Cardiac-Derived Extracellular Matrix Enhances Cardiogenic Properties of Human Cardiac Progenitor Cells

Abstract

The use of biomaterials has been demonstrated as a viable strategy to promote cell survival and cardiac repair. However, limitations on combinational cell-biomaterial therapies exist, as cellular behavior is influenced by the microenvironment and physical characteristics of the material. Among the different scaffolds employed for cardiac tissue engineering, a myocardial matrix hydrogel has been shown to promote cardiogenesis in murine cardiac progenitor cells (mCPCs) in vitro. In this study, we investigated the influence of the hydrogel on Sca-1-like human fetal and adult CPCs (fCPCs and aCPCs) when encapsulated in three-dimensional (3D) material in vitro. fCPCs encapsulated in the myocardial matrix showed an increase in the gene expression level of cardiac markers GATA-4 and MLC2v and the vascular marker vascular endothelial growth factor receptor 2 (VEGFR2) after 4 days in culture, and a significant increase in GATA-4 up to 1 week. Increased gene expression levels of Nkx2.5, MEF2c, VEGFR2, and CD31 were also observed when aCPCs were cultured in the matrix compared to collagen. Cell survival was sustained in both hydrogels up to 1 week in culture with the myocardial matrix capable of enhancing the expression of the proliferation marker Ki-67 after 4 days in culture. When encapsulated CPCs were treated with H 2O2, an improved survival of the cells cultured in the myocardial matrix was observed. Finally, we evaluated the use of the myocardial matrix as hydrogel for in vivo cell transplantation and demonstrated that the gelation properties of the hydrogel are not influenced by the cells. In summary, we showed that the myocardial matrix hydrogel promotes human CPC cardiogenic potential, proliferation, and survival and is a favorable hydrogel for 3D in vitro culture. Furthermore, we demonstrated the in vivo applicability of the matrix as a potential vehicle for cell transplantation.

Controlling stem cell behavior with decellularized extracellular matrix scaffolds

“…The general conclusion was that the decellularized material alone was able to guide differentiation and maturation of cells into a cardiac cell fate. This was demonstrated with hESCs, hESC derived cardiomyocytes, human mesendodermal cells, rat cardiac progenitor cells, and neonatal rat ventricular myocytes on entire decellularized hearts, hydrogels, collagen composite hydrogels, and 2D coatings [42, 49, 51, 72–74]. One of these studies encapsulated hESC embryoid bodies into hydrogels with varying percentages of porcine heart ECM and observed that the higher percentage of ECM correlated with increased cardiac markers and increased number of contracting cells with larger contraction amplitudes [42].…”

Modulating in vivo degradation rate of injectable extracellular matrix hydrogels

“…2,3 Further processing of decellularized ECM into a hydrogel form also allows them to be cast in a variety of 3D shapes for cell culture or injected into host tissue for in situ tissue engineering. 4-8 Stem and progenitor cells seeded on decellularized ECM scaffolds, 9-11 ECM-based coatings, 12,13 and ECM-derived hydrogels 14,15 have been shown to have improved survival, increased proliferation, and differentiate in a tissue-specific manner. Moreover, decellularized ECM and ECM derived hydrogels have been shown to recruit progenitors cells in vivo 16-18 .…”

Processed Tissue–Derived Extracellular Matrices: Tailored Platforms Empowering Diverse Therapeutic Applications

“…Further, dECM exhibits shear thinning behavior upon injection, characterized by a decrease in viscosity upon increases in shear rate, providing a defense layer to injected cells . Numerous studies have shown dECM can be processed into a hydrogel from various tissues, including the heart, pancreas, arteries, brain, lung, meniscus, and dermis . While providing great applicability, dECM hydrogels are characterized by reduced mechanical resilience compared to the native tissue .…”

“…Moreover, the dECM hydrogel enables the retention of injected cells and provides them with a bioactive and supporting microenvironment following transplantation, thus promoting their re‐acclimation, leading to fortification and biological regeneration of the ischemic cardiac tissue. Vast research toward the application of dECM‐based hydrogels for cardiac repair, predominantly led by the Christman group, showed that the biological support of dECM hydrogels promotes the proliferation and differentiation of cardiac progenitor cells,and improves infarcted cardiac function (Figure 2h,i) . On the other hand, the mechanical and physical properties of the hydrogels induce endothelial and smooth muscle cell infiltration, as well as arteriole formation .…”