Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy
- Nankai University, China
- AmCellGene Co Ltd, China
- 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.
Article and author information
Author details
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).
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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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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