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Novel Programmed Death Ligand 1-AKT-engineered Mesenchymal Stem Cells Promote Neuroplasticity to Target Stroke Therapy

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Abstract

Although tissue plasminogen activator (t-PA) and endovascular thrombectomy are well-established treatments for acute ischemic stroke, over half of patients with stroke remain disabled for a long time. Thus, a significant unmet need exists to develop an effective strategy for treating acute stroke. We developed a combination of programmed cell death-ligand 1 (PD-L1) and AKT-modified umbilical cord mesenchymal stem cells (UMSC-PD-L1-AKT) implanted through intravenous (IV) and intracarotid (IA) routes to enhance therapeutic efficacy in a murine stroke model for overcoming the hypoxic environment of the ischemic brain, to prolong stem cell survival, and to attenuate systemic inflammation to protect neuroglial cells from ischemic injury. Higher cellular proliferation and survival upon exposure to toxic agents were observed in UMSC-PD-L1-AKT cells than in UMSCs in vitro. Moreover, increased attenuation of CFSE+ cell proliferation and increased survival of primary cortical cells were verified by the interaction with UMSC-PD-L1-AKT. Consistently, dual-route administration (IV + IA) of UMSC-PD-L1-AKT resulted in a significant reduction in infarction volume and improvement of neurological dysfunction in a stroke model. Furthermore, enhancing CD8+CD122+IL-10+ T-regulatory (Treg) cells and reducing CD11b+CD80+ microglial/macrophages and CD3+CD8+TNF-α+ and CD3+CD8+ IFN-α+ cytotoxic T cells induced an anti-inflammatory microenvironment to protect neuroglial cells in the ischemic brain. Collectively, therapeutic intervention using UMSC-PD-L1-AKT could provide a niche for inducing neuroplastic regeneration in brains after stroke.

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All data generated or analyzed during this study are included in this published article.

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Acknowledgements

The authors thank the National Science and Technology Council for research grants from NSTC-111-2320-B-039-076 and China Medical University Hospital (DMR-111-141).

Funding

This work was supported by grant from the National Science and Technology Council (NSTC-111–2320-B-039–076) and China Medical University Hospital, Taichung, Taiwan (DMR-111–141).

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  1. Syuan-Ling Lin and Wei Lee contributed equally to this work.

Authors and Affiliations

  1. Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan

    Syuan-Ling Lin, Shih-Ping Liu & Woei-Cherng Shyu

  2. Cell Therapy Center, China Medical University Hospital, Taichung, Taiwan

    Wei Lee, Yi-Wen Chang & Long-Bin Jeng

  3. Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan

    Shih-Ping Liu & Woei-Cherng Shyu

  4. Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan

    Long-Bin Jeng

  5. Neuroscience and Brain Disease Center and New Drug Development Center, China Medical University, Taichung, Taiwan

    Woei-Cherng Shyu

  6. Department of Occupational Therapy, Asia University, Taichung, Taiwan

    Woei-Cherng Shyu

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SLL performed most experiments and wrote the manuscript. WL and YWC contributed experience on methods. WCS supervised and reviewed the manuscripts.

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Correspondence to Yi-Wen Chang, Long-Bin Jeng or Woei-Cherng Shyu.

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Supplementary file1 The gating strategy of flow cytometry (GIF 252 KB)

12035_2023_3779_MOESM2_ESM.gif

Supplementary file2 The superior proliferation and anti-apoptotic abilities of UMSCs-PD-L1-AKT compared to UMSCs-AKT (A) Western blotting of UMSC-AKT cells showed that overexpression of AKT level. (B) Cell proliferation was enhanced in the UMSC-PD-L1-AKT than UMSC-AKT and UMSCs by the CCK-8 assay. (C) CCK-8 assay showed the cell viability of UMSCs, UMSC-PD-L1-AKT, and UMSC-AKT were added 0, 80, 100, 200 and 300μM H2O2 for 24, 48, and 72h. Quantization of cell viability showed that UMSC-PD-L1-AKT substantially reduced H2O2-induced cell death in a dose- and time-dependent manner. (GIF 112 KB)

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Lin, SL., Lee, W., Liu, SP. et al. Novel Programmed Death Ligand 1-AKT-engineered Mesenchymal Stem Cells Promote Neuroplasticity to Target Stroke Therapy. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03779-w

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