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Background <p>Hypoxic pretreatment improves the efficacy of adipose-derived mesenchymal stem cells (ADSCs) in the repair of chronic refractory wounds; however, the underlying molecular mechanisms remain poorly understood. Energy metabolism serves as a crucial regulatory factor that influences stem cell fate, proliferation, and self-renewal capabilities. In this study, we established a diabetic skin wound model to systematically investigate the effects of the diabetic microenvironment and hypoxic pretreatment on the energy metabolism and functions of ADSCs, aiming to elucidate the role of adaptive metabolic regulation in increasing stem cell survival rates following transplantation.</p> Methods <p>An in vitro diabetic cell model was established to systematically evaluate the effects of high glucose and hypoxic preconditioning on the proliferation, migration, apoptosis, and cytokine secretion of ADSCs via PCR analysis and CCK-8, cell scratch, and apoptosis assays. The impact of high glucose and hypoxic preconditioning on the energy metabolism characteristics of ADSCs was investigated with a Seahorse XF Analyzer. The regulatory effects of the mTOR/HIF-1α signalling pathway on the energy metabolism and cellular functions of ADSCs was investigated via mTOR pathway inhibitors and siHIF transfection. The therapeutic efficacy of hypoxia preconditioned ADSCs in diabetic wound healing was determined by calculating wound healing rates and performing histopathological analyses.</p> Results <p>Hypoxic preconditioning alleviated high glucose-induced functional impairments in ADSCs, including enhanced cell proliferation, migration, and cytokine secretion capacity, along with reduced apoptosis. Seahorse XF analysis revealed that high-glucose conditions suppressed glycolytic activity and impaired mitochondrial function, whereas hypoxic preconditioning upregulated glycolytic flux and optimized mitochondrial energy metabolism. Notably, cotreatment with mTOR pathway inhibitors or HIF-1α-targeting siRNA attenuated the beneficial effects of hypoxic preconditioning, particularly its regulatory impact on energy metabolism profiles. In vivo experiments confirmed that hypoxic-preconditioned ADSCs significantly improved therapeutic outcomes in diabetic skin wounds. However, these therapeutic enhancements were reversed upon coadministration of mTOR pathway inhibitors.</p> Conclusion <p>The hyperglycaemic microenvironment in diabetic wounds disrupts cellular energy metabolism, while hypoxic preconditioning enhances the therapeutic efficacy of ADSCs in promoting diabetic wound repair by activating the mTOR/HIF-1α signalling pathway to remodel their energy metabolic profile.</p> Graphical Abstract <p></p>

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Hypoxic preconditioning drives metabolic reprogramming to increase the therapeutic efficacy of adipose mesenchymal stem cells in diabetic wounds

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月1日

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  • Haiyue Ren,
  • Hankun Cao,
  • Cai He,
  • Qiqi Zhang,
  • Yuge Wang,
  • Baoling Tian,
  • Chengcheng Xu,
  • Yan Feng,
  • Zhe Wang

摘要

Background

Hypoxic pretreatment improves the efficacy of adipose-derived mesenchymal stem cells (ADSCs) in the repair of chronic refractory wounds; however, the underlying molecular mechanisms remain poorly understood. Energy metabolism serves as a crucial regulatory factor that influences stem cell fate, proliferation, and self-renewal capabilities. In this study, we established a diabetic skin wound model to systematically investigate the effects of the diabetic microenvironment and hypoxic pretreatment on the energy metabolism and functions of ADSCs, aiming to elucidate the role of adaptive metabolic regulation in increasing stem cell survival rates following transplantation.

Methods

An in vitro diabetic cell model was established to systematically evaluate the effects of high glucose and hypoxic preconditioning on the proliferation, migration, apoptosis, and cytokine secretion of ADSCs via PCR analysis and CCK-8, cell scratch, and apoptosis assays. The impact of high glucose and hypoxic preconditioning on the energy metabolism characteristics of ADSCs was investigated with a Seahorse XF Analyzer. The regulatory effects of the mTOR/HIF-1α signalling pathway on the energy metabolism and cellular functions of ADSCs was investigated via mTOR pathway inhibitors and siHIF transfection. The therapeutic efficacy of hypoxia preconditioned ADSCs in diabetic wound healing was determined by calculating wound healing rates and performing histopathological analyses.

Results

Hypoxic preconditioning alleviated high glucose-induced functional impairments in ADSCs, including enhanced cell proliferation, migration, and cytokine secretion capacity, along with reduced apoptosis. Seahorse XF analysis revealed that high-glucose conditions suppressed glycolytic activity and impaired mitochondrial function, whereas hypoxic preconditioning upregulated glycolytic flux and optimized mitochondrial energy metabolism. Notably, cotreatment with mTOR pathway inhibitors or HIF-1α-targeting siRNA attenuated the beneficial effects of hypoxic preconditioning, particularly its regulatory impact on energy metabolism profiles. In vivo experiments confirmed that hypoxic-preconditioned ADSCs significantly improved therapeutic outcomes in diabetic skin wounds. However, these therapeutic enhancements were reversed upon coadministration of mTOR pathway inhibitors.

Conclusion

The hyperglycaemic microenvironment in diabetic wounds disrupts cellular energy metabolism, while hypoxic preconditioning enhances the therapeutic efficacy of ADSCs in promoting diabetic wound repair by activating the mTOR/HIF-1α signalling pathway to remodel their energy metabolic profile.

Graphical Abstract