PMID- 37695201 OWN - NLM STAT- MEDLINE DCOM- 20231005 LR - 20231006 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 12 DP - 2023 Sep 11 TI - Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy. LID - 10.7554/eLife.84820 [doi] LID - e84820 AB - 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 beta-galactosidase (beta-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 beta-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. CI - (c) 2023, Huang, Qian, Liu et al. FAU - Huang, Haoyan AU - Huang H AUID- ORCID: 0000-0001-7753-7242 AD - Nankai University School of Medicine, Tianjin, China. AD - The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, the College of Life Sciences, Tianjin, China. AD - National Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China. FAU - Qian, Meng AU - Qian M AD - The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, the College of Life Sciences, Tianjin, China. FAU - Liu, Yue AU - Liu Y AD - Nankai University School of Medicine, Tianjin, China. FAU - Chen, Shang AU - Chen S AD - Nankai University School of Medicine, Tianjin, China. FAU - Li, Huifang AU - Li H AD - Nankai University School of Medicine, Tianjin, China. FAU - Han, Zhibo AU - Han Z AD - Jiangxi Engineering Research Center for Stem Cell, Shangrao, Jiangxi, China. AD - Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd, Tianjin, China. FAU - Han, Zhong-Chao AU - Han ZC AD - Jiangxi Engineering Research Center for Stem Cell, Shangrao, Jiangxi, China. AD - Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd, Tianjin, China. AD - Beijing Engineering Laboratory of Perinatal Stem Cells, Beijing Institute of Health and Stem Cells, Health & Biotech Co, Beijing, China. FAU - Chen, Xiang-Mei AU - Chen XM AD - National Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China. FAU - Zhao, Qiang AU - Zhao Q AD - The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, the College of Life Sciences, Tianjin, China. FAU - Li, Zongjin AU - Li Z AUID- ORCID: 0000-0002-4603-3743 AD - Nankai University School of Medicine, Tianjin, China. AD - The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, the College of Life Sciences, Tianjin, China. AD - National Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China. AD - Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Hospital of Obstetrics and Gynecology, Tianjin, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230911 PL - England TA - Elife JT - eLife JID - 101579614 RN - 31C4KY9ESH (Nitric Oxide) SB - IM UOF - doi: 10.1101/2022.12.11.519950 MH - Mice MH - Animals MH - Humans MH - Nitric Oxide MH - *Mesenchymal Stem Cells MH - Stem Cells MH - Genetic Engineering MH - *Acute Kidney Injury/therapy PMC - PMC10541176 OAB - Animals are made up of cells of different types, with each type of cell specializing on a specific role. But for the body to work properly, the different types of cells must be able to coordinate with each other to respond to internal and external stimuli. This can be achieved through signaling molecules, that is, molecules released by a cell that can elicit a specific response in other cells. There are many types of different molecules, including hormones and signaling proteins. Gases can also be potent signaling molecules, participating in various biological processes. Nitric oxide (NO) is a gas signaling molecule that can freely diffuse through the membranes of cells and has roles in blood vessel constriction and other disease processes, making it a promising therapeutic agent. Unfortunately, using artificial carriers to deliver nitric oxide to the organs and tissues where it is needed can lead to issues, including immune reactions to the carrier and long-term toxicity. One way to avoid these effects is by using cells to deliver nitric oxide to the right place. Huang, Qian, Liu et al. have used mesenchymal stem cells - which usually develop to form connective tissues such as bone and muscle - to develop a cell-based NO-delivery system. The researchers genetically modified the mesenchymal stem cells to produce a compound called beta-GAL(H363A). On its own beta-GAL(H363A) does not do much, but in its presence, a non-toxic, non-reactive compound developed by Huang, Qian, Liu et al., called MGP, can drive the release of NO from cells. To confirm the usefulness of their cells as a delivery system, Huang, Qian, Liu et al. transplanted some of the genetically modified mesenchymal stem cells into the kidneys of mice, and then showed that when these mice were given MGP, the levels of NO increased in the kidneys but not in other organs. This result confirms that the cell-based delivery system provides spatial and temporal control of the production of NO. These findings demonstrate a new delivery system for therapies using gas molecules, which can be controlled spatiotemporally in mice. In the future, these types of systems could be used in the clinic for long-term treatment of conditions where artificial carriers could lead to complications. OABL- eng OTO - NOTNLM OT - acute kidney injury OT - biochemistry OT - cell biology OT - chemical biology OT - controlled release OT - delivery OT - gaseous signaling molecule OT - genetically engineered mesenchymal stem cell OT - mouse OT - nitric oxide COIS- HH, MQ, YL, SC, HL, XC, QZ, ZL No competing interests declared, ZH is an employee of AmCellGene Co., Ltd. The author has no further interests to declare, ZH is an employee of Health & Biotech Co and AmCellGene Co., Ltd. The author has no further interests to declare EDAT- 2023/09/11 12:42 MHDA- 2023/10/05 06:43 PMCR- 2023/09/11 CRDT- 2023/09/11 09:53 PHST- 2022/11/09 00:00 [received] PHST- 2023/09/08 00:00 [accepted] PHST- 2023/10/05 06:43 [medline] PHST- 2023/09/11 12:42 [pubmed] PHST- 2023/09/11 09:53 [entrez] PHST- 2023/09/11 00:00 [pmc-release] AID - 84820 [pii] AID - 10.7554/eLife.84820 [doi] PST - epublish SO - Elife. 2023 Sep 11;12:e84820. doi: 10.7554/eLife.84820.