- Immune cells play a crucial role in regulating the production of extracellular matrix (ECM) by fibroblasts and determining the extent of fibrosis in response to inflammation.
- The researchers analyzed skin and lung samples from patients with diffuse cutaneous systemic sclerosis, and identified epiregulin – EGFR signaling as a critical pathway between dendritic cells and fibroblasts in maintaining elevated ECM production and accumulation in fibrotic tissue.
- Epiregulin expression in DC3 dendritic cells, triggered by type I interferon, was found to activate EGFR on fibroblasts, creating a positive feedback loop through NOTCH signaling.
- In mouse models of skin and lung fibrosis, the presence of epiregulin was necessary for the persistence of fibrosis in both tissues. This effect could be reversed by genetic deficiency or a neutralizing antibody targeting epiregulin.
- Therapeutic administration of an epiregulin antibody was able to reverse fibrosis in patient skin and lung explants, suggesting that epiregulin represents a potential biologic drug target for treating fibrosis.
- Epiregulin is revealed as a crucial immune signal that maintains fibrosis in the skin and lungs across multiple diseases, making it a promising target for developing antifibrotic treatments.
Cutaneous wound healing stages:
- Vasoconstriction and hemostasis:
- Formation of stable fibrin clot.
- Stops blood loss.
- Provides a scaffold for migrating immune cells.
- Inflammatory phase:
- Accumulation of immunomodulatory mediators in the wound bed.
- Rapid recruitment of neutrophils.
- Infiltration of monocytes and activation of skin-resident immune cells.
- Proinflammatory cytokines (e.g., TNF-α and IL-1) orchestrate the response to pathogens.
- Immune cells release trophic factors and immunomodulatory molecules.
- Proliferative phase:
- Formation of granulation tissue.
- Myofibroblast differentiation advances wound closure.
- Migration of epidermal stem cells and proliferation/differentiation of transiently amplifying cells.
- Neovascularization for oxygen and nutrient delivery.
- Remodeling phase:
- Pruning of newly formed vasculature.
- Extensive rearrangement of extracellular matrix (ECM).
- Formation of rigid scar tissue.
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Chronic wounds and market implications:
- Lifetime prevalence of chronic wounds in developed countries is 1-2%.
- Chronic wounds represent a severe burden for patients and a socioeconomic challenge.
- The annual global market for wound care-related products is projected to reach $15-22 billion by 2024, representing 2-3% of total healthcare budgets in developed countries.
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- Crosstalk between Kupffer cells (KCs) and hepatic stellate cells (HSCs) is significant in various liver disease conditions, including alcohol-associated liver disease (AALD) fibrosis.
- Targeting the KC-HSC crosstalk is a crucial focus for therapeutic interventions in liver diseases.
- A novel modular nanosystem was developed using self-assembly with boric acid and catechol interactions.
- Polymers modified with CXCR4-inhibiting moieties were utilized in the nanosystem design.
- The polymers were used to encapsulate anti-miR-155, aiming to downregulate miR-155 expression in KCs and inhibit CXCR4 signaling in activated HSCs.
- In a mouse model of AALD fibrosis, the simultaneous inhibition of miR-155 and CXCR4 in different liver cell types showed enhanced antifibrosis effects.
- The study demonstrates the significance of blocking the undesirable crosstalk between HSCs and KCs in reversing AALD fibrosis.
New studies showed:
- Cardiac fibroblasts may exhibit heterogeneity in activation, proliferation, and function during cardiac fibrosis.
- Endocardium-derived fibroblasts show preferential proliferation and expansion in response to pressure overload.
- Dual recombinase-mediated genetic lineage tracing was used to investigate this phenomenon.
- Regional expansion of activated fibroblasts occurs after injury, matching the distribution pattern of endocardium-derived fibroblasts in the heart.
- Fibroblast-specific proliferation tracing revealed this expansion.
- Ablation of endocardium-derived fibroblasts reduces cardiac fibrosis and mitigates the decline of heart function after pressure overload injury.
- Specific targeting of this fibroblast subpopulation has therapeutic potential.
- Wnt signaling plays a mechanistic role in the activation and expansion of endocardium-derived fibroblasts during cardiac remodeling.
- Wnt signaling promotes the process.
- Endocardium-derived fibroblasts are identified as a key fibroblast subpopulation responsible for severe cardiac fibrosis after pressure overload injury.
- The origins of wound myofibroblasts and scar tissue are unclear.
- Injury induces a transient migratory state in adipocytes.
- Migratory adipocytes do not contribute to scar formation.
- Migratory adipocytes remain non-fibrogenic in vitro, in vivo, and upon transplantation.
- Wound adipocytes do not convert into fibrogenic myofibroblasts
- Injury-induced migratory adipocytes remain lineage-restricted.
- Migratory adipocytes do not reprogram into a fibrosing phenotype.
- These findings have broad implications for regenerative medicine, wound repair, diabetes, and fibrotic pathologies
Sublethal necroptosis signaling promotes inflammation and liver cancer
- Concomitant necrosome and NF-κB activation in hepatocytes, with low RIPK3 expression, leads to a prolonged “sublethal” state with leaky membranes, turning them into secretory cells.
- The secretory cells release specific chemokines, including CCL20 and MCP-1, triggering hepatic cell proliferation and activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis.
- In contrast, necrosome activation in hepatocytes with inactive NF-κB signaling causes an accelerated execution of necroptosis, limiting alarmin release, and preventing inflammation and hepatocarcinogenesis.
- Intratumoral NF-κB-necroptosis signatures are associated with poor prognosis in human hepatocarcinogenesis.
- Pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.
- The pulmonary vasculature is often overlooked in lung diseases like ARDS, PF, and COPD.
- Emphasis on managing parenchymal disorders typically focuses on epithelial cell injury and repair.
- Increasing evidence points to the active role of vascular endothelium in lung disease development.
- The endothelial cell network exists in capillary beds, arterial, and venous vessels, controlling immune cell migration, vascular tone, and permeability.
- Endothelial cells contribute to remodeling processes in acute and chronic lung diseases.
- Remodeled vessels and altered endothelial cells are present in lung diseases to varying extents due to disease-specific mechanisms.
- Understanding vascular alterations is crucial due to their association with pulmonary hypertension.
Transglutaminases (TGs) are cross-linking enzymes associated with fibrosis, especially, TG2, TG1, and FXIII-A to the progression of fibrosis. TG2 - fibrosis has been reported mainly through transforming growth factor beta (TGF-beta) signaling and matrix cross-linking mechanisms.
Targeted alveolar regeneration with Frizzled-specific agonists
- Wnt ligands oligomerize Frizzled (Fzd) and Lrp5/6 receptors to control the specification and activity of stem cells in various species.
- The mechanism of selectively activating Wnt signaling in different stem cell populations within the same organ is not well understood.
- In lung alveoli, distinct Wnt receptors are expressed by different cell types: epithelial cells express Fzd5/6, endothelial cells express Fzd4, and stromal cells express Fzd1.
- Fzd5 is specifically required for alveolar epithelial stem cell activity, while fibroblasts use different Fzd receptors.
- Using a range of Fzd-Lrp agonists, it is possible to activate canonical Wnt signaling in alveolar epithelial stem cells through either Fzd5 or non-canonical Fzd6.
- Both a Fzd5 agonist (Fzd5ag) and a Fzd6 agonist (Fzd6ag) stimulate alveolar epithelial stem cell activity and enhance survival in mice following lung injury.
- However, only Fzd6ag promotes an alveolar fate in airway-derived progenitors.
- This research identifies a potential strategy for promoting lung regeneration without exacerbating fibrosis during lung injury.
*Mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A) drive clonal hematopoiesis of indeterminate potential (CHIP) and are linked to unfavorable outcomes in heart failure (HF) patients.
*The interactions between CHIP-mutated cells and other cardiac cell types, such as fibroblasts, were previously unknown.
*The study identifies fibroblasts as potential interaction partners with CHIP-mutated monocytes.
*Inactivating DNMT3A in macrophages intensifies interactions with cardiac fibroblasts, leading to increased cardiac fibrosis.
*DNMT3A inactivation amplifies the release of heparin-binding epidermal growth factor-like growth factor, which activates cardiac fibroblasts.
*The findings suggest that DNMT3A CHIP-driver mutations may play a role in the initiation and progression of HF.
*The study provides a basis for developing innovative anti-fibrotic strategies targeting the pathway identified.
Adipose-Derived Stem Cells (ASCs) are considered ideal for regenerative medicine due to their abundance, autologous (self-donated) origin, non-immunogenicity, and easy accessibility with minimal risk to patients.
- Alveolar fibroblasts are the primary source of multiple fibroblast subsets after lung injury.
- These subsets are influenced by inflammatory and pro-fibrotic signals.
- TGFβ suppresses early inflammatory fibroblast subsets while promoting their differentiation into fibrotic fibroblasts, contributing to intra-alveolar fibrosis.Therapeutic Implications*:
- Blocking fibrotic fibroblast differentiation reduces fibrosis but exacerbates lung inflammation, highlighting the dual roles of fibroblasts in injury responses and homeostasis.