The Roles of the Extracellular Matrix in Cardiac Structure and Function: A Commemorative Issue in Honor of Dr. Thomas K. Borg

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

Deadline for manuscript submissions: 30 January 2026 | Viewed by 8880

Special Issue Editors


E-Mail Website
Guest Editor
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA
Interests: fibrosis; extracellular matrix; fibroblast activation; integrins; cardiovascular disease; alcohol abuse; decellularization; tissue engineering
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, 6439 Garners Ferry Rd., Columbia, SC 29209, USA
Interests: fibroblast; myofibroblast; extracellular matrix

Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to Dr. Thomas K. Borg for his substantial contributions to our understanding of the structure–function relationships of the heart, particularly the contributions of the extracellular matrix (ECM).

Dr. Borg was a passionate scientist, energetic collaborator and insightful mentor. He began his illustrious career by receiving his Ph.D. in entomology, utilizing electron microscopy to study the ultrastructure of neurosecretory cells and sensory receptors in insects. Because of his expertise in microscopy, Tom was recruited to Columbia, S.C., in the 1970s to direct the microscopy facility at the new School of Medicine of the University of South Carolina. It was there that he began over four decades of research focused largely on the structure and function of the heart. This began with seminal studies in collaboration with Dr. James Caulfield that characterized the organization and development of the collagen network in the heart. Studies by Tom and others subsequently illustrated that collagen deposition and crosslinking are critical to the mechanical properties, structural integrity, and physiology of the myocardium. Ultrastructural images of the myocardium led to speculation that cardiomyocytes physically interact with ECM components. Collaborations with Drs. Kristofer Rubin, Björn Öbrink, Evy Lundgren, and others from the University of Uppsala and long-time colleague Dr. Louis Terracio provided a foundation for defining how cardiomyocytes interact with components of the extracellular matrix. This group took advantage of the, then relatively novel, use of cultured heart myocytes to identify integrins as the primary ECM receptors in these cells and begin to elucidate the roles of these proteins in the physiology of myocytes and other heart cells. Research such as this by many investigators worldwide has demonstrated the essential role of cell–ECM interactions in cell motility, proliferation, differentiation, and even survival. Dr. Borg had a strong interest in bioengineering, playing an instrumental role in creation of the biomedical engineering program at the University of South Carolina. Some of his later research applied his knowledge of cardiac ECM to engineer model systems that more closely simulated in vivo cardiac biology to advance our understanding of cardiac development and disease.

Dr. Borg’s broad interests and creative insight helped enhance our understanding of heart structure–function relationships, and his collegiality and outgoing nature helped advance the careers of many young scientists. The aim of this Special Issue of Cells is to recognize the impact that Dr. Borg had in advancing our understanding of the structure–function relationships of the heart at the cellular level. In this Special Issue, we invite contributions in the form of original articles and reviews broadly related to the cellular biology of cardiac structure and function.

Prof. Dr. Wayne Carver
Prof. Dr. Edie Goldsmith
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • collagen
  • integrin
  • extracellular matrix
  • cardiomyocyte
  • fibroblast
  • heart bioengineering

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • Reprint: MDPI Books provides the opportunity to republish successful Special Issues in book format, both online and in print.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (8 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

19 pages, 1655 KB  
Article
Knocking Out Rap1a Attenuates Cardiac Remodeling and Fibrosis in a Male Murine Model of Angiotensin II-Induced Hypertension
by Cody S. Porter, Larissa T. Brown, Can’Torrius Lacey, Mason T. Hickel and James A. Stewart, Jr.
Cells 2025, 14(22), 1834; https://doi.org/10.3390/cells14221834 - 20 Nov 2025
Viewed by 599
Abstract
Hypertension is a leading risk factor for cardiovascular disease and is associated with maladaptive cardiac remodeling, including hypertrophy and fibrosis. The roles of the receptor for advanced glycation end-products (RAGE) and the small GTPase Rap1a in angiotensin II (AngII)-induced remodeling remain unclear. This [...] Read more.
Hypertension is a leading risk factor for cardiovascular disease and is associated with maladaptive cardiac remodeling, including hypertrophy and fibrosis. The roles of the receptor for advanced glycation end-products (RAGE) and the small GTPase Rap1a in angiotensin II (AngII)-induced remodeling remain unclear. This study examined how RAGE and Rap1a influence cardiac responses to AngII using wild-type (WT), RAGE knockout (RAGE KO), and Rap1a knockout (RapKO) mice. Cardiac structure and function were evaluated following AngII infusion. RapKO mice were protected from AngII-induced hypertrophy, whereas RAGE KO mice exhibited altered remodeling patterns. AngII consistently increased left ventricular wall thickness across all genotypes, indicating that structural remodeling is primarily treatment-driven. Measures of cardiac output and stroke volume also changed significantly with AngII, suggesting hemodynamic load as a key driver of functional adaptation. In contrast, diastolic functional parameters were genotype-dependent and remained stable with AngII exposure, demonstrating an intrinsic influence of RAGE and Rap1a on myocardial relaxation. These findings highlight distinct roles for RAGE and Rap1a in modulating hypertensive cardiac remodeling and may parallel human hypertensive heart disease, where increased RAGE and Rap1a expression associate with fibrosis and impaired relaxation. Targeting the crosstalk between the RAGE-AT1R axis and the cAMP-EPAC-Rap1a pathway may offer therapeutic potential to reduce adverse cardiac remodeling in hypertension. Full article
Show Figures

Figure 1

20 pages, 2082 KB  
Article
Female Cardioprotection in a Mouse Model of Alcohol-Associated Cardiomyopathy
by Joshua M. Edavettal, Meagan Donovan, Nicholas R. Harris, Xavier R. Chapa-Dubocq, Keishla M. Rodríguez-Graciani, Janos Paloczi, Liz Simon, Bysani Chandrasekar and Jason D. Gardner
Cells 2025, 14(21), 1682; https://doi.org/10.3390/cells14211682 - 27 Oct 2025
Viewed by 725
Abstract
Chronic alcohol misuse is the leading cause of non-ischemic dilated cardiomyopathy, and the molecular mechanisms underlying the development of alcohol-associated cardiomyopathy (ACM), particularly regarding sex-specific susceptibility and mitochondrial contributions, are not fully known. In this study, we utilized a preclinical model of chronic [...] Read more.
Chronic alcohol misuse is the leading cause of non-ischemic dilated cardiomyopathy, and the molecular mechanisms underlying the development of alcohol-associated cardiomyopathy (ACM), particularly regarding sex-specific susceptibility and mitochondrial contributions, are not fully known. In this study, we utilized a preclinical model of chronic + binge ethanol consumption to investigate sex differences in disease severity and mitochondrial function. Male and female C57BL/6J mice were fed ethanol or control liquid diets for 30 days, with 2 binge episodes on days 10 and 30. Cardiac morphology was assessed via echocardiography and cardiac function via left ventricular pressure–volume catheterization. Mitochondrial function was evaluated ex vivo using Seahorse XF analysis, ATP luminescence, and AmplexTM Red fluorescence in isolated ventricular mitochondria. Ethanol feeding induced significant cardiac dysfunction and increased transcriptional expression of inflammatory and fibrotic markers in males, while these effects were not seen in females. Despite these sex-specific cardiac effects, mitochondrial respiration, ATP production, collagen protein expression, and oxidative stress were not significantly altered following alcohol exposure in either sex. Further investigation is warranted to assess the potential role of ovarian hormones in this female cardioprotection against chronic + binge ethanol. Full article
Show Figures

Graphical abstract

16 pages, 5456 KB  
Article
A Novel Peptoid Hybrid of Alpha-Calcitonin Gene-Related Peptide (α-CGRP) Ameliorates Cardiac Remodeling in Pressure Overload-Induced Heart Failure
by Sarah Deloach, Ambrish Kumar, Emily Ruggiero, Ryan Ball, Kamryn Gleason, Jason Kubinak, Donald J. DiPette and Jay D. Potts
Cells 2025, 14(20), 1580; https://doi.org/10.3390/cells14201580 - 11 Oct 2025
Viewed by 1249
Abstract
α-CGRP (alpha-calcitonin gene-related peptide) is a vasoactive and anti-inflammatory neuropeptide that is cardioprotective in transverse aortic constriction (TAC)-induced pressure overload heart failure (HF) models. Our previous investigations established that a peptoid modification of α-CGRP, termed NMEG-CGRP, prevented left ventricular (LV) dysfunction and remodeling [...] Read more.
α-CGRP (alpha-calcitonin gene-related peptide) is a vasoactive and anti-inflammatory neuropeptide that is cardioprotective in transverse aortic constriction (TAC)-induced pressure overload heart failure (HF) models. Our previous investigations established that a peptoid modification of α-CGRP, termed NMEG-CGRP, prevented left ventricular (LV) dysfunction and remodeling when administered subcutaneously every other day for 28 days, starting two days post-TAC surgery (termed prevention study). Here, we determined whether NMEG-CGRP would be cardioprotective when administered after the development of LV dysfunction secondary to TAC surgery (termed treatment study). Starting 15 days post-sham or TAC surgery, we administered NMEG-CGRP (3.6 mg/kg/mouse) subcutaneously every other day for 28 days in mice assigned to treatment groups. In vivo assessments included weekly electrocardiography to evaluate cardiac function and blood sampling for immunophenotyping. On Day 45, mice were euthanized, and hearts were collected for gross, histological, and biochemical analyses. Compared to sham-operated mice, TAC mice exhibited decreased LV ejection fraction and increased hypertrophy, dilation, fibrosis, apoptosis, and oxidative stress. In contrast, TAC mice treated with NMEG-CGRP demonstrated significant improvements in cardiac function and cellular and biochemical parameters when compared to TAC mice. These findings demonstrate the therapeutic potential of NMEG-CGRP in the treatment of established cardiovascular dysfunction and its progression in pressure overload-induced HF. Full article
Show Figures

Figure 1

14 pages, 6536 KB  
Article
Collagen Fiber Maturity and Architecture in MVP-Associated Fibrosis Quantified by Digital Pathology
by Ranan Phookan, Jordan E. Morningstar, Brian Loizzi, Antonia Van Kampen, Cortney Gensemer, Maja-Theresa Dieterlen, Ricardo Spampinato, Louis Petitjean, Mathieu Petitjean, Taylor Petrucci, Roman Fenner, Jake Griner, Kathryn Byerly, Robert A. Levine, Michael A. Borger and Russell A. Norris
Cells 2025, 14(19), 1536; https://doi.org/10.3390/cells14191536 - 30 Sep 2025
Viewed by 1299
Abstract
Recent evidence demonstrates that mitral valve prolapse (MVP) increases mechanical stress on the subvalvular apparatus and is linked to regional myocardial fibrosis and life-threatening ventricular arrhythmias. However, current surgical guidelines do not account for the extent of myocardial fibrosis or the severity of [...] Read more.
Recent evidence demonstrates that mitral valve prolapse (MVP) increases mechanical stress on the subvalvular apparatus and is linked to regional myocardial fibrosis and life-threatening ventricular arrhythmias. However, current surgical guidelines do not account for the extent of myocardial fibrosis or the severity of leaflet involvement, both key features of arrhythmogenic MVP. To address this gap, we conducted histopathological analysis of endomyocardial biopsies from patients with MVP and regionalized myocardial fibrosis (n = 6) who underwent mitral valve repair. Using digital pathology-based quantitative image analysis (QIA), we found that fibrosis in peri-papillary biopsies exhibited a significantly higher Morphometric Composite Score compared with remote biopsies (5.68 ± 0.69 vs. 3.71 ± 0.49, p = 0.042), reflecting larger, more branched, and more assembled collagen fibers, indicative of a mature and persistent fibrotic phenotype. These findings suggest that myocardial scarring in MVP is well-established by the time of surgery and underscore the potential value of earlier surgical intervention to reduce the risk of arrhythmia and preserve post-operative left ventricular function. Full article
Show Figures

Figure 1

14 pages, 2406 KB  
Article
Dynamic Expression and Functional Implications of the Cell Polarity Gene, Dchs1, During Cardiac Development
by Kathryn Byerly, Cayla Wolfe, Hannah Parris, Charlotte Griggs, Emily Wilson, Matthew Huff, Molly Griggs, Jordan Morningstar, Lilong Guo, Fulei Tang, Jan Guz, Taylor Petrucci, Ranan Phookan, Brian Loizzi, Cortney Gensemer and Russell A. Norris
Cells 2025, 14(11), 774; https://doi.org/10.3390/cells14110774 - 24 May 2025
Viewed by 1510
Abstract
Intercellular interactions among cardiac cell populations are essential for cardiac morphogenesis, yet the molecular mechanisms orchestrating these events remain incompletely understood. Dachsous1 (Dchs1), an atypical cadherin linked to mitral valve prolapse, is a core planar cell polarity protein whose function in the developing [...] Read more.
Intercellular interactions among cardiac cell populations are essential for cardiac morphogenesis, yet the molecular mechanisms orchestrating these events remain incompletely understood. Dachsous1 (Dchs1), an atypical cadherin linked to mitral valve prolapse, is a core planar cell polarity protein whose function in the developing heart has not been fully elucidated. To address this, we generated a Dchs1-HA knock-in mouse model to define its spatial, temporal, and cellular expression patterns. Using immunohistochemistry, western blotting, and single-cell transcriptomics across developmental stages, we demonstrate that cardiac Dchs1 expression is restricted to non-cardiomyocyte lineages. DCHS1 displays dynamic subcellular localization and tissue organization depending on the developmental timepoint, with staining being found in epicardial and endocardial surfaces at earlier embryonic stages and in the compact myocardium in later fetal and neonatal stages. During fetal and neonatal stages, DCHS1-positive non-myocyte, non-endothelial cells form polarized extensions that bridge endothelial and non-myocyte, non-endothelial cells, suggesting direct heterotypic and homotypic interactions. Western blotting revealed evidence of DCHS1 proteolytic cleavage, with intracellular C-terminal fragments. RNA co-expression with its binding partner FAT4 supports a conserved, non-myocyte-specific DCHS1-FAT4 signaling axis. These findings identify DCHS1 as a potential molecular tether that is utilized in intercellular communications during cardiac development, with implications for congenital and acquired heart disease. Full article
Show Figures

Figure 1

Review

Jump to: Research

33 pages, 1729 KB  
Review
Versatile hiPSC Models and Bioengineering Platforms for Investigation of Atrial Fibrosis and Fibrillation
by Behnam Panahi, Saif Dababneh, Saba Fadaei, Hosna Babini, Sanjana Singh, Maksymilian Prondzynski, Mohsen Akbari, Peter H. Backx, Jason G. Andrade, Robert A. Rose and Glen F. Tibbits
Cells 2026, 15(2), 187; https://doi.org/10.3390/cells15020187 - 20 Jan 2026
Viewed by 240
Abstract
Atrial fibrillation (AF) is the most common sustained heart rhythm disorder. It is estimated that AF affects over 52 million people worldwide, with its prevalence expected to double in the next four decades. AF significantly increases the risk of stroke and heart failure, [...] Read more.
Atrial fibrillation (AF) is the most common sustained heart rhythm disorder. It is estimated that AF affects over 52 million people worldwide, with its prevalence expected to double in the next four decades. AF significantly increases the risk of stroke and heart failure, contributing to 340,000 excess deaths annually. Beyond these life-threatening complications, AF results in limitations in physical, emotional, and social well-being causing significant reductions in quality of life and resulting in 8.4 million disability-adjusted life-years per year, highlighting the wide-ranging impact of AF on public health. Moreover, AF is increasingly recognized for its association with cognitive decline and dementia. AF is a chronic and progressive disease characterized by rapid and erratic electrical activity in the atria, often in association with structural changes in the heart tissue. AF is often initiated by triggered activity, often from ectopic foci in the pulmonary veins. These triggered impulses may initiate AF via: (1) sustained rapid firing with secondary disorganization into fibrillatory waves, or (2) by triggering micro re-entrant circuits around the pulmonary venous-LA junction and within the atrial body. In each instance, AF perpetuation necessitates the presence of a vulnerable atrial substrate, which perpetuates and stabilizes re-entrant circuits through a combination of slowed and heterogeneous conduction, as well as functional conduction abnormalities (e.g., fibrosis disrupting tissue integrity, and abnormalities in the intercalated disks disrupting effective cell-to-cell coupling). The re-entry wavelength, determined by conduction velocity and refractory period, is shortened by slowed conduction, favoring AF maintenance. One major factor contributing to these changes is the disruption of the extracellular matrix (ECM), which is induced by atrial fibrosis. Fibrosis-driven disruption of the ECM, especially in the heart and blood vessels, is commonly caused by conditions such as aging, hypertension, diabetes, smoking, and chronic inflammatory or autoimmune diseases. These factors lead to excessive collagen and protein deposition by activated fibroblasts (i.e., myofibroblasts), resulting in increased tissue stiffness, maladaptive remodeling, and impaired organ function. Fibrosis typically occurs when cardiac fibroblasts are activated to myofibroblasts, resulting in the deposition of excessive collagen and other proteins. This change in ECM interferes with the normal electrical function of the heart by creating irregular, fibrotic regions. AF and atrial fibrosis have a reciprocal relationship: AF promotes fibrosis through fibroblast activation and extracellular matrix buildup, while atrial fibrosis can sustain and perpetuate AF, contributing to higher rates of AF recurrence after treatments such as catheter ablation or cardioversion. Full article
Show Figures

Figure 1

15 pages, 671 KB  
Review
Cellular Interactions of Cardiac Repair After Myocardial Infarction
by Merry L. Lindsey, Ashton F. Oliver, Amadou Gaye, Pius N. Nde, Kristine Y. DeLeon-Pennell and Germán E. González
Cells 2025, 14(23), 1903; https://doi.org/10.3390/cells14231903 - 1 Dec 2025
Cited by 1 | Viewed by 1274
Abstract
When blood flow to a part of the myocardial muscle is reduced or blocked, it leads to tissue ischemia in that region. Myocardial infarction (MI) occurs when the ischemic insult is of sufficient duration in time to induce cardiomyocyte death and subsequent activation [...] Read more.
When blood flow to a part of the myocardial muscle is reduced or blocked, it leads to tissue ischemia in that region. Myocardial infarction (MI) occurs when the ischemic insult is of sufficient duration in time to induce cardiomyocyte death and subsequent activation of the innate immune response. MI initiates a complex cascade of cellular and molecular events within the left ventricle. Inflammatory cells rapidly infiltrate the infarcted area to remove necrotic tissue, setting the stage for reparative wound healing processes. Over the ensuing days, various cell populations—including leukocytes, fibroblasts, and endothelial cells—are attracted to the infarcted site by inflammatory cytokines and chemokines. The activated cells at the site of injury contribute to tissue remodeling and scar formation through the deposition of extracellular matrix components, particularly collagen. While scar formation is essential for structural stabilization of the infarct region to replace the loss of cardiomyocytes, scar tissue also increases myocardial stiffness and impairs cardiac contractile function. This review summarizes our knowledge regarding cellular dynamics, inflammatory signaling, and cardiac remodeling that govern MI healing. We identify the current gaps in the field and provide a foundational resource for those seeking to understand the biological underpinnings of cardiac repair following MI. Full article
Show Figures

Figure 1

26 pages, 1238 KB  
Review
Temporal Dynamics of Extracellular Matrix Remodeling in Anthracycline-Induced Cardiotoxicity
by Fibi Meshrkey, Somaya Y. Ibrahim, Rushita A. Bagchi and William J. Richardson
Cells 2025, 14(18), 1471; https://doi.org/10.3390/cells14181471 - 20 Sep 2025
Cited by 1 | Viewed by 1363
Abstract
Anthracyclines are widely used chemotherapeutic agents with proven efficacy against a broad range of malignancies, but their clinical utility is limited by a well-documented, dose-dependent cardiotoxicity. While this toxicity has traditionally been attributed to direct cardiomyocyte injury, emerging evidence highlights the pivotal role [...] Read more.
Anthracyclines are widely used chemotherapeutic agents with proven efficacy against a broad range of malignancies, but their clinical utility is limited by a well-documented, dose-dependent cardiotoxicity. While this toxicity has traditionally been attributed to direct cardiomyocyte injury, emerging evidence highlights the pivotal role of cardiac fibroblasts (CFs) in the development and progression of anthracycline-induced cardiotoxicity. This review examines the diverse effects of anthracycline focusing on doxorubicin (DOX) and CFs across the temporal phases of cardiac injury. DOX activates fibroblast-driven extracellular matrix remodeling and promotes fibrosis through enhanced collagen production and the induction of cellular senescence, thereby exacerbating early myocardial inflammation and dysfunction. Clinically, anthracycline cardiotoxicity may present as acute (within days), subacute (within weeks), or chronic progressive forms manifesting either early (within one year) or late (up to decades post-treatment). While early manifestations may be reversible with timely detection and management, late-phase cardiotoxicity is often irreversible, characterized by declining left ventricular ejection fraction and heart failure. A deeper understanding of the molecular and cellular contributions of CFs may uncover novel therapeutic targets to prevent or attenuate anthracycline-related cardiac damage. Full article
Show Figures

Figure 1

Back to TopTop