Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04903-y
Background Acute lung injury/Acute respiratory distress syndrome (ALI/ARDS) is a life-threatening inflammatory lung disorder characterized by high mortality rates and a lack of effective treatment options. Although mesenchymal stem cell (MSC)-based therapies have emerged as a promising approach for ARDS management, optimizing their therapeutic efficacy remains a significant challenge. Recent advances in gene modification techniques have opened new avenues for enhancing MSC functionality. Among these, Fibronectin type III domain-containing protein 5 (Fndc5)/irisin has attracted considerable attention due to its ability to improve endothelial function. This study aims to evaluate the therapeutic potential of Fndc5-modified MSCs in sepsis-induced ALI/ARDS and to elucidate the underlying molecular mechanisms driving their protective effects. Methods To comprehensively evaluate the therapeutic potential of Fndc5-modified MSCs (MSCs-Fndc5) in ARDS, we employed both in vivo and in vitro experimental models. In vivo, a mouse model of sepsis-induced ALI was established through intraperitoneal injection of lipopolysaccharide (LPS), and the protective effects of MSCs-Fndc5 were systematically assessed by analyzing lung histopathology, inflammatory cytokine levels, vascular endothelial integrity, lung wet-to-dry weight ratio, and MSC retention in lung tissue. In parallel, in vitro studies were conducted to investigate the role of MSCs-Fndc5 in mitigating LPS-induced endothelial cell (EC) injury, with a focus on EC proliferation, angiogenesis, barrier permeability, apoptosis, and the regulation of key signaling pathways. Results Fndc5 modification significantly increased the retention rate of MSCs in sepsis-induced ALI murine model while augmenting their in vitro proliferation and migration potential. In vivo, treatment with Fndc5-modified MSCs markedly attenuated lung inflammation, as evidenced by reduced levels of pro-inflammatory cytokines, decreased neutrophil infiltration, and improved lung histopathology. Additionally, MSCs-Fndc5 alleviated pulmonary edema, reduced fibrosis, lowered the lung wet-to-dry weight ratio, and preserved vascular endothelial integrity. In vitro, Fndc5 modification optimizes the therapeutic effect of rat MSCs on sepsis-induced ALI/ARDS via activating the PI3K/AKT signaling pathway.
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04903-y
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.
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04903-y
Background: Acute lung injury/Acute respiratory distress syndrome (ALI/ARDS) is a life-threatening inflammatory lung disorder characterized by high mortality rates and a lack of effective treatment options. Although mesenchymal stem cell (MSC)-based therapies have emerged as a promising approach for ARDS management, optimizing their therapeutic efficacy remains a significant challenge. Recent advances in gene modification techniques have opened new avenues for enhancing MSC functionality. Among these, Fibronectin type III domain-containing protein 5 (Fndc5)/irisin has attracted considerable attention due to its ability to improve endothelial function. This study aims to evaluate the therapeutic potential of Fndc5-modified MSCs in sepsis-induced ALI/ARDS and to elucidate the underlying molecular mechanisms driving their protective effects. Methods: To comprehensively evaluate the therapeutic potential of Fndc5-modified MSCs (MSCs-Fndc5) in ARDS, we employed both in vivo and in vitro experimental models. In vivo, a mouse model of sepsis-induced ALI was established through intraperitoneal injection of lipopolysaccharide (LPS), and the protective effects of MSCs-Fndc5 were systematically assessed by analyzing lung histopathology, inflammatory cytokine levels, vascular endothelial integrity, lung wet-to-dry weight ratio, and MSC retention in lung tissue. In parallel, in vitro studies were conducted to investigate the role of MSCs-Fndc5 in mitigating LPS-induced endothelial cell (EC) injury, with a focus on EC proliferation, angiogenesis, barrier permeability, apoptosis, and the regulation of key signaling pathways. Results: Fndc5 modification significantly increased the retention rate of MSCs in sepsis-induced ALI murine model while augmenting their in vitro proliferation and migration potential. In vivo, treatment with Fndc5-modified MSCs markedly attenuated lung inflammation, as evidenced by reduced levels of pro-inflammatory cytokines, decreased neutrophil infiltration, and improved lung histopathology. Additionally, MSCs-Fndc5 alleviated pulmonary edema, reduced fibrosis, lowered the lung wet-to-dry weight ratio, and preserved vascular endothelial integrity. In vitro, MSCs-Fndc5 significantly enhanced cell proliferation, migration, angiogenesis, endothelial barrier function, apoptosis inhibition, likely via PI3K/AKT pathway activation. Conclusions: Fndc5 overexpression in MSCs augments their therapeutic efficacy in sepsis-induced ALI/ARDS, which may be achieved by activating the endothelial PI3K/AKT pathway and improving MSCs retention in vivo. These findings propose MSCs-Fndc5 as a promising therapeutic strategy for sepsis-induced ALI/ARDS by enhancing endothelial repair, curbing inflammation, and modulating pivotal signaling pathways.