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

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 this 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, MSCs were genetically modified to produce mutant {beta}-galactosidase ({beta}-GALH363A). Furthermore, a new NO prodrug, 6-methyl-galactose-benzyl-oxy NONOate (MGP), was designed. MGP can entrance into cell and selectively trigger the NO release from genetically engineered MSCs (eMSCs) in the presence of {beta}-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. SignificanceGaseous signaling molecules (GSMs), such as nitric oxide (NO), hold tremendous potential in regenerative medicine and tissue engineering. However, the delivery of GSMs with stem cells to target tissues or organs in response to demand has never been reported. This study designed engineered mesenchymal stem cells (eMSCs) that produce mutant {beta}-galactosidase ({beta}-GALH363A) and trigger NO release when the NO prodrug is systemically administered, which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs in a mouse model of acute kidney injury (AKI). 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/519950v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1d8f4e4org.highwire.dtl.DTLVardef@b5e548org.highwire.dtl.DTLVardef@1dff1edorg.highwire.dtl.DTLVardef@184130e_HPS_FORMAT_FIGEXP M_FIG C_FIG