Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy.
Haoyan HuangMeng QianYue LiuShang ChenHuifang LiZhibo HanZhong-Chao HanXiangmei ChenQiang ZhaoZongjin LiPublished in: eLife (2023)
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-GAL H363A ). 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-GAL H363A . 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.
Keyphrases
- mesenchymal stem cells
- acute kidney injury
- umbilical cord
- nitric oxide
- cell therapy
- stem cells
- cardiac surgery
- bone marrow
- mouse model
- endothelial cells
- induced apoptosis
- cancer therapy
- hydrogen peroxide
- high throughput
- risk assessment
- human health
- drug release
- cell cycle arrest
- big data
- endoplasmic reticulum stress
- wild type
- room temperature
- pi k akt