Abstract 12561: iPS Cells Derived From MSCs Show Superior Angiogenesis Following Transplantation into the Infarcted Heart due to Differential miRNA Expression
Background: In vivo studies using MSC-derived iPS cells (MiPS) and fibroblast-derived iPS cells showed significantly higher angiogenic potential of MiPS following transplantation into the infarcted myocardium. As iPS cells have epigenetic memory, the pro-angiogenic properties of MSC may contribute to improved angiogenesis observed with MiPS transplantation. Since miRNAs play a critical role in regulating angiogenesis, we hypothesized that altered miRNA expression in MiPS during reprogramming contributed to their superior angiogenic potential.
Methods & Results: To elucidate the mechanism of superior angiogenic potential in MiPS, microarray analysis was done in MSCs, MiPS, and embryonic stem cells (ESC), which were used as a pluripotent cell control. MiPS expressed a number of pluripotency-regulating miRNAs similar to ESCs, including the miR-290 family. However, our results reveal that MiPS expressed a unique miRNA signature that was significantly different from ESCs. MiPS were similar to MSCs in terms of pro-angiogenic miRNA expression. In both MSCs and MiPS, expression of miR-320 was reduced compared to ESCs, along with an increased expression of insulin growth factor (IGF-1), a target of miR-320. Also, there was a marked decrease in miR-215 and two of its targets, IGF-1 and the activin receptor Acvr2b were upregulated in MSCs and MiPS. We observed increased expression of pro-angiomiRs including miR-210 in MSCs and MiPS compared to ESCs, and observed a decrease in Ephrin-A3 expression, the miR-210 target. Furthermore, in vitro tube formation assays using conditioned media from MSCs (MSCCM), MiPS (MiPSCM), and ESCs (ESCCM) showed significantly higher number of branch points in HUVECs treated with MSCCM and MiPSCM when compared to ESCCM.
Conclusions: Our results indicate that MiPS are not identical to ESCs as they have a significantly different miRNA expression profile. Since miRNAs are critical regulators in angiogenesis, the expression of pro-angiogenic miRNAs in MiPS makes them better candidates for stem cell therapy and re-vascularization of the ischemic heart. Moreover, the improved angiogenic potential of MiPS may be due to their epigenetic memory as pro-angiogenic miRNAs that are expressed in MSCs are also expressed in MiPS.
- © 2013 by American Heart Association, Inc.