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Prolonged engraftment of transplanted hepatocytes in the liver by transient pro-survival factor supplementation using ex vivo mRNA transfection.
Journal of Controlled Release 2018 September 11
Cell transplantation therapy needs engraftment efficiency improvement of transplanted cells to the host tissues. Ex vivo transfection of a pro-survival gene to transplanted cells is a possible solution; however prolonged expression and/or genomic integration of the gene can be cancer promoting. To supply pro-survival protein only when it is needed, we used mRNA transfection, which exhibits transient protein expression profiles without the risk of genomic integration. Ex vivo transfection of mRNA encoding Bcl-2, a pro-survival factor, led to enhanced hepatocyte engraftment in both of normal and diseased mouse liver, effectively supporting liver function in a model of chronic hepatitis. The transplanted hepatocytes maintained their viability and function in the liver for at least one month, though Bcl-2 expression from mRNA was sustained for just a few days. Mechanism analyses suggest that Bcl-2 inhibits Kupffer cell-mediated hepatocyte clearance, which occurs within 2 days after transplantation. Within 2 days, hepatocytes migrated to the liver parenchyma, presumably a suitable place for the hepatocytes to survive without Bcl-2 expression. Thus, the duration of Bcl-2 expression from mRNA was sufficient to achieve prolonged engraftment. Ex vivo mRNA transfection allows supply of pro-survival factors to transplanted cells with minimal safety concerns accompanying prolonged expression, providing an effective platform to improve engraftment efficiency in cell transplantation therapy.
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