related macular degeneration (AMD). This single-center prospective study evaluated its ability to visualize pathological features in AMD. AO-TFI images were acquired using the prototype Cellularis^® camera over six 5 × 5° macular zones in patients with good fixation and no exudative changes. Conventional imaging modalities, including spectral-domain optical coherence tomography (OCT), color fundus photography and fundus autofluorescence, were used for comparison. AO-TFI images were correlated with OCT using a custom method (Fiji software, v. 2.9). Eleven eyes of nine patients (70 ± 8.3 years) with early (n = 5), intermediate (n = 1) and atrophic (n = 5) AMD were analyzed. AO-TFI identified relevant patterns in dry AMD. RPE cell visibility was impaired in affected eyes, but AO-TFI distinguished cuticular drusen with hyporeflective centers and bright edges, large ill-defined drusen and stage 3 subretinal drusenoid deposits as prominent hyperreflective spots. It provided superior resolution for small drusen compared to OCT and revealed crystalline structures and hyporeflective dots in atrophic regions. Atrophic borders remained isoreflective unless RPE displacement was absent, allowing precise delineation. These findings highlight AO-TFI’s potential as a sensitive imaging tool for characterizing early AMD and clinical research. Full article

(This article belongs to the Special Issue Advances in the Discovery of Retinal Degeneration)

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21 pages, 2149 KiB

Open AccessArticle

The Efficacy of Targeted Monoclonal IgA Antibodies Against Pancreatic Ductal Adenocarcinoma

by Léon Raymakers, Elsemieke M. Passchier, Meggy E. L. Verdonschot, Mitchell Evers, Chilam Chan, Karel C. Kuijpers, G. Mihaela Raicu, I. Quintus Molenaar, Hjalmar C. van Santvoort, Karin Strijbis, Martijn P. W. Intven, Lois A. Daamen, Jeanette H. W. Leusen and Patricia A. Olofsen

Cells 2025, 14(9), 632; https://doi.org/10.3390/cells14090632 - 24 Apr 2025

Viewed by 217

Abstract

The efficacy of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) remains limited. The tumor microenvironment (TME), characterized by the accumulation of suppressive myeloid cells including neutrophils, attributes to immunotherapy resistance in PDAC. IgA monoclonal antibodies (mAbs) can activate neutrophils to kill tumor cells; this [...] Read more.

The efficacy of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) remains limited. The tumor microenvironment (TME), characterized by the accumulation of suppressive myeloid cells including neutrophils, attributes to immunotherapy resistance in PDAC. IgA monoclonal antibodies (mAbs) can activate neutrophils to kill tumor cells; this can be further enhanced by blocking the myeloid immune checkpoint CD47. In this study, we investigated the potential of this therapeutic strategy for PDAC. We determined the expression of tumor-associated antigens (TAAs) on PDAC cell lines and fresh patient samples, and the results showed that the TAAs epithelial cell adhesion molecule (EpCAM), trophoblast cell surface antigen 2 (TROP2) and mucin-1 (MUC1), as well as CD47 were consistently expressed on PDAC. In line with this, we showed that IgA mAbs against EpCAM can activate neutrophils to lyse various PDAC cell lines and tumor cells, which can be augmented by addition of CD47 blockade. In addition, we observed that neutrophils were present in patient tumors and expressed the receptor for IgA. In conclusion, our results indicate that a combination of IgA mAb with CD47 blockade is a promising preclinical treatment strategy for PDAC, which merits further investigation. Full article

(This article belongs to the Section Cellular Immunology)

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30 pages, 2540 KiB

Open AccessReview

Ion Channel Regulation in Caveolae and Its Pathological Implications

by Jianyi Huo, Liangzhu Mo, Xiaojing Lv, Yun Du and Huaqian Yang

Cells 2025, 14(9), 631; https://doi.org/10.3390/cells14090631 - 24 Apr 2025

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Abstract

Caveolae are distinctive, flask-shaped structures within the cell membrane that play critical roles in cellular signal transduction, ion homeostasis, and mechanosensation. These structures are composed of the caveolin protein family and are enriched in cholesterol and sphingolipids, creating a unique lipid microdomain. Caveolae [...] Read more.

Caveolae are distinctive, flask-shaped structures within the cell membrane that play critical roles in cellular signal transduction, ion homeostasis, and mechanosensation. These structures are composed of the caveolin protein family and are enriched in cholesterol and sphingolipids, creating a unique lipid microdomain. Caveolae contribute to the functional regulation of various ion channels through both physical interactions and involvement in complex signaling networks. Ion channels localized within caveolae are involved in critical cellular processes such as the generation and propagation of action potentials, cellular responses to mechanical forces, and regulation of metabolism. Dysregulation of caveolae function has been linked to the development of various diseases, including cardiovascular disorders, neurodegenerative diseases, metabolic syndrome, and cancer. This review summarizes the ion channel function and regulation in caveolae, and their pathological implications, offering new insights into their potential as therapeutic targets for ion channel-related diseases. Full article

(This article belongs to the Special Issue Function and Dysfunction of the Caveolar Network in Cell Signaling and Human Disease: An Update after 70 Years of the Discovery of Caveolae)

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27 pages, 26805 KiB

Open AccessArticle

Combined Transplantation of Mesenchymal Progenitor and Neural Stem Cells to Repair Cervical Spinal Cord Injury

by Seok Voon White, Yee Hang Ethan Ma, Christine D. Plant, Alan R. Harvey and Giles W. Plant

Cells 2025, 14(9), 630; https://doi.org/10.3390/cells14090630 (registering DOI) - 23 Apr 2025

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Abstract

Mesenchymal progenitor cells (MPC) are effective in reducing tissue loss, preserving white matter, and improving forelimb function after a spinal cord injury (SCI). We proposed that by preconditioning the mouse by the intravenous delivery (IV) of MPCs for 24 h following SCI, this [...] Read more.

Mesenchymal progenitor cells (MPC) are effective in reducing tissue loss, preserving white matter, and improving forelimb function after a spinal cord injury (SCI). We proposed that by preconditioning the mouse by the intravenous delivery (IV) of MPCs for 24 h following SCI, this would provide a more favorable tissue milieu for an NSC intraspinal bridging transplantation at day three and day seven. In combination, these transplants will provide better anatomical and functional outcomes. The intravenous MSCs would provide cell protection and reduce inflammation. NSCs would provide a tissue bridge for axonal regeneration and myelination and reconnect long tract spinal pathways. Results showed that initial protection of the injury site by IV MPCs transplantation resulted in no increased survival of the NSCs transplanted at day seven. However, integration of transplanted NSCs was increased at the day three timepoint, indicating MPCs influence very early immune signaling. We show, in this study, that MPC transplantation resulted in a co-operative NSC cell survival improvement on day three post-SCI. In addition to increased NSC survival on day three, there was an increase in NSC-derived mature oligodendrocytes at this early timepoint. An in vitro analysis confirmed MPC-driven oligodendrocyte differentiation, which was statistically increased when compared to control NSC-only cultures. These observations provide important information about the combination, delivery, and timing of two cellular therapies in treating SCI. This study provides important new data on understanding the MPC inflammatory signaling within the host tissue and timepoints for cellular transplantation survival and oligodendroglia differentiation. These results demonstrate that MPC transplantation can alter the therapeutic window for intraspinal transplantation by controlling both the circulating inflammatory response and local tissue milieu. Full article

(This article belongs to the Special Issue Stem Cell, Differentiation, Regeneration and Diseases)

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14 pages, 2980 KiB

Open AccessReview

Inflammatory Factors: A Key Contributor to Stress-Induced Major Depressive Disorder

by Qian Liu, Baowen Nie, Xuemin Cui, Wang Wang and Dongxiao Duan

Cells 2025, 14(9), 629; https://doi.org/10.3390/cells14090629 - 23 Apr 2025

Viewed by 138

Abstract

Major depressive disorder (MDD) is a prevalent psychiatric disorder with a complex pathogenesis influenced by various factors. Recent research has highlighted a significant connection between psychological stress and MDD, with inflammation playing a central role in this relationship. Studies have demonstrated that peripheral [...] Read more.

Major depressive disorder (MDD) is a prevalent psychiatric disorder with a complex pathogenesis influenced by various factors. Recent research has highlighted a significant connection between psychological stress and MDD, with inflammation playing a central role in this relationship. Studies have demonstrated that peripheral immune changes in patients with MDD and in mouse models of social stress are closely linked to depressive symptoms. These findings suggest that targeting peripheral immune factors could represent a novel approach for treating stress-related neuropsychiatric disorders. Stress triggers a cascade of inflammatory responses, leading to disruptions in neurotransmitter metabolism and reduced synaptic plasticity. These changes exacerbate depression and contribute to cognitive decline. This study examines the bidirectional relationship between MDD and stress, focusing on the role of inflammation in this complex interplay. Recent studies have identified specific immune factors that are elevated in the serum of patients with MDD and stress-exposed mice, indicating a mechanism by which peripheral immune responses can affect central nervous system function and behavior. Furthermore, proteins, such as nuclear factor kappa-B (NF-κB), reportedly play a critical role in the regulation of stress hormones and are associated with depressive behaviors. Understanding these mechanisms is essential for advancing diagnostic, intervention, and treatment strategies for MDD. Full article

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11 pages, 4908 KiB

Open AccessBrief Report

The Influence of the COVID-19 Pandemic in NK Cell Subpopulations from CML Patients Enrolled in the Argentina Stop Trial

by María Belén Sanchez, Bianca Vasconcelos Cordoba, Carolina Pavlovsky, Beatriz Moiraghi, Ana Ines Varela, Isabel Giere, Mariana Juni, Nicolas Flaibani, José Mordoh, Julio Cesar Sanchez Avalos, Estrella Mariel Levy and Michele Bianchini

Cells 2025, 14(9), 628; https://doi.org/10.3390/cells14090628 - 23 Apr 2025

Viewed by 192

Abstract

Treatment-free remission (TFR) is a key therapeutic goal for chronic myeloid leukemia (CML) patients in deep molecular response (DMR). While predicting patient outcome remains challenging, different NK cell populations seem crucial. We conducted an immunological sub-study from the Argentina Stop Trial (AST), including [...] Read more.

Treatment-free remission (TFR) is a key therapeutic goal for chronic myeloid leukemia (CML) patients in deep molecular response (DMR). While predicting patient outcome remains challenging, different NK cell populations seem crucial. We conducted an immunological sub-study from the Argentina Stop Trial (AST), including 46 patients in 2019 (AST I) and 35 new patients between 2022 and 2023 (AST II). To characterize NK cell subsets in patients attempting TFR, peripheral blood mononuclear cell samples were collected before stopping treatment and phenotype and functional characteristics were assessed by flow cytometry. Non-relapsing patients from AST I exhibited NK cell subpopulations with cytomegalovirus-related memory features, high expression of cytotoxicity markers, and robust functionality. Remarkably, though clinical variables were very similar between cohorts, significant immune differences were observed. NK cell percentage and CD16 and CD57 receptor expression levels were significantly reduced in AST II (p = 0.0051; p = 0.0222; p = 0.0033, respectively), whereas NKp46, NKp44 and PD-1 expression levels were significantly increased (p = 0.0081; p < 0.0001; p < 0.0001, respectively). NK cells from AST II patients demonstrated higher overall functionality and more memory-like subpopulations, characterized mainly by the expression of CD57, NKG2C, NKp30 and NKp46 receptors among CD56^dim NK cells, also with enhanced functional performance. However, in AST II, we were unable to report an association with clinical outcome. Given the enrollment time of both cohorts and that they appear to be clinically homogeneous, we consider that COVID could be impacting the immune landscape; accordingly, serum samples from AST II, but not AST I, confirmed the presence of anti-SARS-CoV-2 IgG. The influence of the COVID pandemic and the different vaccine platforms on NK cells cannot be underestimated when evaluating the role of the immune system in cancer. Full article

(This article belongs to the Special Issue Emerging Insights into Natural Killer Cell Immunity in Infection and Cancer)

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27 pages, 4284 KiB

Open AccessArticle

Revitalizing the Epigenome of Adult Jaw Periosteal Cells: Enhancing Diversity in iPSC-Derived Mesenchymal Stem Cells (iMSCs)

by Felix Umrath, Valerie Wendt, Gilles Gasparoni, Yasser Narknava, Jörn Walter, Bernd Lethaus, Josefin Weber, Victor Carriel, Meltem Avci-Adali and Dorothea Alexander

Cells 2025, 14(9), 627; https://doi.org/10.3390/cells14090627 - 22 Apr 2025

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Abstract

Induced pluripotent stem cells (iPSCs) are rapidly emerging as a transformative resource in regenerative medicine. In a previous study, our laboratory achieved a significant milestone by successfully reprograming jaw periosteal cells (JPCs) into iPSCs, which were then differentiated into iPSC-derived mesenchymal stem cells [...] Read more.

Induced pluripotent stem cells (iPSCs) are rapidly emerging as a transformative resource in regenerative medicine. In a previous study, our laboratory achieved a significant milestone by successfully reprograming jaw periosteal cells (JPCs) into iPSCs, which were then differentiated into iPSC-derived mesenchymal stem cells (iMSCs). Using an optimized protocol, we generated iMSCs with a remarkable osteogenic potential while exhibiting lower expression levels of the senescence markers p16 and p21 compared to the original JPCs. This study aimed to explore the epigenetic landscape by comparing the DNA methylation and transcription profiles of iMSCs with their JPC precursors, seeking to uncover key differences. Additionally, this analysis provided an opportunity for us to investigate the potential rejuvenation effects associated with cellular reprogramming. To assess the safety of the generated cells, we evaluated their ability to form teratomas through subcutaneous injection into immunodeficient mice. Our findings revealed that, while the methylation profile of iMSCs closely mirrored that of JPCs, distinct iMSC-specific methylation patterns were evident. Strikingly, the application of DNA methylation (DNAm) clocks for biological age estimation showed a dramatic reduction in DNAm age to approximately zero in iPSCs—a rejuvenation effect that persisted in the derived iMSCs. This profound reset in biological age, together with our transcriptome data, indicate that iMSCs could possess an enhanced regenerative potential compared to adult MSCs. Future in vivo studies should validate this hypothesis. Full article

(This article belongs to the Special Issue Updates of Stem Cell Applications in Bone Tissue Engineering)

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