What is the role of fibroblasts in disease and how are conditions with detrimental fibroblast activity managed?

Fibroblasts in Disease: Roles and Management

Fibroblasts are heterogeneous mesenchymal cells that play dual roles in disease—they can both promote pathology through excessive extracellular matrix production and inflammation, and paradoxically serve protective functions in tissue repair and homeostasis. 1

Core Functions and Heterogeneity

Fibroblasts are far from the homogeneous cell population once believed; they represent diverse cellular states with distinct functional roles across tissues 2, 1:

• Constitute approximately 11% of total cardiac cells and originate from multiple sources including primary mesenchymal cells, circulating mesenchymal stem cells, and endothelial-mesenchymal transition 3
• Produce complex extracellular matrix (ECM) including structural proteins, and secrete cytokines, chemokines, and growth factors that regulate tissue microenvironments 3, 1
• Exhibit transcriptional and functional heterogeneity both across and within organs, encoding regional positional information 1

Detrimental Roles in Disease Pathology

Cardiac Ischemia-Reperfusion Injury

In myocardial ischemia-reperfusion injury (IRI), fibroblasts demonstrate harmful effects 3:

• Hypoxic fibroblast-conditioned medium enhances cardiomyocyte susceptibility to ROS-induced mitochondrial permeability transition and reduces cardiomyocyte viability 3
• ATP release from cardiomyocytes through pannexin 1 channels activates fibroblasts during the early ischemic phase 3
• However, fibroblasts also release protective factors: FGF-2 (low molecular weight isoform) mediates cardioprotective effects independent of pro-angiogenic actions when delivered during reperfusion 3

Fibrotic Diseases

Fibroblasts are central drivers of organ fibrosis, which accounts for nearly half of all deaths in the United States 4:

• Myofibroblasts—specialized fibroblast populations—drive collagen secretion and interstitial fibrosis progression in lung, liver, and kidney disease 3
• In renal fibrosis, epithelial cells undergo partial EMT (epithelial-mesenchymal transition), losing tubular function and releasing paracrine signals (particularly TGFβ) that convert existing fibroblasts into myofibroblasts 3
• EMT transcription factor expression is a prerequisite for fibrosis development in mouse models, though debate continues about whether epithelial cells directly become myofibroblasts 3

Cancer Progression

Fibroblasts contribute to tumor progression through multiple mechanisms 4, 5:

• Create stromal fibroinflammatory reactions that disrupt normal tissue integrity 5
• Promote tissue stiffening and disease progression through ECM remodeling 5
• However, emerging evidence reveals disease-restraining fibroblast populations exist, such as Meflin-positive fibroblasts that may suppress rather than promote cancer progression 5

Inflammatory Diseases

In rheumatoid arthritis and inflammatory bowel disease, fibroblasts function as inflammatory cells themselves 6:

• Recruit leukocytes, drive angiogenesis, and enable chronic inflammation in affected tissues 6
• Exhibit powerful cell-intrinsic amplification loops that synergize with primary stimuli to produce striking inflammatory responses 6

Management Strategies for Detrimental Fibroblast Activity

Cardiac Protection Approaches

Multi-targeted combination therapy directed at multiple cellular players (cardiomyocytes, microvasculature, fibroblasts, inflammatory cells, platelets) offers the most promise for limiting IRI damage 3:

• P2Y12 platelet inhibitors reduce MI size when administered at reperfusion onset via conditioning signaling pathways 3
• Target novel inflammatory mediators including inflammasomes, extracellular nucleic acids, and neutrophil extracellular traps to attenuate initial inflammatory responses 3
• FGF-2 and FGF21 administration during reperfusion may provide cardioprotective effects by modulating fibroblast responses 3

Fibrosis Management

The pathophysiologic basis guides treatment selection 3:

For bronchiolocentric fibrosis (from inhalation injury, aspiration, or systemic disease with airway inflammation):

• Address the underlying exposure or systemic disease driving centrilobular injury 3
• Examples include smoking cessation for respiratory bronchiolitis, antigen avoidance for hypersensitivity pneumonitis 3

For diffuse alveolar inflammation-driven fibrosis (NSIP pattern):

• Target circulating factors and systemic inflammation as these diseases are driven by factors affecting alveolar tissue diffusely 3
• Immunosuppression for connective tissue disease-associated fibrosis, drug discontinuation for drug-induced disease 3

For usual interstitial pneumonia pattern (aberrant senescence-driven):

• Recognize this represents abnormal senescence with telomere shortening and telomerase pathway mutations rather than pure inflammation 3
• Antifibrotic agents targeting fibroblast proliferation and ECM deposition are the mainstay 3

Emerging Therapeutic Concepts

Phenotype conversion strategies represent a novel approach 5:

• Convert pro-disease fibroblasts to anti-disease phenotypes rather than simply depleting all fibroblasts 5
• Target specific disease-promoting fibroblast populations while preserving protective subsets 5, 6

Recognize fibroblast plasticity as both a therapeutic target and challenge 1:

• Fibroblasts easily reenter the cell cycle and exhibit reversible phenotypic plasticity 1
• These properties enable tissue repair when properly regulated but drive fibrotic disorders when aberrantly activated 1

Critical Clinical Pitfalls

• Do not assume all fibroblasts are pathologic—protective fibroblast populations exist and may be essential for tissue repair 5
• Avoid single-target approaches in complex diseases like cardiac IRI where multiple cellular players interact; combination therapy targeting different cell types provides additive protection 3
• Distinguish fibrosis patterns histologically as they indicate different underlying mechanisms requiring distinct therapeutic approaches 3
• Recognize that desmoplasia terminology should only be used in the presence of invasive carcinoma, not for other forms of fibrosis 3