Preconditioning Stem Cells from Fat with Viagra Improves their Therapeutic Efficacy

Rackesh Kukreja is professor of internal medicine, biochemistry, and molecular biology, physiology and biophysics, and scientific director of the Virginia Commonwealth University Pauley Heart Center. In his laboratory, Nicholas Hoke and other co-workers have discovered a way to improve the therapeutic capacity of fat-derived mesenchymal stem cells (MSCs).

MSCs from fat can be transformed into heart muscle cells in the laboratory (see Rangappa et al., Ann Thorac Surg. 2003; 75(3):775-9). While these cells will beat in culture, it is unclear if these cells have the calcium ion-handling machinery that allows them to synchronously beat together. When implanted into the hearts of laboratory animals that have suffered heart attacks, stem cells from brown fat shrink the infarcted area and improve the function of the left ventricle. This improvement seems to occur by means of replacing dead heart muscle cells (see Yamada, et al., Biochem Biophys Res Commun. 2006; 342(2):662-70). Several experiments have established that MSCs from fat tissue can improve the function of a rodent’s heart after a heart attack. Sheets of fat-derived MSCS (see Miyahara et al., Nat Med. 2006; 12(4):459-65), cord blood MSCs co-cultured with brown fat stem cells (see Yamada, et al., Biochem Biophys Res Commun. 2007; 353(1):182-8), or even MSCs derived from white adipose tissue (see Schenke-Layland K, et al., J Surg Res; 153(2):217-23; Mazo M, et al., Eur J Heart Fail. 2008; 10(5):454-62; Valina C, et al., Eur Heart J. 2007; 28(21):2667-77) all improved heart function after a heart, the fat-derived MSCs from white fat seemed to do so by enhancing blood vessels formation in the infarcted heart. Other studies showed that white fat derived MSCs did not survive well in the heart after a heart attack (van der Bogt, et al., Transplantation. 2009; 87(5):642-52). Other studies showed that fat-derived MSCs could be converted into heart muscle cells (Gwak, et al., Cell Biochem Funct. 2009; 27(3):148-54), and transplantation of these cells could improve heart function after a heart attack (Okura H, et al., Tissue Eng Part C Methods. 2010; 16(3):417-25). Therefore, fat-derived MSCs have the potential to help an ailing heart, but can we tweek them so that they can survive within the hostile environment of a heart that has just had a heart attack?

Into this gap steps Rackesh Kukreja, Nicholas Hoke and co-workers and their experiments on fat-derived MSCs. They soaked fat-derived MSCs in sildenafil (Viagra) before they transplanted them into rodent hearts after a heart attack. Before you snicker about this, sildenafil is an inhibitor of enzymes called “phosphodiesterases.” Phosphodiesterases degrade signaling molecules like cyclic AMP and cyclic GMP. Both of these molecules are made when cells receive messages from other cells, and the concentration of these molecules inside can determine if a cell survives under certain conditions or dies. Therefore, by treating the cells with sildenafil (Viagra), they increased the intracellular concentration of these signaling molecules.

The results were remarkable. When they injected these preconditioned cells directly into the heart muscle of mice that had experienced a heart attack, the preconditioned cells released more growth factors, survived better than non-conditioned fat-derived MSCs, and also helped repair the heart much more effectively. There was decreased cell death in the hearts treated with the preconditioned MSCs, greater density of new blood vessels, and far less scarring of the heart.
These results demonstrate that preconditioning MSCs from fat with drugs like Viagra is a powerfully simple and novel approach to improve stem cell therapy following a heart attack.