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Background <p>Intracerebral hemorrhage (ICH) represents one of the most severe forms of cerebrovascular injury, characterized by high mortality and lasting neurological dysfunction. Neural stem cells (NSCs), which are indispensable for neurogenesis, are mainly distributed in the hippocampus, a brain region essential for learning and memory. However, alterations in hippocampal NSCs following ICH and the mechanisms that mediate these changes remain poorly defined. The present study investigates the effects of ICH on hippocampal NSCs, focusing on the regulatory role of MTHFD2 in maintaining mitochondrial redox homeostasis through NADPH metabolism.</p> Methods <p>Both in vivo and in vitro ICH models were used, including a collagenase-induced mouse model and a hemin-treated NSC model, to examine molecular and cellular responses of hippocampal NSCs to hemorrhagic injury. Western blotting, RNA sequencing, CUT&amp;Tag profiling, and ChIP-qPCR were employed to analyze the related pathways.</p> Results <p>We found that NSCs exhibited a time-dependent response after ICH, showing initial activation followed by gradual functional exhaustion and increased apoptosis. ICH induced persistent endoplasmic reticulum stress and significantly upregulated MTHFD2, a mitochondrial enzyme essential for one-carbon metabolism. Mechanistically, MTHFD2 was required to maintain mitochondrial integrity and redox homeostasis by regulating NADPH levels. Knockdown of MTHFD2 reduced NSC proliferation, increased apoptosis, and worsened cognitive impairment in ICH mice. Exogenous NADPH supplementation partially restored these changes, emphasizing the importance of redox balance in NSC survival and function.</p> Conclusions <p>Our findings identify MTHFD2 as a key metabolic regulator supporting NSC adaptation to ICH through NADPH-dependent mitochondrial mechanisms. Targeting mitochondrial redox metabolism may provide a potential strategy for preserving NSC function and improving cognitive recovery after ICH.</p>

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MTHFD2 modulates neural stem cell proliferation and apoptosis after intracerebral hemorrhage by regulating mitochondrial NADPH homeostasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Yikui Liu,
  • Canxin Xu,
  • Baofeng Wang,
  • Fengzhen Cui,
  • Aoqian Xu,
  • Yuxiao Ma,
  • Qixiang Zhang,
  • Qingfang Sun,
  • Yongtao Zheng,
  • Yuhao Sun,
  • Liuguan Bian

摘要

Background

Intracerebral hemorrhage (ICH) represents one of the most severe forms of cerebrovascular injury, characterized by high mortality and lasting neurological dysfunction. Neural stem cells (NSCs), which are indispensable for neurogenesis, are mainly distributed in the hippocampus, a brain region essential for learning and memory. However, alterations in hippocampal NSCs following ICH and the mechanisms that mediate these changes remain poorly defined. The present study investigates the effects of ICH on hippocampal NSCs, focusing on the regulatory role of MTHFD2 in maintaining mitochondrial redox homeostasis through NADPH metabolism.

Methods

Both in vivo and in vitro ICH models were used, including a collagenase-induced mouse model and a hemin-treated NSC model, to examine molecular and cellular responses of hippocampal NSCs to hemorrhagic injury. Western blotting, RNA sequencing, CUT&Tag profiling, and ChIP-qPCR were employed to analyze the related pathways.

Results

We found that NSCs exhibited a time-dependent response after ICH, showing initial activation followed by gradual functional exhaustion and increased apoptosis. ICH induced persistent endoplasmic reticulum stress and significantly upregulated MTHFD2, a mitochondrial enzyme essential for one-carbon metabolism. Mechanistically, MTHFD2 was required to maintain mitochondrial integrity and redox homeostasis by regulating NADPH levels. Knockdown of MTHFD2 reduced NSC proliferation, increased apoptosis, and worsened cognitive impairment in ICH mice. Exogenous NADPH supplementation partially restored these changes, emphasizing the importance of redox balance in NSC survival and function.

Conclusions

Our findings identify MTHFD2 as a key metabolic regulator supporting NSC adaptation to ICH through NADPH-dependent mitochondrial mechanisms. Targeting mitochondrial redox metabolism may provide a potential strategy for preserving NSC function and improving cognitive recovery after ICH.