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Cells, Volume 14, Issue 19 (October-1 2025) – 5 articles

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8329 KB

Open AccessArticle

Prolonged Heat-Treated Mesenchymal Precursor Cells Induce Positive Outcomes Following Transplantation in 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(19), 1488; https://doi.org/10.3390/cells14191488 (registering DOI) - 23 Sep 2025

Abstract

Cellular transplantation therapies have been extensively used in experimental spinal cord injury research. However, there is no consensus as to what the most effective cellular controls for the therapeutic cell of interest are. For this reason, we examined whether dead cells obtained through prolonged heat treatment can act as an appropriate cellular control for intravenously injected Sca-1+ mesenchymal precursor cells (MPCs) in C5 unilateral contusion cervical spinal cord injury. This was tested in single intravenous MPC injection alone or intravenous MPC plus intraspinal neural stem cell (NSC) combinatory transplantation studies. MPCs were isolated from the compact bone of FVB mice, while NSCs were isolated from the subventricular zone of luciferase–GFP transgenic FVB mice. Dead MPCs were obtained by heating at 72 °C for at least 12 h. In the MPC-ikofrt\Rftuen45only transplant study, injured mice received an injection of 1 × 10⁶ dead or live MPCs D1 post-injury. Mice were then sacrificed at 8 weeks post-injury. In this study, intravenous injections of dead MPCs showed no statistical difference in injured paw usage compared to live MPCs, but behavior was improved compared to the media-vehicle-only control at D7 and D21. In the combinatory MPC plus NSC transplant study, injured mice received an intravenous injection of 1 × 10⁶ dead or live MPCs D1 post-injury followed by intraspinal injection of 100,000 NSCs at D3 or D7 post-injury. Another two cohorts of mice received only NSCs at D3 or D7 post-injury. Mice were then sacrificed at 6 weeks post-injury. In this study, there was no functional difference in any of the groups in the dual injection study. Morphologically, mice receiving IV injection of dead MPCs had a smaller lesion size compared to the vehicular control, but the lesion size was larger than that of the lesion size in mice receiving live MPC injection. Dead cells elicited functional and anatomical benefits for the spinal-cord-injured mice. In summary, dead cells obtained through prolonged heat treatment proved to be inconsistent and not optimal for use as cellular controls for cell transplantation studies in spinal cord injury but provide positive evidence for non-transplantation-based cell therapies. Full article

(This article belongs to the Section Stem Cells)

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5191 KB

Open AccessArticle

Reactivation of Human X-Linked Gene and Stable X-Chromosome Inactivation Observed in Generation and Differentiation of iPSCs from a Female Patient with HNRNPH2 Mutation

by Guibin Chen, Alexander Rodriguez-Lopez, Darawalee Wangsa, Richa Madan Lomash, Xiuli Huang, Catherine Z. Chen, Rodney A. Bowling, Jr., Neda Ghousifam, Courtney J. Banks, Kerstin A. Hurd, Jizhong Zou and Wei Zheng

Cells 2025, 14(19), 1486; https://doi.org/10.3390/cells14191486 (registering DOI) - 23 Sep 2025

Abstract

X chromosome inactivation (XCI) is a fundamental epigenetic process that balances X-linked gene expression between females and males by silencing one X chromosome in female cells. Variability or skewing of XCI can influence the clinical presentation of X-linked disorders. Bain type X-linked intellectual disability syndrome (MRXSB), caused by mutations in the X-linked HNRNPH2 gene, is characterized by intellectual disability, developmental delay, and neurological abnormalities. In female patients, XCI heterogeneity complicates disease modeling and therapeutic development. Induced pluripotent stem cells (iPSCs) offer a unique platform to study patient-specific disease mechanisms, but the dynamics of XCI during iPSC reprogramming, maintenance, and differentiation are not fully understood. In this study, we generated 12 iPSC clones from fibroblasts of a female MRXSB patient heterozygous for the HNRNPH2 c.340C > T mutation. Four clones expressed the mutant HNRNPH2 allele and eight expressed the wild-type allele, indicating X chromosome reactivation (XCR) followed by random XCI during reprogramming. Importantly, these XCI patterns remained stable during long-term iPSC propagation and subsequent differentiation into the three germ layers and neural stem cells. Our findings provide new insights into XCI and XCR dynamics in the context of X-linked neurodevelopmental disorders and emphasize the importance of careful clone selection for accurate disease modeling using iPSC-based approaches. Full article

(This article belongs to the Special Issue Advances in the Regulation of Proteins and Genes for Stem Cells)

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2394 KB

Open AccessArticle

Prostaglandin D₂ Synthase: A Novel Player in the Pathological Signaling Mechanism of the Aldosterone–Mineralocorticoid Receptor Pathway in the Heart

by Ankita Garg, Malte Juchem, Sinje Biss, Carla Nunes Borisch, Julia Leonardy, Christian Bär, Shashi Kumar Gupta and Thomas Thum

Cells 2025, 14(19), 1485; https://doi.org/10.3390/cells14191485 (registering DOI) - 23 Sep 2025

Abstract

Background: A deregulated aldosterone (Aldo)–mineralocorticoid receptor (MR) pathway is linked to cardiovascular disease (CVD), including hypertension and heart failure. Despite the association of elevated plasma Aldo levels with cardiac stress, inflammation, myocardial fibrosis, and cardiac remodeling, the underlying mechanisms remain elusive. Methods: To study the impact of Aldo–MR pathway overactivation on cardiac health, a novel mouse model with AAV9-mediated MR overexpression and Aldo administration via subcutaneous osmotic pumps was generated. Echocardiographic analyses, transcriptome sequencing, and loss-of-function experiments of an identified lead candidate gene were performed. Additionally, cardiac tissue samples from human patients with end-stage heart failure were analyzed in the study. Results: Mice with an overactivated Aldo–MR pathway exhibited increased neutrophil gelatinase-associated lipocalin (NGAL) expression, cardiac dysfunction, hypertrophy, and fibrosis. Transcriptomics identified prostaglandin D₂ synthase (Ptgds) as a novel downstream effector of the cardiac Aldo–MR pathway. SiRNA-mediated inhibition of Ptgds in primary cardiomyocytes reduced NGAL levels and the hypertrophic impact of Aldo, suggesting a role in mediating Aldo-induced cardiac pathologies. Elevated expression of PTGDS was observed in hiPSC-CMs treated with the pro-hypertrophic cytokine leukemia inhibitory factor (LIF) and in end-stage heart failure patients, ascertaining its importance in cardiac disease settings. Conclusions: PTGDS is a newly identified mediator of Aldo–MR-induced cardiac remodeling and may represent a potential therapeutic target for CVD. Full article

(This article belongs to the Special Issue Advances in the Cellular and Molecular Mechanisms of Cardiovascular Diseases)

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22 pages, 20248 KB

Open AccessArticle

The Role of Nesprin-4 in Breast Cancer Migration and Invasion

by Badria Fouad Al-Sammak, Lutfiye Yildiz Ozer, Hend Salah Fayed, Nada Mohamed Kafour, Johan Ericsson, Ayman Al Haj Zen and Henning F. Horn

Cells 2025, 14(19), 1484; https://doi.org/10.3390/cells14191484 - 23 Sep 2025

Abstract

Cancer metastasis is responsible for most cancer-related deaths. Migration and invasion, key steps in the metastatic cascade, require nuclear pliability to traverse the physical barriers of the extracellular matrix and cell–cell junctions. The nuclear envelope (NE) contains LINC complex proteins, including nesprin-4, which regulate nuclear integrity, stiffness, and cell movement. We report that nesprin-4 expression is generally upregulated in breast cancer samples but is reduced in triple-negative breast cancer (TNBC) samples compared to other subtypes. A nesprin-4 expression analysis in 62 breast cancer cell lines showed that nesprin-4 expression correlates positively with cell lines representing less aggressive tumors, while TNBC cell lines have low or no nesprin-4 expression. To determine the role of nesprin-4, we modulated nesprin-4 expression levels in three breast cancer cell lines: MCF7, T47D (luminal A and nesprin-4-positive), and MDA-MB-231 (TNBC and nesprin-4-negative). We found that nesprin-4 promotes migration and invasion by driving cell polarization. However, we also found that nesprin-4 impedes intravasation into endothelial microvessels. Thus, we propose that nesprin-4 plays a dual role in breast cancer, promoting efficient migration and invasion, but blocking intravasation. Full article

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15 pages, 1773 KB

Open AccessArticle

MicroRNA-21 Protects Hypoxic-Induced Cardiomyocytes Injury by Targeting Smad-7

by Md Sayed Ali Sheikh, A. Alduraywish, Basil Mohammed Alomair, Muhannad Almubarak and Umme Salma

Cells 2025, 14(19), 1483; https://doi.org/10.3390/cells14191483 - 23 Sep 2025

Abstract

Globally acute myocardial infarction is the leading independent cause of unexpected death. This study aimed to explore the diagnostic and molecular impact of miR-21, miR-488, and miR-126 in acute myocardial infarction patients (AMI). We enrolled 95 non-ST-elevation myocardial infarction (NSTEMI) patients, 152 ST-elevation myocardial infarction (STEMI) patients, and 95 healthy individuals, additionally using three-month-old mice and their ventricular-derived H9c2 cells. The circulatory plasma miR-21 and miR-488 levels were significantly upregulated, while plasma miR-126 levels were remarkably downregulated in NSTEMI and STEMI subjects. The receiver operating characteristic curve showed that plasma miR-21, miR-488, and miR-126 were able to clearly differentiate NSTEMI and STEMI from healthy subjects. Moreover, H9c2 hypoxic cells treated with inhibitor miR-21 markedly reduced intracellular ROS levels, capase-3 activities levels, and cellular apoptosis rates and significantly enhanced cellular viability through up regulation of Smad-7 mRNA and protein expressions. In geriatric STEMI and NSTEMI subjects, plasma miR-21 levels were evidently higher than in comparatively younger subjects. Upregulated plasma miR-21 and miR-488 levels and downregulated miR-126 levels might be considered potential clinical biomarkers for myocardial infarction patients, while inhibition of miR-21, which significantly reduced hypoxia-exposed H9c2 cellular injury via targeting Smad-7, could be a new therapeutic target for AMI patients. Low levels plasma miR-21 may have a significant impact on delaying the aging process. Full article

(This article belongs to the Special Issue Advances in the Cellular and Molecular Mechanisms of Cardiovascular Diseases)

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