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

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.

Heart regeneration after myocardial infarction using synthetic biomaterials

“…Animals that received iPS-hydrogel, regardless of whether cells over-expressed the therapeutic proteins or not, showed a significant increase in capillary density and cardiac function and a decrease in fibrotic and apoptotic indexes. Administration of SCs over-expressing both proteins resulted in better outcomes [58]. Positive results were also observed by Wang H. et al, who combined PEG with fumarate.…”

Direct hydrogel encapsulation of pluripotent stem cells enables ontomimetic differentiation and growth of engineered human heart tissues

“…PEG-fibrinogen can be rapidly photocrosslinked using a non-toxic photoinitiator and visible light, creating a controlled 3D microenvironment for encapsulated cells with potential for automation of the tissue production process using bioprinting of structurally organized microislands and other printed 3D tissue geometries 40, 41 or microfluidics for microsphere production 42, 43 . Previous studies have optimized the initial mechanical properties of the PEG-fibrinogen hydrogels for neonatal CM encapsulation 16 , pre-differentiated SC-CMs encapsulation 16, 44 , or SC-CMs seeded onto PEG-fibrinogen hydrogels 45 (Table S1). However, encapsulation and maintenance of hiPSCs within PEG-fibrinogen, and their direct differentiation in the presence of PEG-fibrinogen, had not previously been investigated.…”

Optimal Environmental Stiffness for Stem Cell Mediated Ischemic Myocardium Repair

“…Additionally, its angiogenic role following myocardial ischemia makes this an attractive system for possible catheter-based cell therapy of the heart [59]. A semisynthetic hydrogel has also previously been used for cardiac and skeletal muscle regeneration [60]. This type of hydrogel has a distinct advantage over other types of scaffolds because its mechanical properties are highly malleable while leaving the functionality of the encapsulated cells well preserved by the backbone of the polymeric network.…”