2. Academic Validation
  3. Lysosome-Featured Cell Aggregate-Released Extracellular Vesicles Regulate Iron Homeostasis and Alleviate Post-Irradiation Endothelial Ferroptosis for Mandibular Regeneration

Lysosome-Featured Cell Aggregate-Released Extracellular Vesicles Regulate Iron Homeostasis and Alleviate Post-Irradiation Endothelial Ferroptosis for Mandibular Regeneration

  • Adv Sci (Weinh). 2025 Jun 23:e05070. doi: 10.1002/advs.202505070.
Yuan-Yuan Li 1 2 3,  Bo Ma 4,  Jia-Wei Lu 1,  Kai-Chao Zhang 1,  Chao Ma 1,  Sheng-Feng Bai 1,  Yan-Jiao Li 3,  Si-Qi Ying 1,  Wei-Zong Weng 5,  Kai Zhang 1,  Xi-Wang Hu 6,  Rang Li 1,  Chen-Xi Zheng 1,  Xiao-Ru Xu 1 7,  Ji Chen 1,  Fang Jin 3,  Hao-Kun Xu 1,  Jian-Wei Xie 4,  Yan Jin 1,  Yi Shuai 8 9,  Bing-Dong Sui 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
  • 2 Department of General Dentistry, Xiamen University Affiliated Chenggong Hospital, Xiamen, Fujian, 361001, China.
  • 3 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
  • 4 Laboratory of Toxicant Analysis, Academy of Military Medical Sciences, Beijing, 100850, China.
  • 5 Department of Orthopedics, Xiamen University Affiliated Chenggong Hospital, Xiamen, Fujian, 361001, China.
  • 6 State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
  • 7 School of Stomatology, Xi'an Medical University, Xi'an, Shaanxi, 710021, China.
  • 8 Department of Stomatology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210002, China.
  • 9 Department of Stomatology, General Hospital of Eastern Theater Command, Nanjing, Jiangsu, 210002, China.
PMID: 40546115 DOI: 10.1002/advs.202505070
Abstract

Ferroptosis, a form of regulated cell death driven by iron accumulation and lipid peroxidation, is implicated in various diseases, but effective therapeutic strategies remain limited. Lysosomal impairments cause iron dysregulation and initiate Ferroptosis, which potentially contribute to ionizing radiation-induced tissue damages. Here, the role of intercellular lysosomal regulation in governing iron homeostasis and protecting against Ferroptosis is investigated in models of stem cell aggregation and mandibular regeneration post-irradiation. Lysosomes are discovered to accumulate in specific regions within multi-stem cell aggregates and regulate cell aggregate formation based on iron control, which is occurred through hypoxic signaling-driven lysosomal redistribution mediated by extracellular vesicles. These vesicles exhibit lysosomal features and possess iron-regulating properties, which rescue lysosomal defects to restore iron homeostasis and mitigate Ferroptosis in recipient endothelial cells against the irradiation challenge. Based on lysosomal regulation and anti-ferroptosis, these cell aggregate-released extracellular vesicles (CA-EVs) stimulate the growth of CD31+endomucin+ specialized vessels despite irradiation both in vitro and in vivo, which further promote bone regeneration of post-irradiation mandibular defect. These findings highlight the potential of taking CA-EVs as natural therapeutic agents to safeguard lysosomal function, modulate iron metabolism, and protect against Ferroptosis, paving an avenue for combating post-irradiation endothelial injuries and enhancing tissue regeneration.

Keywords

extracellular vesicles; ferroptosis; iron; irradiation; lysosomes; stem cells; tissue regeneration.

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