Cells

20 pages, 2762 KiB

Open AccessArticle

Granulocyte-Macrophage Colony-Stimulating Factor Inhibition Ameliorates Innate Immune Cell Activation, Inflammation, and Salt-Sensitive Hypertension

by Hannah L. Smith, Bethany L. Goodlett, Gabriella C. Peterson, Emily N. Zamora, Ava R. Gostomski and Brett M. Mitchell

Cells 2025, 14(15), 1144; https://doi.org/10.3390/cells14151144 - 24 Jul 2025

Abstract

Hypertension (HTN) is a major contributor to global morbidity and manifests in several variants, including salt-sensitive hypertension (SSHTN). SSHTN is defined by an increase in blood pressure (BP) in response to high dietary salt, and is associated with heightened cardiovascular risk, renal damage, [...] Read more.

Hypertension (HTN) is a major contributor to global morbidity and manifests in several variants, including salt-sensitive hypertension (SSHTN). SSHTN is defined by an increase in blood pressure (BP) in response to high dietary salt, and is associated with heightened cardiovascular risk, renal damage, and immune system activation. However, the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) has not yet been explored in the context of SSHTN. Previously, we reported that GM-CSF is critical in priming bone marrow-derived (BMD)-macrophages (BMD-Macs) and BMD-dendritic cells (BMD-DCs) to become activated (CD38+) in response to salt. Further exploration revealed these cells differentiated into BMD-M1 Macs, CD38+ BMD-M1 Macs, BMD-type-2 conventional DCs (cDC2s), and CD38+ BMD-cDC2s. Additionally, BMD-monocytes (BMDMs) grown with GM-CSF and injected into SSHTN mice traffic to the kidneys and differentiate into Macs, CD38+ Macs, DCs, and CD38+ DCs. In the current study, we treated SSHTN mice with an anti-GM-CSF antibody (aGM) and found that preventive aGM treatment mitigated BP, prevented renal inflammation, and altered renal immune cells. In mice with established SSHTN, aGM treatment attenuated BP, reduced renal inflammation, and differentially affected renal immune cells. Adoptive transfer of aGM-treated BMDMs into SSHTN mice resulted in decreased renal trafficking. Additionally, aGM treatment of BMD-Macs, CD38+ BMD-M1 Macs, BMD-DCs, and CD38+ BMD-cDC2s led to decreased pro-inflammatory gene expression. These findings suggest that GM-CSF plays a role in SSHTN and may serve as a potential therapeutic target. Full article

25 pages, 1314 KiB

Open AccessArticle

Light Exposure as a Tool to Enhance the Regenerative Potential of Adipose-Derived Mesenchymal Stem/Stromal Cells

by Kaarthik Sridharan, Tawakalitu Okikiola Waheed, Susanne Staehlke, Alexander Riess, Mario Mand, Juliane Meyer, Hermann Seitz, Kirsten Peters and Olga Hahn

Cells 2025, 14(15), 1143; https://doi.org/10.3390/cells14151143 - 24 Jul 2025

Abstract

Photobiomodulation (PBM) utilizes different wavelengths of light to modulate cellular functions and has emerged as a promising approach in regenerative medicine. In this study, we examined the effects of blue (455 nm), red (660 nm), and near-infrared (810 nm) light, both individually and [...] Read more.

Photobiomodulation (PBM) utilizes different wavelengths of light to modulate cellular functions and has emerged as a promising approach in regenerative medicine. In this study, we examined the effects of blue (455 nm), red (660 nm), and near-infrared (810 nm) light, both individually and in combination, on human adipose-derived mesenchymal stem/stromal cells (adMSCs). A single, short-term exposure of adMSCs in suspension to these wavelengths using an integrating sphere revealed distinct wavelength- and dose-dependent cellular responses. Blue light exposure led to a dose-dependent increase in intracellular reactive oxygen species, accompanied by reduced cell proliferation, metabolic activity, interleukin-6/interleukin-8 secretion, and adipogenic differentiation. In contrast, red and near-infrared light preserved cell viability and metabolic function while enhancing cell migration, consistent with their documented ability to stimulate proliferation and mitochondrial activity in mesenchymal stem cells. These findings highlight the necessity of precise wavelength and dosage selection in PBM applications and support the potential of PBM as a customizable tool for optimizing patient-specific regenerative therapies. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells: Current Applications and Future Directions)

14 pages, 7293 KiB

Open AccessArticle

Components of Mineralocorticoid Receptor System in Human DRG Neurons Co-Expressing Pain-Signaling Molecules: Implications for Nociception

by Shaaban A. Mousa, Xueqi Hong, Elsayed Y. Metwally, Sascha Tafelski, Jan David Wandrey, Jörg Piontek, Sascha Treskatsch, Michael Schäfer and Mohammed Shaqura

Cells 2025, 14(15), 1142; https://doi.org/10.3390/cells14151142 - 24 Jul 2025

Abstract

The mineralocorticoid receptor (MR), traditionally associated with renal function, has also been identified in various extrarenal tissues, including the heart, brain, and dorsal root ganglion (DRG) neurons in rodents. Previous studies suggest a role for the MR in modulating peripheral nociception, with MR [...] Read more.

The mineralocorticoid receptor (MR), traditionally associated with renal function, has also been identified in various extrarenal tissues, including the heart, brain, and dorsal root ganglion (DRG) neurons in rodents. Previous studies suggest a role for the MR in modulating peripheral nociception, with MR activation in rat DRG neurons by its endogenous ligand, aldosterone. This study aimed to determine whether MR, its protective enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), its endogenous ligand aldosterone, and the aldosterone-synthesizing enzyme CYP11B2 are expressed in human DRG neurons and whether they colocalize with key pain-associated signaling molecules as potential targets for genomic regulation. To this end, we performed mRNA transcript profiling and immunofluorescence confocal microscopy on human and rat DRG tissues. We detected mRNA transcripts for MR, 11β-HSD2, and CYP11B2 in human DRG, alongside transcripts for key thermosensitive and nociceptive markers such as TRPV1, the TTX-resistant sodium channel Nav1.8, and the neuropeptides CGRP and substance P (Tac1). Immunofluorescence analysis revealed substantial colocalization of MR with 11β-HSD2 and CGRP, a marker of unmyelinated C-fibers and thinly myelinated Aδ-fibers, in human DRG. MR immunoreactivity was primarily restricted to small- and medium-diameter neurons, with lower expression in large neurons (>70 µm). Similarly, aldosterone colocalized with CYP11B2 and MR with nociceptive markers including TRPV1, Nav1.8, and TrkA in human DRG. Importantly, functional studies demonstrated that prolonged intrathecal inhibition of aldosterone synthesis within rat DRG neurons, using an aldosterone synthase inhibitor significantly downregulated pain-associated molecules and led to sustained attenuation of inflammation-induced hyperalgesia. Together, these findings identify a conserved peripheral MR signaling axis in humans and highlight its potential as a novel target for pain modulation therapies. Full article

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

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10 pages, 772 KiB

Open AccessBrief Report

Prolonged Exposure to Neonatal Hyperoxia Impairs Neuronal and Oligodendrocyte Maturation Associated with Long-Lasting Neuroinflammatory Responses in Juvenile Mice

by Stefanie Obst, Meray Serdar, Karina Kempe, Dharmesh Hirani, Ursula Felderhoff-Müser, Josephine Herz, Miguel A. Alejandre Alcazar and Ivo Bendix

Cells 2025, 14(15), 1141; https://doi.org/10.3390/cells14151141 - 24 Jul 2025

Abstract

Preterm infants often require oxygen supplementation, resulting in high risk for bronchopulmonary dysplasia (BPD) and neurodevelopmental deficits. Despite a growing number of studies, there is still little knowledge about brain injury in BPD models. Therefore, we exposed neonatal C57BL/6 mice to 85% oxygen [...] Read more.

Preterm infants often require oxygen supplementation, resulting in high risk for bronchopulmonary dysplasia (BPD) and neurodevelopmental deficits. Despite a growing number of studies, there is still little knowledge about brain injury in BPD models. Therefore, we exposed neonatal C57BL/6 mice to 85% oxygen from birth to postnatal day (P) 14. At P28, two weeks after recovery under normoxic conditions, right hemisphere was used for the analysis of mRNA and the left hemisphere for protein expression of neuronal cells, neuroinflammatory and vascularisation markers, analysed by real-time PCR and Western blot, respectively. Hyperoxia led to an altered expression of markers associated with neuronal and oligodendrocyte maturation and neuroinflammation such as Dcx, Nestin, Il-1β, Il-6, NG2, and YM1/2. These changes were accompanied by an increased expression of genes involved in angiogenesis and vascular remodelling, e.g., Vegf-a, Nrp-1, and Icam-1. Together, 14 days of hyperoxia triggered a phenotypic response, resembling signs of encephalopathy of prematurity (EoP). Full article

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11 pages, 2647 KiB

Open AccessCommunication

The Interaction of pT73-Rab10 with Myosin Va, but Not Myosin Vb, Is Regulated Though a Site in the Globular Tail Domain

by Lynne A. Lapierre, Elizabeth H. Manning, Kyra S. Thomas, Catherine Caldwell and James R. Goldenring

Cells 2025, 14(15), 1140; https://doi.org/10.3390/cells14151140 - 24 Jul 2025

Abstract

The phosphorylation of Rab10 (pT73-Rab10) by LRRK2 promotes the establishment of epithelial cell polarity by controlling the trafficking to the primary cilia membrane of cilia-resident proteins and signaling proteins. Previous studies have identified a site in the globular tail domain of MYO5A that [...] Read more.

The phosphorylation of Rab10 (pT73-Rab10) by LRRK2 promotes the establishment of epithelial cell polarity by controlling the trafficking to the primary cilia membrane of cilia-resident proteins and signaling proteins. Previous studies have identified a site in the globular tail domain of MYO5A that specifically binds to only the phosphorylated form of Rab10. In this work, we have demonstrated that pT73-Rab10 does not associate with the globular tail of MYO5B. We have mapped the putative binding site to a required three amino acids (MEN, 1473–1475) in the MYO5A globular tail domain that are not found in the MYO5B globular tail. Substitution of the MEN amino acid sequence found in MYO5A into the paralogous position in the MYO5B globular tail conferred the ability to associate with pT73-Rab10. The results demonstrate that the interactors with MYO5A and MYO5B are not completely overlapping and that the interaction of pT73-Rab10 is specific to the MYO5A globular tail domain. Full article

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14 pages, 595 KiB

Open AccessReview

The Mechanical Properties of Erythrocytes Are Influenced by the Conformational State of Albumin

by Ivana Pajic-Lijakovic, Milan Milivojevic, Gregory Barshtein and Alexander Gural

Cells 2025, 14(15), 1139; https://doi.org/10.3390/cells14151139 - 24 Jul 2025

Abstract

The mechanical stability and deformability of erythrocytes are vital for their function as they traverse capillaries, where shear stress can reach up to 10 Pa under physiological conditions. Human serum albumin (HSA) is known to help maintain erythrocyte stability by influencing cell shape, [...] Read more.

The mechanical stability and deformability of erythrocytes are vital for their function as they traverse capillaries, where shear stress can reach up to 10 Pa under physiological conditions. Human serum albumin (HSA) is known to help maintain erythrocyte stability by influencing cell shape, membrane integrity, and resistance to hemolysis. However, the precise mechanisms by which albumin exerts these effects remain debated, with some studies indicating a stabilizing role and others suggesting the opposite. This review highlights that under high shear rates, albumin molecules may undergo unfolding due to normal stress differences. Such structural changes can significantly alter albumin’s interactions with the erythrocyte membrane, thereby affecting cell mechanical stability. We discuss two potential scenarios explaining how albumin influences erythrocyte mechanics under shear stress, considering both the viscoelastic properties of blood and those of the erythrocyte membrane. Based on theoretical analyses and experimental evidence from the literature, we propose that albumin’s effect on erythrocyte mechanical stability depends on (i) the transition between unfolded and folded states of the protein and (ii) the impact of shear stress on the erythrocyte membrane’s ζ-potential. Understanding these factors is essential for elucidating the complex relationship between albumin and erythrocyte mechanics in physiological and pathological conditions. Full article

(This article belongs to the Special Issue Cell Behavior Under Blood Flow)

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17 pages, 3646 KiB

Open AccessArticle

Nonmuscle Myosin-2B Regulates Apical Cortical Mechanics, ZO-1 Dynamics and Cell Size in MDCK Epithelial Cells

by Marine Maupérin, Niklas Klatt, Thomas Glandorf, Thomas Di Mattia, Isabelle Méan, Andreas Janshoff and Sandra Citi

Cells 2025, 14(15), 1138; https://doi.org/10.3390/cells14151138 - 23 Jul 2025

Abstract

In epithelial cells, nonmuscle myosin-2B (NM2B) shows a cortical localization and is tethered to tight junctions (TJs) and adherens junctions (AJs) by the junctional adaptor proteins cingulin and paracingulin. MDCK cells knock-out (KO) for cingulin show decreased apical membrane cortex stiffness and decreased [...] Read more.

In epithelial cells, nonmuscle myosin-2B (NM2B) shows a cortical localization and is tethered to tight junctions (TJs) and adherens junctions (AJs) by the junctional adaptor proteins cingulin and paracingulin. MDCK cells knock-out (KO) for cingulin show decreased apical membrane cortex stiffness and decreased TJ membrane tortuosity, and the rescue of these phenotypes requires the myosin-binding region of cingulin. Here, we investigated whether NM2B contributes to these phenotypes independently of cingulin by generating and characterizing clonal lines of MDCK cells KO for NM2B. The loss of NM2B resulted in decreased stiffness and increased fluidity of the apical cortex and reduced accumulation of E-cadherin and phalloidin-labeled actin filaments at junctions but had no significant effect on TJ membrane tortuosity. Fluorescence recovery after photobleaching (FRAP) showed that the KO of NM2B increased the dynamics of the TJ scaffold protein ZO-1, correlating with decreased ZO-1 accumulation at TJs. Finally, the KO of NM2B increased cell size in cells grown both in 2D and 3D but did not alter lumen morphogenesis of cysts. These results extend our understanding of the functions of NM2B by describing its role in the regulation of the mechanical properties of the apical membrane cortex and cell size and validate our model about the role of cingulin–NM2B interaction in the regulation of ZO-1 dynamics. Full article

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13 pages, 1110 KiB

Open AccessArticle

The Effect of Ursodeoxycholic Acid (UDCA) on Serum Expression of miR-34a and miR-506 in Patients with Chronic Cholestatic Liver Diseases

by Eliza Cielica, Alicja Łaba, Piotr Milkiewicz, Beata Kruk, Agnieszka Kempinska-Podhorodecka, Patrycja Kłos, Pedro M. Rodrigues, Beatriz Val, Maria J. Perugorria, Jesus M. Banales and Malgorzata Milkiewicz

Cells 2025, 14(15), 1137; https://doi.org/10.3390/cells14151137 - 23 Jul 2025

Abstract

Ursodeoxycholic acid (UDCA) is widely used to treat cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), yet its molecular mechanisms remain unclear. This study investigated the impact of long-term UDCA therapy on circulating levels of the microRNAs [...] Read more.

Ursodeoxycholic acid (UDCA) is widely used to treat cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), yet its molecular mechanisms remain unclear. This study investigated the impact of long-term UDCA therapy on circulating levels of the microRNAs miR-34a and miR-506, which are implicated in PBC pathogenesis, and explored associated changes in inflammatory markers and signaling pathways. Serum samples from patients with PBC and PSC were collected before and after UDCA treatment and analyzed for miRNA expression as well as levels of TREM-2 and sCD163. In vitro studies using human cholangiocytes and lipopolysaccharide (LPS) stimulation assessed changes in the expression of miR-34a, TREM-2, and ADAM17. The results showed that the baseline levels of miR-34a and miR-506 were significantly elevated in PBC patients compared to controls and were significantly reduced after UDCA therapy in PBC but not in PSC. UDCA also decreased serum levels of TREM-2 and sCD163. In vitro, it suppressed the LPS-induced expression of miR-34a and ADAM17 while enhancing TREM-2 expression. Single-cell RNA sequencing of liver tissue and immunofluorescence staining confirmed TREM-2 expression in cholangiocytes. These findings suggest that UDCA modulates key inflammatory pathways and miRNAs in PBC, providing mechanistic insights into its therapeutic effect Full article

(This article belongs to the Special Issue Gastrointestinal Disease: From Cellular Mechanisms to Targeted Therapy)

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21 pages, 1549 KiB

Open AccessReview

Nanotechnology-Based Delivery of CRISPR/Cas9 for Cancer Treatment: A Comprehensive Review

by Mohd Ahmar Rauf, Afifa Rao, Siva Sankari Sivasoorian and Arun K. Iyer

Cells 2025, 14(15), 1136; https://doi.org/10.3390/cells14151136 - 23 Jul 2025

Abstract

CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9)-mediated genome editing has emerged as a transformative tool in medicine, offering significant potential for cancer therapy because of its capacity to precisely target and alter the genetic modifications associated with the disease. However, a [...] Read more.

CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9)-mediated genome editing has emerged as a transformative tool in medicine, offering significant potential for cancer therapy because of its capacity to precisely target and alter the genetic modifications associated with the disease. However, a major challenge for its clinical translation is the safe and efficient in vivo delivery of CRISPR/Cas9 components to target cells. Nanotechnology is a promising solution to this problem. Nanocarriers, owing to their tunable physicochemical properties, can encapsulate and protect CRISPR/Cas9 components, enabling targeted delivery and enhanced cellular uptake. This review provides a comprehensive examination of the synergistic potential of CRISPR/Cas9 and nanotechnology in cancer therapy and explores their integrated therapeutic applications in gene editing and immunotherapy. A critical aspect of in vivo CRISPR/Cas9 application is to achieve effective localization at the tumor site while minimizing off-target effects. Nanocarriers can be engineered to overcome biological barriers, thereby augmenting tumor-specific delivery and facilitating intracellular uptake. Furthermore, their design allows for controlled release of the therapeutic payload, ensuring sustained efficacy and reduced systemic toxicity. The optimization of nanocarrier attributes, including size, shape, surface charge, and composition, is crucial for improving the cellular internalization, endosomal escape, and nuclear localization of CRISPR/Cas9. Moreover, surface functionalization with targeting ligands can enhance the specificity of cancer cells, leading to improved gene-editing accuracy. This review thoroughly discusses the challenges associated with in vivo CRISPR/Cas9 delivery and the innovative nanotechnological strategies employed to overcome them, highlighting their combined potential for advancing cancer treatment for clinical application. Full article

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22 pages, 26510 KiB

Open AccessArticle

Loss of C-Terminal Coiled-Coil Domains in SDCCAG8 Impairs Centriolar Satellites and Causes Defective Sperm Flagellum Biogenesis and Male Fertility

by Kecheng Li, Xiaoli Zhou, Wenna Liu, Yange Wang, Zilong Zhang, Houbin Zhang and Li Jiang

Cells 2025, 14(15), 1135; https://doi.org/10.3390/cells14151135 - 23 Jul 2025

Abstract

Sperm flagellum defects are tightly associated with male infertility. Centriolar satellites are small multiprotein complexes that recruit satellite proteins to the centrosome and play an essential role in sperm flagellum biogenesis, but the precise mechanisms underlying this role remain unclear. Serologically defined colon [...] Read more.

Sperm flagellum defects are tightly associated with male infertility. Centriolar satellites are small multiprotein complexes that recruit satellite proteins to the centrosome and play an essential role in sperm flagellum biogenesis, but the precise mechanisms underlying this role remain unclear. Serologically defined colon cancer autoantigen protein 8 (SDCCAG8), which encodes a protein containing eight coiled-coil (CC) domains, has been associated with syndromic ciliopathies and male infertility. However, its exact role in male infertility remains undefined. Here, we used an Sdccag8 mutant mouse carrying a CC domains 5–8 truncated mutation (c.1351–1352insG p.E451GfsX467) that models the mutation causing Senior–Løken syndrome (c.1339–1340insG p.E447GfsX463) in humans. The homozygous Sdccag8 mutant mice exhibit male infertility characterized by multiple morphological abnormalities of the flagella (MMAF) and dysmorphic structures in the sperm manchette. A mechanistic study revealed that the SDCCAG8 protein is localized to the manchette and centrosomal region and interacts with PCM1, the scaffold protein of centriolar satellites, through its CC domains 5–7. The absence of the CC domains 5–7 in mutant spermatids destabilizes PCM1, which fails to recruit satellite components such as Bardet–Biedl syndrome 4 (BBS4) and centrosomal protein of 131 kDa (CEP131) to satellites, resulting in defective sperm flagellum biogenesis, as BBS4 and CEP131 are essential to flagellum biogenesis. In conclusion, this study reveals the central role of SDCCAG8 in maintaining centriolar satellite integrity during sperm flagellum biogenesis. Full article

(This article belongs to the Special Issue Advances in Spermatogenesis)

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31 pages, 4221 KiB

Open AccessArticle

Estradiol Downregulates MicroRNA-193a to Mediate Its Angiogenic Actions

by Lisa Rigassi, Mirel Adrian Popa, Ruth Stiller, Brigitte Leeners, Marinella Rosselli and Raghvendra Krishna Dubey

Cells 2025, 14(15), 1134; https://doi.org/10.3390/cells14151134 - 23 Jul 2025

Abstract

Estrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recent evidence that microRNAs (miRNAs) play [...] Read more.

Estrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recent evidence that microRNAs (miRNAs) play an important role in vascular health and disease as well as in regulating Estrogen actions in many cell types. We hypothesize that E2 may mediate its vascular protective actions via the regulation of miRNAs. Following initial screening, we found that E2 downregulates the levels of miR-193a-3p in ECs. Moreover, miR-193a-3p downregulation by miR-193a-3p-antimir mimicked the effects as E2 on EC growth, migration, and capillary formation. Restoring miR-193a-3p levels with mimics after E2 treatment abrogated the vasculogenic actions of E2, suggesting a key role of miR-193a-3p in E2-mediated EC-growth-promoting effects. We further investigated the cellular mechanisms involved and found that miR-193a-3p inhibits angiogenesis by blocking phosphoinositide-3-kinase (PI3K)/Akt-vascular endothelial growth factor (VEGF) and Activin receptor-like kinase 1 (ALK1)/SMAD1/5/8 signaling in ECs, both pathways that are important in E2-mediated vascular protection. Additionally, using reverse transcription polymerase chain reaction (RT-PCR), we demonstrate that E2 downregulates miR-193a-3p in ECs via Estrogen Receptor (ER)α, but not ERβ or G protein-coupled estrogen receptor (GPER). Moreover, these actions occur post-transcriptionally, as the expression of pri-miR-193a-3p was not affected. The anti-angiogenic actions of miR-193a-3p were also observed in in vivo Matrigel implant-based capillary formation studies in ovariectomized mice where E2 induced capillary formation, and these effects were abrogated in the presence of miR-193a-3p, but not in the control mimic. Assessment of miR-193a-3p levels in plasma collected from in vitro fertilization (IVF) subjects with low and high E2 levels showed significantly lower miR-193a-3p levels in responders during the high E2 period. Hence, our findings provide the first evidence that miR-193a-3p mimic inhibits angiogenesis whereas its antimir is angiogenic. Importantly, E2 mediates its regenerative actions on ECs/capillary formation by downregulating endogenous miR-193a-3p expression. Both miR-193a-3p mimic or antimir may represent important therapeutic molecules to prevent or to induce endothelial function in treating pathophysiologies associated with capillary growth. Full article

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17 pages, 2227 KiB

Open AccessArticle

Divergent Mechanisms of H2AZ.1 and H2AZ.2 in PRC1-Mediated H2A Ubiquitination

by Xiangyu Shen, Chunxu Chen, Amanda E. Jones, Xiaokun Jian, Gengsheng Cao and Hengbin Wang

Cells 2025, 14(15), 1133; https://doi.org/10.3390/cells14151133 - 23 Jul 2025

Abstract

The histone H2A variant H2AZ plays pivotal roles in shaping chromatin architecture and regulating gene expression. We recently identified H2AZ.2 in histone H2A lysine 119 ubiquitination (H2AK119ub)-enriched nucleosomes, but it is not known whether its highly related isoform H2AZ.1 also regulates this modification. [...] Read more.

The histone H2A variant H2AZ plays pivotal roles in shaping chromatin architecture and regulating gene expression. We recently identified H2AZ.2 in histone H2A lysine 119 ubiquitination (H2AK119ub)-enriched nucleosomes, but it is not known whether its highly related isoform H2AZ.1 also regulates this modification. In this study, we employed isoform-specific epitope-tagged knock-in mouse embryonic stem cell (ESC) lines to dissect the roles of each isoform in Polycomb Repressive Complex 1 (PRC1)-mediated H2AK119ub. Our results show that H2AZ.1 and H2AZ.2 share highly overlapping genomic binding profiles, both co-localizing extensively with H2AK119ub-enriched loci. The knockdown of either isoform led to reduced H2AK119ub levels; however, the two isoforms appear to function through distinct mechanisms. H2AZ.1 facilitates the recruitment of Ring1B, the catalytic subunit of PRC1, thereby promoting the deposition of H2AK119ub. In contrast, H2AZ.2 does not significantly affect Ring1B recruitment but instead functions as a structural component that stabilizes H2AK119ub-modified nucleosomes. In vitro ubiquitination assays indicate that H2AZ.1-containing nucleosomes serve as more efficient substrates for PRC1-mediated ubiquitination compared to those containing H2AZ.2. Thus, these findings define the distinct mechanisms of the two H2AZ variants in regulated PRC1-mediated H2AK119 ubiquitination and highlight a functional division of labor in epigenetic regulation. Full article

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32 pages, 10235 KiB

Open AccessArticle

Estradiol Downregulates MicroRNA-193a to Mediate Its Anti-Mitogenic Actions on Human Coronary Artery Smooth Muscle Cell Growth

by Lisa Rigassi, Marinella Rosselli, Brigitte Leeners, Mirel Adrian Popa and Raghvendra Krishna Dubey

Cells 2025, 14(15), 1132; https://doi.org/10.3390/cells14151132 - 23 Jul 2025

Abstract

The abnormal growth of smooth muscle cells (SMCs) contributes to the vascular remodeling associated with coronary artery disease, a leading cause of death in women. Estradiol (E2) mediates cardiovascular protective actions, in part, by inhibiting the abnormal growth (proliferation and migration) of SMCs [...] Read more.

The abnormal growth of smooth muscle cells (SMCs) contributes to the vascular remodeling associated with coronary artery disease, a leading cause of death in women. Estradiol (E2) mediates cardiovascular protective actions, in part, by inhibiting the abnormal growth (proliferation and migration) of SMCs through various mechanism. Since microRNAs (miRNAs) play a major role in regulating cell growth and vascular remodeling, we hypothesize that miRNAs may mediate the protective actions of E2. Following preliminary leads from E2-regulated miRNAs, we found that platelet-derived growth factor (PDGF)-BB-induced miR-193a in SMCs is downregulated by E2 via estrogen receptor (ER)α, but not the ERβ or G-protein-coupled estrogen receptor (GPER). Importantly, miR-193a is actively involved in regulating SMC functions. The ectopic expression of miR-193a induced vascular SMC proliferation and migration, while its suppression with antimir abrogated PDGF-BB-induced growth, effects that were similar to E2. Importantly, the restoration of miR-193a abrogated the anti-mitogenic actions of E2 on PDGF-BB-induced growth, suggesting a key role of miR-193a in mediating the growth inhibitory actions of E2 in vascular SMCs. E2-abrogated PDGF-BB, but not miR-193a, induced SMC growth, suggesting that E2 blocks the PDGF-BB-induced miR-193a formation to mediate its anti-mitogenic actions. Interestingly, the PDGF-BB-induced miR-193a formation in SMCs was also abrogated by 2-methoxyestradiol (2ME), an endogenous E2 metabolite that inhibits SMC growth via an ER-independent mechanism. Furthermore, we found that miR-193a induces SMC growth by activating the phosphatidylinositol 3-kinases (PI3K)/Akt signaling pathway and promoting the G1 to S phase progression of the cell cycle, by inducing Cyclin D1, Cyclin Dependent Kinase 4 (CDK4), Cyclin E, and proliferating-cell-nuclear-antigen (PCNA) expression and Retinoblastoma-protein (RB) phosphorylation. Importantly, in mice, treatment with miR-193a antimir, but not its control, prevented cuff-induced vascular remodeling and significantly reducing the vessel-wall-to-lumen ratio in animal models. Taken together, our findings provide the first evidence that miR-193a promotes SMC proliferation and migration and may play a key role in PDGF-BB-induced vascular remodeling/occlusion. Importantly, E2 prevents PDGF-BB-induced SMC growth by downregulating miR-193a formation in SMCs. Since, miR-193a antimir prevents SMC growth as well as cuff-induced vascular remodeling, it may represent a promising therapeutic molecule against cardiovascular disease. Full article

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42 pages, 2555 KiB

Open AccessReview

Prosaposin: A Multifaceted Protein Orchestrating Biological Processes and Diseases

by Xin Li and Liang Guo

Cells 2025, 14(15), 1131; https://doi.org/10.3390/cells14151131 - 22 Jul 2025

Abstract

Prosaposin (PSAP), a multifunctional protein, plays a central role in various biological processes and diseases. It is the precursor of lysosomal activating protein, which is important for lipid metabolism and glucose metabolism. PSAP is implicated in cell signaling, neuroprotection, immunomodulation, and tumorigenesis. In [...] Read more.

Prosaposin (PSAP), a multifunctional protein, plays a central role in various biological processes and diseases. It is the precursor of lysosomal activating protein, which is important for lipid metabolism and glucose metabolism. PSAP is implicated in cell signaling, neuroprotection, immunomodulation, and tumorigenesis. In neurological disorders, PSAP acts as a neurotrophic factor influencing nerve cell survival and synapse growth, and its dysfunction is associated with a variety of diseases. It modulates immune responses and macrophage functions, affecting inflammation and immune cell activities. The role of PSAP in cancers is complex, because it promotes or inhibits tumor growth depending on the context and it serves as a potential biomarker for various malignancies. This review examines current research on the functional and pathological roles of PSAP, emphasizing the importance of PSAP in Gaucher disease, neurodegenerative diseases, cardiovascular diseases, and cancer. In order to develop targeted therapies for various diseases, it is essential to understand the mechanisms of action of PSAP in different biological processes. Full article

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17 pages, 1402 KiB

Open AccessReview

Rethinking Short-Chain Fatty Acids: A Closer Look at Propionate in Inflammation, Metabolism, and Mucosal Homeostasis

by Sonia Facchin, Matteo Calgaro and Edoardo V. Savarino

Cells 2025, 14(15), 1130; https://doi.org/10.3390/cells14151130 - 22 Jul 2025

Abstract

Propionate is a short-chain fatty acid (SCFA) produced by gut microbiota through the fermentation of dietary fibers. Among the SCFAs, butyrate stands out and has been extensively studied for its beneficial effects; however, propionate has received less attention despite its relevant roles in [...] Read more.

Propionate is a short-chain fatty acid (SCFA) produced by gut microbiota through the fermentation of dietary fibers. Among the SCFAs, butyrate stands out and has been extensively studied for its beneficial effects; however, propionate has received less attention despite its relevant roles in immune modulation, metabolism, and mucosal homeostasis. This narrative review focuses on propionate’s effects on metabolism, inflammation, microbiota, and gastrointestinal diseases. Propionate acts as a signalling molecule through FFAR2/FFAR3 receptors and modulates immunity, energy metabolism, and gut–brain communication. It has beneficial effects in metabolic disorders, inflammatory bowel disease (IBD), and alcohol-related liver disease (ALD). However, excessive accumulation is linked to neurotoxicity, autism spectrum disorder (ASD), and mitochondrial dysfunction. Its effects are dose-dependent and tissue-specific, with both protective and harmful potentials depending on the context. Propionate use requires a personalized approach, considering the pathological context, host microbiota composition, and appropriate dosage to avoid adverse effects. Full article

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17 pages, 707 KiB

Open AccessReview

Liver Regeneration as a Model for Studying Cellular Plasticity in Mammals: The Roles of Hepatocytes and Cholangiocytes

by Andrey Elchaninov, Polina Vishnyakova, Valeria Glinkina, Timur Fatkhudinov and Gennady Sukhikh

Cells 2025, 14(15), 1129; https://doi.org/10.3390/cells14151129 - 22 Jul 2025

Abstract

In most countries, liver disease is one of the most common pathologic conditions among the population. In this regard, the development of new methods to treat liver diseases is not possible without understanding the mechanisms of regeneration of this organ. A characteristic reaction [...] Read more.

In most countries, liver disease is one of the most common pathologic conditions among the population. In this regard, the development of new methods to treat liver diseases is not possible without understanding the mechanisms of regeneration of this organ. A characteristic reaction of the liver to certain damaging factors is a pronounced cellular plasticity; this primarily concerns hepatocytes and cholangiocytes. This property is also characteristic of Ito stellate cells and macrophages. In this study, we focus on the plasticity of hepatocytes and cholangiocytes. We consider such manifestations of plasticity as the ability to enter the mitotic cycle, as well as transdifferentiation. The contribution of each type of plasticity to liver regeneration is considered, as well as the molecular mechanisms providing the cellular plasticity of hepatocytes and cholangiocytes. Full article

(This article belongs to the Special Issue Cellular Differentiation in Health and Disease)

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3 pages, 2251 KiB

Open AccessCorrection

Correction: Akintade, D.D.; Chaudhuri, B. Apoptosis, Induced by Human α-Synuclein in Yeast, Can Occur Independent of Functional Mitochondria. Cells 2020, 9, 2203

by Damilare D. Akintade and Bhabatosh Chaudhuri

Cells 2025, 14(15), 1128; https://doi.org/10.3390/cells14151128 - 22 Jul 2025

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Abstract

In the original publication [...] Full article

(This article belongs to the Section Cell Signaling)

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12 pages, 10788 KiB

Open AccessArticle

Characteristics of Scar Formation After Intracerebral Hemorrhage in Aged Rats: Effects of Deferoxamine

by Xiongjie Fu, Yingfeng Wan, Ya Hua, Guohua Xi and Richard F. Keep

Cells 2025, 14(15), 1127; https://doi.org/10.3390/cells14151127 - 22 Jul 2025

Viewed by 121

Abstract

Intracerebral hemorrhage (ICH), a severe stroke subtype common in the elderly, often results in high morbidity and mortality, with limited treatment options for long-term recovery. While glial scar formation is increasingly recognized as key to central nervous system (CNS) repair, its role and [...] Read more.

Intracerebral hemorrhage (ICH), a severe stroke subtype common in the elderly, often results in high morbidity and mortality, with limited treatment options for long-term recovery. While glial scar formation is increasingly recognized as key to central nervous system (CNS) repair, its role and characteristics in the aging brain post-ICH remain unclear. This study investigated glial scar formation after ICH (100 μL autologous blood injected into the right basal ganglia model) in aged Fischer 344 rats and assessed the effects of deferoxamine (DFX) treatment. Histological and immunohistochemical analyses were conducted on days 7, 28, and 60 post-ICH using cell-specific and iron-related markers, with DFX administered at 100 mg/kg daily for 14 days in separate groups. Over time, the lesion core showed increased hemosiderin accumulation and astrogliosis. By day 60, the area of astrogliosis corresponded to an area with persistent neuronal loss (DARPP-32-negative). Glial composition shifted from microglia dominance on day 28 to astrocyte predominance by day 60. DFX treatment reduced iron deposition, astrogliosis, and DARPP-32-negative regions while enhancing oligodendrocyte presence. Iron-related markers (HO-1, ferritin, Perls’ staining) and PDGFRβ-positive fibrotic cells were concentrated in the scar core. These findings provide novel insights into scar formation after ICH in aged rats and suggest DFX as a potential therapy to improve outcomes in elderly stroke patients. Full article

(This article belongs to the Special Issue Neuroinflammation in Brain Health and Diseases)

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11 pages, 1161 KiB

Open AccessCommentary

The Role of Nuclear Phosphoinositides in the p53-MDM2 Nexus

by Jeong Hyo Lee, Muhammad Khalil Salah, Xiangqin Chen, Nickolas Vladimir Kucherenko, Vincent L. Cryns and Richard A. Anderson

Cells 2025, 14(15), 1126; https://doi.org/10.3390/cells14151126 - 22 Jul 2025

Viewed by 115

Abstract

Recent insights into the p53-MDM2 nexus have advanced deeper understanding of their regulation and potent impact on cancer heterogeneity. The roles of nuclear phosphoinositide (PIP_ns) in modulating this pathway are emerging as a key mechanism. Here, we dissect the molecular mechanisms [...] Read more.

Recent insights into the p53-MDM2 nexus have advanced deeper understanding of their regulation and potent impact on cancer heterogeneity. The roles of nuclear phosphoinositide (PIP_ns) in modulating this pathway are emerging as a key mechanism. Here, we dissect the molecular mechanisms by which nuclear PIP_ns stabilize p53 through the recruitment of small heat shock proteins (sHSPs), activate the nuclear phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascade, and modulate MDM2 function to regulate the p53-MDM2 interaction. We propose potential mechanisms by which nuclear PIP_ns coordinate signaling with nuclear p53, AKT, and MDM2. Ultimately, we highlight that nuclear PIP_ns serve as a ‘third messenger’ within the p53-MDM2 axis, expanding the current framework of non-canonical nuclear signaling in cancer biology. Full article

(This article belongs to the Section Cell Microenvironment)

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Cells, Volume 14, Issue 15 (August-1 2025) – 19 articles

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