Mechanistic insights into adipose-derived stem cells and exosomes in ischemia-reperfusion injury repair: from shared pathways to organ-specific therapeutics

Abstract

Ischemia-reperfusion injury (IRI) has become a significant challenge for clinical treatment due to the complex multi-mechanism pathological cascade response, including oxidative stress, inflammatory bursts, and programmed cell death. Adipose-derived stem cells (ADSCs) and their exosomes (ADSCs-exosomes) are emerging as a breakthrough therapeutic strategy to reverse IRI, owing to their multi-target synergistic effects. This review systematically analyzes the two major repair modes of ADSCs and ADSCs-exosomes: the "common protection" mechanism, which includes anti-inflammatory, anti-oxidative, and anti-apoptotic effects through paracrine regulation of miRNAs targeting the NF-κB/NRF2/β-catenin signaling axis; and precision repair, which is achieved through organ-specific targets, including hepatic mitochondrial dynamics and pyroptosis inhibition, cardiac macrophage polarization and neutrophil clearance, renal anti-fibrosis and erythropoietin (EPO) activation, as well as brain iron death regulation and microglial remodeling. From the perspective of the mechanism interaction network, this paper first proposes a theoretical framework of "multi-organ shared core pathways and dynamic regulation of different targets." It also reviews the translational potential of combined therapeutic strategies based on engineered exosomes delivery systems and biomaterials, emphasizing the optimization of delivery efficiency and functional enhancement to address the bottleneck of clinical applications. The ADSCs-mediated IRI intervention system provides an essential theoretical and technical basis for the development of individualized precision therapies.

Keywords: adipose-derived stem cells; exosomes; ischemia-reperfusion injury; multimechanism synergy; therapeutic strategy.

FIGURE 1

ADSCs/ADSCs-exosomes mediates a multidimensional network of mechanisms for IRI repair. (A) ADSCs/ADSCs-exosomes mainly act on four major pathways: the Wnt/β-catenin signaling pathway is a key regulator that promotes cell proliferation and tissue regeneration; the NF-κB signaling pathway is a key mediator that inhibits inflammatory responses; the STAT3 signaling pathway is a key factor that enhances the ability of neovascularization; the NRF2 signaling pathwayis an important target for anti-oxidative stress. The four core intervention directions of ADSCs therapy: anti-inflammation, anti-oxidation, anti-apoptosis and pro-regeneration. (B) ADSCs/ADSCs-exosomes have different core intervention strategies for different organs: heart - macrophage polarization, liver - mitochondrial dynamics, brain - iron death blockade, kidney - pathological fibrosis process blockade.

FIGURE 2

Interdisciplinary technical routes for clinical translation of therapies for ADSCs.Clinical translation of ADSCs therapies follows a four-stage pathway: cell preparation, delivery optimization, functional enhancement, and real-time monitoring. The figure reveals the main areas of concentration of current research in each area.

FIGURE 3

From mechanism to clinic: a 10-year route to therapeutic development in ADSCs. It predicts that ADSCs therapies will evolve in the next decade in phases from three dimensions, and reveals the key nodes in each phase.