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Journal Article Research Support, Non-U.S. Gov't Epublish 4 citations

PubMed: 39310100 DOI: 10.7150/thno.100991

Clearance of senescent cells enhances skin wound healing in type 2 diabetic mice.

Theranostics 14(14):5429-5442

Authors: Priyadarshani Nadeeshika Samarawickrama, Guiqin Zhang, Enfang Zhu, Xin Dong, Ayesha Nisar, Hong Zhu, Yuan Ma, Zheyan Zhou, Honglin Yang, Li Gui, Mei Cao, Wei Li, Yu Chang, Meiting Zi, Haoling Cui, Zhongping Duan, Xuan Zhang, Wen Li, Yonghan He

Affiliations

  • Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China. Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China. University of Chinese Academy of Sciences, Beijing 100049, China.
  • Department of Endocrinology, the Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province), Kunming, Yunnan 650011, China.
  • Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
  • Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
  • Department of Orthopedics, the Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, China.
  • Department of Pathology, the Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, China.
  • Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China. Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
  • Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Abstract

Background: Diabetic foot ulcers (DFUs) pose a substantial healthcare challenge due to their high rates of morbidity, recurrence, disability, and mortality. Current DFU therapeutics continue to grapple with multiple limitations. Senescent cells (SnCs) have been found to have a beneficial effect on acute wound healing, however, their roles in chronic wounds, such as DFU, remain unclear. Methods and results: We collected skin, fat, and muscle samples from clinical patients with DFU and lower limb fractures. RNA-sequencing combined with qPCR analyses on these samples demonstrate a significant accumulation of SnCs at DFU, as indicated by higher senescence markers (e.g., p16 and p21) and a senescence-associated secretory phenotype (SASP). We constructed a type 2 diabetic model of db/db mice, fed with a high-fat diet (Db-HFD), which were wounded using a 6 mm punch to the dorsal skin. HFD slightly affected wound healing in wild-type (WT) mice, but high glucose significantly delayed wound healing in the Db-HFD mice. We injected the mice with a previously developed fluorescent probe (XZ1208), which allows the detection of SnCs in vivo, and observed a strong senescence signal at the wound site of the Db-HFD mice. Contrary to the beneficial effects of SnCs in acute wound healing, our results demonstrated that clearance of SnCs using the senolytic compound ABT263 significantly accelerated wound healing in Db-HFD mice. Conclusion: Collectively, these findings suggest that SnCs critically accumulate at wound sites, delaying the healing process in DFUs. Thus, targeting SnCs with senolytic therapy represents a promising approach for DFU treatment, potentially improving the quality of life for patients with DFUs.

MeSH

Skin, Cells, Nanomedicine, Cellular Senescence, Therapeutics

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