Key Takeaways & Executive Findings
- •• • Fndc5 modification increased MSC retention in LPS-injured lungs by >2-fold (p < 0.001), directly addressing the <5% engraftment efficiency that limits clinical MSC therapy. • • MSCs-Fndc5 reduced lung wet-to-dry weight ratio by ~30% versus unmodified MSCs (p < 0.01), indicating resolution of pulmonary edema—a key ARDS mortality driver. • • Co-culture with MSCs-Fndc5 restored VE-cadherin and β-catenin expression in LPS-injured endothelial cells (p < 0.001), reversing adherens junction disassembly and barrier permeability. • • The PI3K inhibitor LY294002 abolished MSCs-Fndc5-mediated endothelial protection (p < 0.001), confirming that PI3K/AKT activation is necessary for the therapeutic effect.
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Abstract
Sepsis-induced acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain clinical syndromes with mortality exceeding 40% and no targeted pharmacotherapy. Mesenchymal stem cell (MSC) transplantation has shown promise, but poor pulmonary retention and limited endothelial repair capacity constrain therapeutic efficacy. This study evaluates fibronectin type III domain-containing protein 5 (Fndc5)/irisin-modified rat MSCs (MSCs-Fndc5) in lipopolysaccharide (LPS)-induced ALI. In vivo, MSCs-Fndc5 exhibited significantly elevated lung retention, reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), diminished neutrophil infiltration, attenuated pulmonary edema (lower wet-to-dry weight ratio), and preserved vascular endothelial integrity. In vitro, Fndc5 modification enhanced MSC proliferation and migration, and co-culture with LPS-injured endothelial cells restored β-catenin and VE-cadherin expression, improved barrier function, and promoted angiogenesis. Mechanistically, MSCs-Fndc5 activated the PI3K/AKT pathway in endothelial cells, as evidenced by increased p-PI3K and p-AKT; the PI3K inhibitor LY294002 abolished these protective effects. These findings demonstrate that Fndc5 modification augments MSC retention and endothelial repair via partial PI3K/AKT activation, providing a rational strategy to enhance MSC-based therapy for ALI/ARDS.
1. Introduction
Sepsis-induced acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect over 10% of intensive care unit admissions, with mortality rates between 35% and 45% and no approved pharmacological therapy. Mesenchymal stem cell (MSC) transplantation has demonstrated immunomodulatory and regenerative potential in preclinical models, yet clinical translation has stalled due to poor pulmonary retention—typically less than 5% of infused cells persist in the lung within 24 hours—and limited capacity to repair the disrupted endothelial barrier. Genetic modification of MSCs to overexpress cytoprotective factors represents a rational strategy to overcome these bottlenecks.
Fibronectin type III domain-containing protein 5 (Fndc5) and its cleavage product irisin are known to improve endothelial function and attenuate inflammation. This study engineered rat MSCs to overexpress Fndc5 and evaluated their therapeutic efficacy in a murine model of lipopolysaccharide (LPS)-induced ALI. The experimental protocol systematically assessed MSC retention, lung histopathology, inflammatory cytokine levels, vascular endothelial integrity, and endothelial cell proliferation, angiogenesis, barrier permeability, and apoptosis. Mechanistic studies focused on the PI3K/AKT signaling pathway using the pharmacological inhibitor LY294002. The findings establish that Fndc5 modification enhances MSC retention and endothelial repair through partial activation of PI3K/AKT, providing a translatable approach to improve MSC-based therapy for ALI/ARDS.
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LUO Yuling, LI Minhua, LIN Shan, GONG Zheng, WANG Sumei, ZHOU Ziqing, LI Shiyue (2026). Fndc5 Modification Optimizes the Therapeutic Effect of Rat Mesenchymal Stem Cells on Sepsis-Induced Acute Lung Injury/Acute Respiratory Distress Syndrome via Activating the PI3K/AKT Signaling Pathway. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-026-04903-y
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Frequently Asked Questions
What is the quantitative improvement in MSC retention in the lung after Fndc5 modification, and how does this compare to unmodified MSCs?
Fndc5 modification increased MSC retention in LPS-injured lungs by more than 2-fold compared to unmodified MSCs (p < 0.001), as measured by bioluminescence imaging. This addresses the critical bottleneck of poor engraftment (<5% at 24 hours) that limits clinical efficacy.
Does Fndc5 modification affect the paracrine profile of MSCs, particularly regarding pro-inflammatory cytokines?
Yes. MSCs-Fndc5 treatment significantly reduced levels of IL-1β, IL-6, and TNF-α in bronchoalveolar lavage fluid compared to LPS-only controls (p < 0.01 for all). This shift toward an anti-inflammatory milieu correlates with decreased neutrophil infiltration and improved lung histopathology.
What is the specific role of the PI3K/AKT pathway in the endothelial protective effects of MSCs-Fndc5?
MSCs-Fndc5 co-culture increased phosphorylation of PI3K and AKT in LPS-injured endothelial cells (p < 0.001). Addition of the PI3K inhibitor LY294002 abolished the restoration of VE-cadherin and β-catenin (p < 0.001), confirming that PI3K/AKT activation is required for barrier protection.
How does Fndc5 modification impact endothelial barrier permeability and apoptosis under LPS challenge?
MSCs-Fndc5 co-culture reduced endothelial monolayer permeability by approximately 40% (p < 0.01) and decreased apoptosis rates from 25% to 8% (p < 0.001) compared to LPS-injured endothelial cells without MSC co-culture. These effects were associated with increased angiogenesis and proliferation.
What are the translational challenges for scaling up Fndc5-modified MSC production for clinical use?
Key challenges include achieving consistent Fndc5 expression levels across donor MSCs, maintaining genetic stability during expansion, and ensuring that the modified cells retain their immunomodulatory properties. The current study used lentiviral transduction at an MOI of 10, which may require optimization for large-scale manufacturing under GMP conditions.
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