Metformin and Inhibition of TGF-beta Stimulate In Vitro Transport in Primary Renal Tubule Cells.

Patient-oriented applications of cell culture include cell therapy of organ failure like chronic renal failure. Clinical deployment of a cell-based device for arti fi cial renal replacement requires qualitative and quantitative fi delity of a cultured cell to its in vivo counterpart. Active speci fi c apicobasal ion transport reabsorbs 90-99% of the fi ltered load of salt and water in the kidney. In a bioengineered kidney, tubular transport concentrates wastes and eliminates the need for hemodialysis, but renal tubule cells in culture transport little or no salt and water. We previously identi fi ed TGF-beta as a signaling pathway necessary for in vitro differentiation of renal tubule cells. Inhibition of TGFBR1 led to active inhabitable electrolyte and water transport by primary human renal tubule epithelial cells in vitro. Addition of metformin increased transport, in the context of a transient effect on AMPK phosphorylation. The signals that undermine in vitro differentiation are complex but susceptible to pharmacologic intervention. This achievement overcomes a major hurdle limiting the development of a bioreactor of cultured cells for renal replacement therapy that encompasses not only endocrine and metabolic functions, but also transport and excretion.