Liver Cells from Circulating Blood Cells Under Clinically Safe Conditions

Can we convert circulating blood cells into working liver cells? Think of what this would mean for people who have liver problems. While is sounds like science fiction, the laboratory of James Ross at the University of Edinburgh, in collaboration with other scientists, has managed to do exactly that.

Ross and his colleagues developed an efficient method for converting circulating white blood cells into induced pluripotent stem cells (iPSCs). As previously mentioned on this blog, iPSCs are made from mature, adult cells by genetically engineering those cells with a cocktail of genes (in this case Oct4, Sox2, Klf4, L-Myc, and Lin28), and then culturing the cells in a special culture system that allows them to grow and become pluripotent stem cells that can theoretically differentiate into any of the 210 adult cell types in the human body.

Since the production of iPSCs from mature cells requires the insertion of particular genes into those cells, scientists typically use viruses or other vehicles to do this, which can introduce mutations into the genomes of the cells. Ross and his coworkers, however, used a non-integration method for reprogramming fresh or frozen white blood cells. They inserted small circles of DNA called “episomes” into these cells using a technique called “electroporation,” which binds the DNA to the surfaces of the cells and then subjects them to an electrical pulse that quickly moves the DNA into the cells without harming them. The genes on the episome are then expressed, but only transiently, which is all that is required to reprogram the adult cells into iPSCs. The cells were also cultured in a feeder-free system, which means that no animal products were involved in the production of these iPSC lines.  This constitutes, so-called “Good Manufacturing Practice” or GMP, which is required is a product is to be used for human patients.

Ross and others achieved a reprogramming efficiency of up to 0.033% (65 colonies from 2×105 seeded MNC), and when they used the same protocol to cord blood or fetal liver-derived blood-making (CD34+) cells, they achieved a reprogramming rate of 0.148% (148 iPSC colonies from 105 seeding cells). These iPSC lines were then used to make differentiated liver cells. This procedure tends to produce quasi-liver cells that do not have the characteristics of mature liver cells, but in this case, Ross and others derived cells that have proper drug metabolic function. This suggests that the iPSC-derived liver cells were at least mature enough to express many of the enzymes necessary to properly metabolize drugs. While these cells were probably not fully mature, they were a good deal further along than those derived in other experiments.

These experiments show that it is feasible to make liver cells for drug screen from circulating blood cells in a manner that is clinically safe. It is presently unclear if these cells can serve as material to heal a damaged liver, and that will take more work. Also, this procedure almost certainly would cost a good deal of money, and for that reason, banked iPSCs from white blood cells that have been fully tissue typed might be a better way to use cells made in this manner.

See Jing Liu, and others, Experimental Cell Research, 6 August 2015, Article ECR15383.