Targeting Cellular Microenvironment in Aging and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: 20 March 2026 | Viewed by 1316

Special Issue Editors


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Guest Editor
Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), Leipziger Str. 44/64, 39120 Magdeburg, Germany
Interests: extracellular matrix; cell adhesion; synaptogenesis; synaptic plasticity; intrinsic plasticity; dementia; schizophrenia; mental retardation; epilepsy
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Guest Editor
Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstraße 55, 45122 Essen, Germany
Interests: neuroplasticity; extra cellulat matrix; superresolution microscopy; astrocyte; microglia; stroke; network activity; synapse

Special Issue Information

Dear Colleagues,

The cellular microenvironment governs tissue development and homeostasis through multiple regulatory mechanisms, including soluble ligand–receptor interactions, extracellular vesicle release, and cell–cell- and cell–matrix-mediated intercellular communication. In addition, the physicochemical properties of the microenvironment, such as the local stiffness, viscosity, osmolarity and diffusion properties, can critically affect cellular physiology.

The cellular microenvironment changes during aging and disease. During the progression of joint diseases, such as osteoarthritis, inflammation drives the active remodeling of the extracellular matrix (ECM). ECM alterations, in turn, change the biomechanical environment of cells, which leads to metabolic changes and further drives the pathologic cascades. In cancer, ECM remodeling promotes immune escape, tumor survival and metastasis. In the brain, alterations in ECM composition and integrity contribute to the pathophysiology of epilepsy, dementia and psychiatric disorders. In neurological conditions such as stroke, multiple sclerosis and neurodegenerative diseases, EVs and the ECM regulate neuroplasticity.

In this Special Issue, we aim to explore how the cellular microenvironment can be targeted to prevent or modify the time course of diseases in different organs, including the brain, cartilage, skin, liver, lung, kidney and cardiovascular system. Particularly, but not exclusively, we expect to collect reviews, as well as experimental and bioinformatic studies focusing on the following:

  • New mechanisms of extracellular signaling, particularly “vicious cycles” linking impaired proteostasis, aggregation of peptides/proteins, extracellular vesicle release and inflammation with ECM and tissue remodeling;
  • Cellular dysfunctions during acute and chronic phases of tissue repair triggered by the dysregulation of extracellular proteases and their tissue inhibitors;
  • Role of extracellular vesicles in pathophysiological and recovery mechanisms;
  • Novel antifibrotic strategies;
  • Drugs targeting biosynthesis, glycosylation, proteolysis and other posttranslational modifications of ECM molecules and their receptors, and related biomarkers;
  • Emerging gene therapies targeting the regulation of ECM abundance and composition.

Prof. Dr. Alexander Dityatev
Dr. Egor Dzyubenko
Guest Editors

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Keywords

  • proteoglycans
  • glycans
  • glycoproteins
  • matricellular proteins
  • integrins
  • matrix metalloproteinases
  • extracellular vesicles
  • EV release
  • exosomes
  • extracellular scaffold
  • ECM remodeling
  • fibrosis
  • ECM gene therapy
  • ECM pharmacology
  • synthetic ECM

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Published Papers (1 paper)

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Research

20 pages, 4459 KB  
Article
Substrate Stiffness Modulates Hypertrophic Chondrocyte Reversion and Chondrogenic Phenotype Restoration
by Da-Long Dong and Guang-Zhen Jin
Cells 2025, 14(16), 1291; https://doi.org/10.3390/cells14161291 - 20 Aug 2025
Viewed by 708
Abstract
The stiffness of the extracellular matrix (ECM) plays a pivotal role in the progression of osteoarthritis (OA), particularly by promoting hypertrophic differentiation of chondrocytes, which hinders cartilage regeneration and accelerates pathological ossification. This study aimed to investigate how substrate stiffness modulates hypertrophic chondrocyte [...] Read more.
The stiffness of the extracellular matrix (ECM) plays a pivotal role in the progression of osteoarthritis (OA), particularly by promoting hypertrophic differentiation of chondrocytes, which hinders cartilage regeneration and accelerates pathological ossification. This study aimed to investigate how substrate stiffness modulates hypertrophic chondrocyte behavior and whether it can reverse their phenotype towards a more stable, chondrogenic state. A series of tunable polydimethylsiloxane (PDMS) substrates with stiffnesses ranging from 78 to 508 kPa were fabricated to simulate varying mechanical microenvironments. Hypertrophic chondrocytes were cultured on these substrates, and their morphology, nuclear architecture, gene/protein expression, and mechanotransductive signaling pathways were systematically evaluated. After 7 to 21 days of culture, the chondrocytes on stiffer matrices exhibited enlarged nuclei, increased cytoskeletal tension, and enhanced focal adhesion signaling. This corresponded with the upregulation of osteogenic and hypertrophic markers such as RUNX2, COL10A1, and COL1A1. In contrast, cells on softer substrates (78 kPa) displayed reduced nuclear YAP localization, higher levels of phosphorylated YAP, and significantly increased expression of COL2A1 and SOX9, indicating reversion to a chondrogenic phenotype. Furthermore, differential activation of Smad1/5/8 and Smad2/3 pathways was observed depending on matrix stiffness, contributing to the phenotype shift. Matrix stiffness exerts a significant regulatory effect on hypertrophic chondrocytes via YAP-mediated mechanotransduction. Soft substrates promote phenotype reversion and cartilage-specific gene expression, offering a promising biomechanical strategy for cartilage tissue engineering and OA intervention. Full article
(This article belongs to the Special Issue Targeting Cellular Microenvironment in Aging and Disease)
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