Human umbilical cord derived mesenchymal stem cells overexpressing HO‐1 attenuate neural injury and enhance functional recovery by inhibiting inflammation in stroke mice

• Published in: CNS neuroscience & therapeutics 2024-02, Vol.30 (2), p.e14412-n/a
• Main Authors: Yang, Yu, Liu, Qianqian, Deng, Song, Shao, Qian, Peng, Long, Ling, Yuejuan, Huang, Yue, Zheng, Siqi, Jiang, Qiaoji, Nie, Dekang, Chen, Jian
• Format: Article
• Language: English
• Subjects: Antibiotics; Apoptosis; Astrocytes; Brain slice preparation; Brain-derived neurotrophic factor; Catalytic oxidation; Cell culture; Cerebral blood flow; Cytokines; Flow cytometry; Gene expression; Growth factors; Heme oxygenase (decyclizing); heme oxygenase‐1; Immunofluorescence; Inflammation; Interleukin 1 receptor antagonist; Interleukin 1 receptors; Interleukins; Ischemia; Lymphocytes; Macrophages; Mesenchymal stem cells; Microglia; Nervous system; Neural stem cells; Original; Polarization; Recovery of function; Stem cells; Stroke; Transforming growth factor-b; Transplantation; Traumatic brain injury; Tumor necrosis factor-α; Umbilical cord
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.14412

Aims The current evidence demonstrates that mesenchymal stem cells (MSCs) hold therapeutic potential for ischemic stroke. However, it remains unclear how changes in the secretion of MSC cytokines following the overexpression of heme oxygenase‐1 (HO‐1) impact excessive inflammatory activation in a mouse ischemic stroke model. This study investigated this aspect and provided further insights. Methods The middle cerebral artery occlusion (MCAO) mouse model was established, and subsequent injections of MSC, MSCHO‐1, or PBS solutions of equal volume were administered via the mice's tail vein. Histopathological analysis was conducted on Days 3 and 28 post‐MCAO to observe morphological changes in brain slices. mRNA expression levels of various factors, including IL‐1β, IL‐6, IL‐17, TNF‐α, IL‐1Ra, IL‐4, IL‐10, TGF‐β, were quantified. The effects of MSCHO‐1 treatment on neurons, microglia, and astrocytes were observed using immunofluorescence after transplantation. The polarization direction of macrophages/microglia was also detected using flow cytometry. Results The results showed that the expression of anti‐inflammatory factors in the MSCHO‐1 group increased while that of pro‐inflammatory factors decreased. Small animal fluorescence studies and immunofluorescence assays showed that the homing function of MSCsHO‐1 was unaffected, leading to a substantial accumulation of MSCsHO‐1 in the cerebral ischemic region within 24 h. Neurons were less damaged, activation and proliferation of microglia were reduced, and polarization of microglia to the M2 type increased after MSCHO‐1 transplantation. Furthermore, after transplantation of MSCsHO‐1, the mortality of mice decreased, and motor function improved significantly. Conclusion The findings indicate that MSCs overexpressing HO‐1 exhibited significant therapeutic effects against hyper‐inflammatory injury after stroke in mice, ultimately promoting recovery after ischemic stroke. Transfected human umbilical cord mesenchymal stem cells (hUC‐MSCs) transplanted into MCAO mice migrate to injured areas in the brain. hUC‐MSCs that overexpress HO‐1 can release high levels of brain‐derived neurotrophic factor and promote the production of M2‐type microglia. This reduces inflammatory damage after ischemia–reperfusion.