Abstract
The vascularization of tissue engineered products represents a key issue in regenerative medicine which needs to be addressed before the translation of these protocols to the bedside can be foreseen. Here we propose a multistep procedure to prepare pre-vascularized three-dimensional (3D) cardiac bio-substitutes using dynamic cell cultures and highly porous biocompatible gelatin scaffolds. The strategy adopted exploits the peculiar differentiation potential of two distinct subsets of adult stem cells to obtain human vascularized 3D cardiac tissues. In the first step of the procedure, human mesenchymal stem cells (hMSCs) are seeded onto gelatin scaffolds to provide interconnected vessel-like structures, while human cardiomyocyte progenitor cells (hCMPCs) are stimulated in vitro to obtain their commitment toward the cardiac phenotype. The use of a modular bioreactor allows the perfusion of the whole scaffold, providing superior performance in terms of cardiac tissue maturation and cell survival. Both the cell culture on natural-derived polymers and the continuous medium perfusion of the scaffold led to the formation of a densely packaged proto-tissue composed of vascular-like and cardiac-like cells, which might complete maturation process and interconnect with native tissue upon in vivo implantation. In conclusion, the data obtained through the approach here proposed highlight the importance to provide stem cells with complementary signals in vitro able to resemble the complexity of cardiac microenvironment.
Highlights
The successful regeneration of injured areas of the myocardium by tissue-engineered constructs relies on the long time viability and persistence of the bio-substitute in vivo, given the harsh conditions cells in the infarcted milieu are exposed to
By taking advantage of the peculiar differentiation potential of human mesenchymal stem cells (hMSCs) and human cardiomyocyte progenitor cells, in the present investigation we propose a multistep procedure to obtain human pre-vascularized three-dimensional (3D) cardiac bio-substitutes based on highly porous gelatin scaffolds displaying the stiffness of cardiac tissue
Rebuilding functional portions of the myocardium requires the generation of bio-substitutes that best recapitulate the structure and function of the healthy myocardium, providing new cardiomyocytes with a functional vascular network, which may prevent or reduce pathological decline and improve cardiac function after injury (Simons and Ware, 2003; Kang et al, 2013)
Summary
The successful regeneration of injured areas of the myocardium by tissue-engineered constructs relies on the long time viability and persistence of the bio-substitute in vivo, given the harsh conditions cells in the infarcted milieu are exposed to. Previous investigations revealed the sudden disappearance of cells administered by injection—systemically or locally—independent of cell type This negative outcome has been ascribed to the low retention and high mortality of cells in the hypoxic environment characterized by an inflammatory response and the lack of local blood supply (Gnecchi et al, 2008; Menasche, 2011). The issue of promoting ischemic area vascularization has been lately addressed by cardiac tissue engineers through different approaches: (i) the administration of pro-angiogenic factors supplied by direct injection or through drug-releasing carriers (Sato et al, 2001; Chiu and Radisic, 2010; Singh et al, 2012); (ii) the infusion of endothelial progenitors (EPCs) or mature endothelial cells (ECs; Lian et al, 2008); and (iii) the pre-vascularization of the tissue constructs produced in vitro before implantation (Caspi et al, 2007; Dvir et al, 2009). The adoption of scaffolds displaying an interconnected porosity itself www.frontiersin.org
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