Hypoxic BMSC-derived exosomes-induced mitophagy quenches intestinal inflammation via HIF-1α/BNIP3 pathway

Dec 20, 2025Scientific reports

Exosomes from low-oxygen bone marrow stem cells reduce intestinal inflammation by triggering cell cleanup through the HIF-1α/BNIP3 pathway

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Regenerative Health on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Hypoxia-preconditioned exosomes (HP-Exos) reduced apoptosis and reactive oxygen species (ROS) in colon tissues during ulcerative colitis treatment.

HP-Exos enhanced the process of removing damaged mitochondria, known as mitophagy, in HT-29 cells and colon tissues.
The accumulation of reactive oxygen species (ROS) was inhibited by HP-Exos, which is often associated with cell damage.
Expression of Bcl-2 19-kDa interacting protein 3 (BNIP3), linked to the regulation of mitophagy, was increased by HP-Exos.
Knockdown of hypoxia-inducible factor 1α (HIF-1α) counteracted the beneficial effects of HP-Exos on mitophagy and apoptosis.
HP-Exos may protect against colitis induced by dextran sulfate sodium (DSS) by reducing cell death and oxidative stress.

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The use of hypoxia-preconditioned exosomes (HP-Exos) to modulate intestinal immunity in ulcerative colitis (UC) represents a promising therapeutic strategy. However, the effects of hypoxic preconditioning on exosomes derived from bone marrow mesenchymal stem cells (BMSCs) and the underlying mechanisms in UC treatment remain inadequately understood. This study sought to elucidate the regulatory roles and molecular mechanisms of HP-Exos in the context of UC. HP-Exos were isolated from BMSCs and characterized. We employed hypoxia-inducible factor 1α (HIF-1α)-silenced lentivirus-interfered HP-Exos to assess their effects in both in vivo and in vitro models. A series of experiments were conducted to evaluate the effects of HP-Exos on mitophagy, oxidative stress, and apoptosis in HT-29 cells and colonic tissues and to comprehensively analyze the immunoprotective mechanisms of HP-Exos. The results demonstrated that HP-Exos enhanced mitophagy, inhibited reactive oxygen species (ROS) accumulation and apoptosis in HT-29 cells and colon tissues, and upregulated the expression of Bcl-2 19-kDa interacting protein 3 (BNIP3), a downstream effector of HIF-1α. Conversely, HIF-1α knockdown markedly reversed the increase in mitophagy and the inhibition of apoptosis. Our findings indicate that HP-Exos protect against DSS-induced colitis by mitigating apoptosis and ROS production through HIF-1α-BNIP3-mediated mitophagy.

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Hypoxic BMSC-derived exosomes-induced mitophagy quenches intestinal inflammation via HIF-1α/BNIP3 pathway

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