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VCAM-1+ hUC-MSCs Exert Considerable Neuroprotection Against Cerebral Infarction in Rats by Suppression of NLRP3-Induced Pyroptosis

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Abstract

Mesenchymal stem/stromal cells (MSCs) are spindle-like heterogeneous cell populations with advantageous bidirectional immunomodulatory and hematopoietic support effects. Vascular cellular adhesion molecule-1 (VCAM-1)+ MSCs have been reported to exhibit immunoregulatory and proangiogenic capacities. Here, we studied the effects of VCAM-1+ human umbilical cord (hUC)-MSCs on neuroprotection against cerebral infarction. Sprague–Dawley rats were subjected to middle cerebral artery occlusion (MCAO), and VCAM-1− and VCAM-1+ hUC-MSCs were intravenously injected into the rat 4 h post-MCAO surgery. Thereafter, modified neurological severity scores (mNSS) were determined, and the Morris water maze test, 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin (H&E), Nissl, TUNEL staining, and qRT-PCR were conducted. Following induction of oxygen–glucose deprivation/reoxygenation (OGD/R), SH-SY5Y cells were co-cultured with VCAM-1− and VCAM-1+ hUC-MSCs. CCK-8, flow cytometry, ELISA, and western blot analyses were performed in vitro. Compared with VCAM-1− hUC-MSCs, administration of VCAM-1+ hUC-MSCs revealed improved therapeutic efficacy against cerebral infarction in rats, as confirmed by lower mNSS scores and infarct volumes, as well as improved learning and memory capacities. In addition, VCAM-1+ hUC-MSCs exhibited improved efficacy against neurological defects in rats with cerebral infarction, accompanied by inhibition of the NLRP3-mediated inflammatory response. VCAM-1+ hUC-MSC co-culture improved the viability and diminished NLRP3-mediated inflammatory response in OGD/R-treated SH-SY5Y cells. Moreover, NLRP3 overexpression in SH-SY5Y cells prevented the beneficial effects of VCAM-1+ hUC-MSC co-culture. Overall, our findings demonstrated the relevance of VCAM-1+ hUC-MSC-based cytotherapy for preclinical neuroprotection against cerebral infarction.

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Data availability

All data generated or analysed during this study, together with the additional file, are included in this published article. Meanwhile, the datasets involved in the current study are available from the corresponding author on reasonable request.

Abbreviations

MSCs:

Mesenchymal stem/stromal cells

hUC-MSCs:

Human umbilical cord MSCs

PSC:

Pluripotent stem cells

NLRP3:

NOD-like receptor thermal protein domain-associated protein 3

ASC:

Apoptosis associated speck like protein containing CARD

VCAM-1:

Vascular cellular adhesion molecule-1

EAM:

Experimental autoimmune myocarditis

DEGs:

Differentially expressed genes

GO:

Gene ontology

mNSS:

Modified neurological severity scores

MCAO:

Middle cerebral artery occlusion

OGD/R:

Oxygen-glucose deprivation/reoxygenation

FCM:

Flow cytometry

NDA:

New drug application

GSEA:

Gene set enrichment analysis

PFA:

Paraformaldehyde

WHO:

World Health Organization

MCA:

Middle cerebral artery

qRT-PCR:

Quantitative real-time polymerase chain reaction

ELISA:

Enzyme-linked immunosorbent assay

sEVs:

Small extracellular vesicles

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Acknowledgements

The coauthors thank the members in the laboratory research team of the Second Hospital of Shandong University for their professional assistance. We also thank the Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province & NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor in Gansu Provincial Hospital, and Key Laboratory of Radiation Technology and Biophysics, Hefei Institute of Physical Science in Chinese Academy of Sciences for their technical support.

Funding

This work was supported by grants from the National Natural Science Foundation of China (81870848, 82260031, 82171410), Rongxiang Regenerative Medicine Foundation of Shandong University (No. 2019SDRX-09), Jinan clinical medical science and technology innovation program (201907056, 202134018), Foundation of the Second Hospital of Shandong University (2022YP93), the project Youth Fund supported by Shandong Provincial Natural Science Foundation (ZR2020QC097), Jiangxi Provincial Natural Science Foundation (20224BAB206077, 20212BAB216073), Jiangxi Provincial Leading Talent of “Double Thousand Plan” (2022 to L.S.Z.).

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Authors and Affiliations

  1. Department of Neurology, The Second Hospital of Shandong University, Jinan, 250033, China

    Xiao Zhang, Xiaoyu Sang, Yanting Chen, Xiaolei Zheng, Xiao Wang, Hui Yang, Jianzhong Bi & Ping Wang

  2. School of Medicine, Nankai University, Tianjin, 300071, China

    Hao Yu

  3. The Second Hospital of Shandong University, Jinan, 250033, China

    Yuan Sun

  4. Department of Biostatistics, School of Public Health, Yale University, 38 Crown Street, APT 203, New Haven, CT, 06510, USA

    Xilong Liang

  5. Department of Neurosurgery, Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, China

    Leisheng Zhang

  6. Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, 730000, China

    Leisheng Zhang

  7. Key Laboratory of Radiation Technology and Biophysics, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China

    Leisheng Zhang

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  1. Xiao Zhang
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Contributions

X.Z. and P.W.: designed and performed the experiments, collection and assembly of data, manuscript writing; X.S., Y.C., H.Y., Y.S., X.L., X.L.Z., X.W., H.Y., and J.B.: helped with experiments, collection and assembly of data; X.Z., L.Z., and P.W.: data analysis and interpretation, manuscript writing; L.Z., and P.W.: conception and design, revision, final approval of manuscript. All coauthors have read and approved the final manuscript.

Corresponding authors

Correspondence to Leisheng Zhang or Ping Wang.

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The coauthors declare there’s no competing interests and all the coauthors consent to publish the data.

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This study was performed according to the principle of Declaration of Helsinki. Meanwhile, ethical approval of this research was approved by the Ethics Committee of Institutional Animal Care and Use Committee of the Second Hospital of Shandong University to the National Institutes of Health (NIH) guidelines for the Care and use of Laboratory Animals(Ethics approval No. KYLL-2022LW157).

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Zhang, X., Sang, X., Chen, Y. et al. VCAM-1+ hUC-MSCs Exert Considerable Neuroprotection Against Cerebral Infarction in Rats by Suppression of NLRP3-Induced Pyroptosis. Neurochem Res 48, 3084–3098 (2023). https://doi.org/10.1007/s11064-023-03968-y

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