PlGF–MMP9-engineered iPS cells supported on a PEG–fibrinogen hydrogel scaffold possess an enhanced capacity to repair damaged myocardium

C Bearzi,C Gargioli,R Rizzi,D Seliktar,O Kossover,D Baci,G Condorelli,K Shapira-Schweitzer,O Fortunato,M V G Latronico

doi:10.1038/cddis.2014.12

Abstract

Cell-based regenerative therapies are significantly improved by engineering allografts to express factors that increase vascularization and engraftment, such as placental growth factor (PlGF) and matrix metalloproteinase 9 (MMP9). Moreover, the seeding of therapeutic cells onto a suitable scaffold is of utmost importance for tissue regeneration. On these premises, we sought to assess the reparative potential of induced pluripotent stem (iPS) cells bioengineered to secrete PlGF or MMP9 and delivered to infarcted myocardium upon a poly(ethylene glycol)–fibrinogen scaffold. When assessing optimal stiffness of the PEG–fibrinogen (PF) scaffold, we found that the appearance of contracting cells after cardiogenic induction was accelerated on the support designed with an intermediate stiffness. Revascularization and hemodynamic parameters of infarcted mouse heart were significantly improved by injection into the infarct of this optimized PF scaffold seeded with both MiPS (iPS cells engineered to secrete MMP9) and PiPS (iPS cells engineered to secrete PlGF) cells as compared with nonengineered cells or PF alone. Importantly, allograft-derived cells and host myocardium were functionally integrated. Therefore, survival and integration of allografts in the ischemic heart can be significantly improved with the use of therapeutic cells bioengineered to secrete MMP9 and PlGF and encapsulated within an injectable PF hydrogel having an optimized stiffness.

Highlights

On the second point, survival of engrafted cells within damaged myocardial tissue is critically dependent upon support by an adequate blood supply
We have previously reported that induced pluripotent stem (iPS) cells can be generated – through the conventional ‘Yamanaka approach’ – from still-replicating 1-day-old mouse CMs, and that these cells more efficiently differentiate into cardiac progenitors than iPS cells generated from other cell types: the efficiency of cardiogenic differentiation of CM-derived iPS cells was 53–57% compared with 33–39% for mouse embryonic stem cells and 25–33% for cardiac fibroblast-derived iPS cells.[5]
After ascertaining that bioengineered iPS cells were capable of synthesizing placental growth factor (PlGF) and matrix metalloproteinase 9 (MMP9) (Figure 1a and Supplementary Figure 1 online), we examined the biological activity of the secreted factors

Summary

Introduction

Survival of engrafted cells within damaged myocardial tissue is critically dependent upon support by an adequate blood supply. Received 07.11.13; revised 06.12.13; accepted 12.12.13; Edited by G Melino processes9,13 – overcomes this limitation by creating an environment conducive to the migration of resident and/or circulating stem cells.[13]. Another fundamental aspect that improves the survival of cell allografts and, the repair of damaged tissue, is the presence of a biomimetic scaffold onto which the therapeutic cells can be seeded. We assessed the capacity of these bioengineered iPS cells to aid myocardial repair in an AMI mouse model, by injecting them into infarcts as part of a cell-seeded PF hydrogel construct

Methods

Results

Conclusion