Mesenchymal stem cells support hepatocyte function in engineered liver grafts

Abstract

Recent studies suggest that organ decellularization is a promising approach to facilitate the clinical application of regenerative therapy by providing a platform for organ engineering. This unique strategy uses native matrices to act as a reservoir for the functional cells which may show therapeutic potential when implanted into the body. Appropriate cell sources for artificial livers have been debated for some time. The desired cell type in artificial livers is primary hepatocytes, but in addition, other supportive cells may facilitate this stem cell technology. In this context, the use of mesenchymal stem cells (MSC) is an option meeting the criteria for therapeutic organ engineering. Ideally, supportive cells are required to (1) reduce the hepatic cell mass needed in an engineered liver by enhancing hepatocyte function, (2) modulate hepatic regeneration in a paracrine fashion or by direct contact, and (3) enhance the preservability of parenchymal cells during storage. Here, we describe enhanced hepatic function achieved using a strategy of sequential infusion of cells and illustrate the advantages of co-cultivating bone marrow-derived MSCs with primary hepatocytes in the engineered whole-liver scaffold. These co-recellularized liver scaffolds colonized by MSCs and hepatocytes were transplanted into live animals. After blood flow was established, we show that expression of adhesion molecules and proangiogenic factors was upregulated in the graft.

Recellularization via the bile duct supports functional allogenic and xenogenic cell growth on a decellularized rat liver scaffold

“…20 However, the ability to reproducibly generate a robust recellularized construct has proven elusive. 7,11,17,21 Early studies attempted to seed the scaffold with primary hepatocytes, and these efforts were followed by the use of stem and progenitor cells. 10,11,17,21,22 More recent work has demonstrated the importance of cell-to-cell interactions, thus highlighting the importance of multiple cell lineages in recreating a functional native liver.…”

“…7,11,17,21 Early studies attempted to seed the scaffold with primary hepatocytes, and these efforts were followed by the use of stem and progenitor cells. 10,11,17,21,22 More recent work has demonstrated the importance of cell-to-cell interactions, thus highlighting the importance of multiple cell lineages in recreating a functional native liver. 21 Transplantation of the recellularized construct has resulted in rapid graft thrombosis, likely secondary to exposed collagen in the deendothelialized vasculature.…”

“…10,11,17,21,22 More recent work has demonstrated the importance of cell-to-cell interactions, thus highlighting the importance of multiple cell lineages in recreating a functional native liver. 21 Transplantation of the recellularized construct has resulted in rapid graft thrombosis, likely secondary to exposed collagen in the deendothelialized vasculature. 19 Progress in the field is limited by the inability to generate a fully endothelialized construct containing multiple cell lines comparable to a native organ.…”

Current status of stem cell therapy: opportunities and limitations

“…Combination of multiple cell types, like hepatocytes and MSCs, with acellular matrixes for organ reconstruction is another field with promising results (Kadota et al, 2014).…”

Beneficial Effects of Human Mesenchymal Stromal Cells on Porcine Hepatocyte Viability and Albumin Secretion

“…Multipotent mesenchymal stromal cells, also called mesenchymal stem cells (MSC), support the growth of rodent hepatocytes by favoring cellular adhesion in vitro [12,13] and in vivo [14]. Several studies in rodents have shown that cotransplantation of free primary hepatocytes with rat MSC prolonged graft function with a decrease in alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin [15][16][17].…”