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Induced Neural Cells from Human Dental Pulp Ameliorate Functional Recovery in a Murine Model of Cerebral Infarction

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Abstract

Human mesenchymal stem cells are a promising cell source for the treatment of stroke. Their primary mechanism of action occurs via neuroprotective effects by trophic factors, anti-inflammatory effects, and immunomodulation. However, the regeneration of damaged neuronal networks by cell transplantation remains challenging. We hypothesized that cells induced to neural lineages would fit the niche, replace the lesion, and be more effective in improving symptoms compared with stem cells themselves. We investigated the characteristics of induced neural cells from human dental pulp tissue and compared the transplantation effects between these induced neural cells and uninduced dental pulp stem cells. Induced neural cells or dental pulp stem cells were intracerebrally transplanted 5 days after cerebral infarction induced by permanent middle cerebral artery occlusion in immunodeficient mice. Effects on functional recovery were also assessed through behavior testing. We used immunohistochemistry and neuron tracing to analyze the differentiation, axonal extension, and connectivity of transplanted cells to the host’s neural circuit. Transplantation of induced neural cells from human dental pulp ameliorated functional recovery after cerebral infarction compared with dental pulp stem cells. The induced neural cells comprised both neurons and glia and expressed functional voltage, and they were more related to neurogenesis in terms of transcriptomics. Induced neural cells had a higher viability than did dental pulp stem cells in hypoxic culture. We showed that induced neural cells from dental pulp tissue offer a novel therapeutic approach for recovery after cerebral infarction.

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Data Availability

Data supporting the findings of this study are available from the corresponding author upon reasonable request. Microarray data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series accession number GSE174260.

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Acknowledgements

We thank Dr. Murakoshi and Dr. Okabe from the Department of Cardiology, University of Tsukuba for a data acquirement of the multielectrode array, Ms. Tsukada and Ms. Miyakawa from Graduate School of Comprehensive Human Sciences, University of Tsukuba for their technical support.

Funding

This work was supported by Grant-in-Aid for Scientific Research (C) for Yuji Matsumaru (No. 19K09450), Scientific Research (B) for Aiki Marushima (no. 20H03787), and Grant-in-Aid for JSPS Fellows for Hideaki Matsumura (no. 20J12956) from the Japan Society for the Promotion of Science (JSPS), supported by Translational Research Program (University of Tsukuba, A18-36) for the Japan Agency for Medical Research and Development for Aiki Marushima.

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Authors and Affiliations

  1. Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Hideaki Matsumura, Aiki Marushima, Hiroshi Ishikawa, Junko Toyomura, Akihiro Ohyama, Miho Watanabe, Akira Matsumura, Yuji Matsumaru & Eiichi Ishikawa

  2. Doctoral Program in Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan

    Hideaki Matsumura & Shohei Takaoka

  3. Laboratory of Clinical Regenerative Medicine, Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

    Hideaki Matsumura, Aiki Marushima, Hiroshi Ishikawa, Junko Toyomura, Akihiro Ohyama, Miho Watanabe, Shohei Takaoka & Yuji Matsumaru

  4. Department of Legal Medicine, Osaka City University Medical School, Osaka, Japan

    Miho Watanabe

  5. Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

    Shohei Takaoka & Hiroki Bukawa

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  1. Hideaki Matsumura
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Contributions

HM, AM, HI conceived and designed the experiments. HM, HI, JT, AO, MW, and ST performed the experiments and analyzed the data. Hideaki Matsumura wrote the manuscript. AM, HI, HB, AM, YM, and EI investigated and supervised the experiment. All authors read and approved the final version of the manuscript. All authors revised and approved the manuscript that must be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work is appropriately investigated and resolved.

Corresponding author

Correspondence to Aiki Marushima.

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The authors declare that they have no competing interest.

Ethical Approval

The Ethics Committee of the University of Tsukuba Hospital approved this study (Approval Number: H30-181). The Institutional Animal Care and Use Committee of the University of Tsukuba approved all experimental mouse studies (Approval Number: 18-108).

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Matsumura, H., Marushima, A., Ishikawa, H. et al. Induced Neural Cells from Human Dental Pulp Ameliorate Functional Recovery in a Murine Model of Cerebral Infarction. Stem Cell Rev and Rep 18, 595–608 (2022). https://doi.org/10.1007/s12015-021-10223-w

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