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Neuritin Promotes Bone Marrow-Derived Mesenchymal Stem Cell Migration to Treat Diabetic Peripheral Neuropathy

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Abstract

The purpose of this study is to explore the effect and mechanism of neuritin overexpression in the bone marrow on peripheral neuropathy in type 2 diabetic (db/db) mice. We analyzed the impact of bone marrow neuritin overexpression on diabetic peripheral neuropathy and migration of bone marrow mesenchymal stem cells in db/db mice. Antagonists were used to inhibit the stromal cell-derived factor (SDF)-1α/C-X-C chemokine receptor type 4 (CXCR4)-phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in primary cultured bone marrow mesenchymal stem cells. Immunofluorescence, transmission electron microscopy, Oil Red O staining, and transwell migration assays were used. Bone marrow-specific overexpression of neuritin in db/db mice was successfully established. Overexpression of neuritin in the bone marrow ameliorated hyperglycemia, prevented diabetic peripheral neuropathy, protected the ultrastructure of the sciatic nerve and intra-epidermal nerve fiber density, and promoted Schwann cell proliferation and remyelination in the sciatic nerve. Moreover, it ameliorated fat accumulation, adipocyte number, and vascular and nerve densities; decreased glutamate content in serum and bone marrow; restored gradient SDF-1α contents between bone marrow, blood, and sciatic nerve; and promoted impaired diabetic bone marrow mesenchymal stem cell migration. Neuritin improves bone marrow mesenchymal stem cell migration via the SDF-1α/CXCR4-PI3K/Akt signaling pathway in vitro. Overexpression of neuritin in the bone marrow can locally ameliorate neuropathy in the bone marrow. This improves the migration capability of bone marrow mesenchymal stem cells and repairs diabetic peripheral neuropathy, at least partly by activating the PI3K/Akt pathway through the SDF-1α/CXCR4 axis.

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Data Availability

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Code Availability

Not applicable.

Abbreviations

CXCR4:

CXC chemokine receptor 4

G-CSF:

Granulocyte colony-stimulating factor

GFAP:

Glial fibrillary acidic protein

MSCs:

Mesenchymal stem cells

NMDA:

N-methyl-D-aspartate receptor

SDF-1α:

Stromal cell-derived factor-1α

VGLUT1:

Vesicular glutamate transporter 1

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Funding

This study is supported by grants from the National Natural Science Foundation of China (No. 81770806), the Chongqing Natural Science Foundation (No. cstc2021jcyj-msxmX0249), and the Special Project for Enhancing Science and Technology Innovation Ability of Army Medical University (No. 2019XYY16).

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  1. Zuo Zhang and Yuanzhi Liu are equal contributors.

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  1. National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, China

    Zuo Zhang, Yuanzhi Liu & Jiyin Zhou

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J.Z. conceived the study and wrote the paper. Z.Z. and Y.L. performed the experimental work. J.Z. contributed to the study design, with reagents, and in writing the manuscript. All authors reviewed and approved the paper.

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Correspondence to Jiyin Zhou.

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Zhang, Z., Liu, Y. & Zhou, J. Neuritin Promotes Bone Marrow-Derived Mesenchymal Stem Cell Migration to Treat Diabetic Peripheral Neuropathy. Mol Neurobiol 59, 6666–6683 (2022). https://doi.org/10.1007/s12035-022-03002-2

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