Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy

  1. Haoyan Huang
  2. Meng Qian
  3. Yue Liu
  4. Shang Chen
  5. Huifang Li
  6. Zhibo Han
  7. Zhong-chao Han
  8. Xiangmei Chen
  9. Qiang Zhao  Is a corresponding author
  10. Zongjin Li  Is a corresponding author
  1. Nankai University, China
  2. AmCellGene Co Ltd, China
  3. Chinese PLA General Hospital, China

Abstract

Nitric oxide (NO), as a gaseous therapeutic agent, shows great potential for the treatment of many kinds of diseases. Although various NO delivery systems have emerged, the immunogenicity and long-term toxicity of artificial carriers hinder the potential clinical translation of these gas therapeutics. Mesenchymal stem cells (MSCs), with the capacities of self-renewal, differentiation, and low immunogenicity, have been used as living carriers. However, MSCs as gaseous signaling molecule (GSM) carriers have not been reported. In this study, human MSCs were genetically modified to produce mutant β-galactosidase (β-GALH363A). Furthermore, a new NO prodrug, 6-methyl-galactose-benzyl-oxy NONOate (MGP), was designed. MGP can enter cells and selectively trigger NO release from genetically engineered MSCs (eMSCs) in the presence of β-GALH363A. Moreover, our results revealed that eMSCs can release NO when MGP is systemically administered in a mouse model of acute kidney injury (AKI), which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs. This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells.

Data availability

All raw data for bulk RNA sequencing has been deposited in the NCBI Sequence Read Archive under accession code PRJNA910491 (https://www.ncbi.nlm.nih.gov/bioproject); Source data file has been provided for Figure 1- source data 1.

The following data sets were generated

Article and author information

Author details

  1. Haoyan Huang

    Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Meng Qian

    Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Yue Liu

    Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Shang Chen

    Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Huifang Li

    Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Zhibo Han

    AmCellGene Co Ltd, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Zhong-chao Han

    AmCellGene Co Ltd, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Xiangmei Chen

    State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Qiang Zhao

    Nankai University, Tianjin, China
    For correspondence
    qiangzhao@nankai.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  10. Zongjin Li

    Nankai University, Tianjin, China
    For correspondence
    zongjinli@nankai.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4603-3743

Funding

National Key Research and Development Program of China (2017YFA0103200)

  • Zongjin Li

National Natural Science Foundation of China (81925021,U2004126)

  • Qiang Zhao
  • Zongjin Li

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to the Nankai University Animal Care and Use Committee Guidelines (approval no. 2021-SYDWLL-000426).

Reviewing Editor

  1. Ambra Pozzi, Vanderbilt University Medical Center, United States

Version history

  1. Received: November 9, 2022
  2. Accepted: September 8, 2023
  3. Accepted Manuscript published: September 11, 2023 (version 1)

Copyright

© 2023, Huang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Haoyan Huang
  2. Meng Qian
  3. Yue Liu
  4. Shang Chen
  5. Huifang Li
  6. Zhibo Han
  7. Zhong-chao Han
  8. Xiangmei Chen
  9. Qiang Zhao
  10. Zongjin Li
(2023)
Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy
eLife 12:e84820.
https://doi.org/10.7554/eLife.84820

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