Three-Dimensional Bioreactor Technologies for the Cocultivation of Human Mesenchymal Stem/Stromal Cells and Beta Cells

Abstract

Diabetes is a prominent health problem caused by the failure of pancreatic beta cells. One therapeutic approach is the transplantation of functional beta cells, but it is difficult to generate sufficient beta cells in vitro and to ensure these cells remain viable at the transplantation site. Beta cells suffer from hypoxia, undergo apoptosis, or are attacked by the host immune system. Human mesenchymal stem/stromal cells (hMSCs) can improve the functionality and survival of beta cells in vivo and in vitro due to direct cell contact or the secretion of trophic factors. Current cocultivation concepts with beta cells are simple and cannot exploit the favorable properties of hMSCs. Beta cells need a three-dimensional (3D) environment to function correctly, and the cocultivation setup is therefore more complex. This review discusses 3D cultivation forms (aggregates, capsules, and carriers) for hMSCs and beta cells and strategies for large-scale cultivation. We have determined process parameters that must be balanced and considered for the cocultivation of hMSCs and beta cells, and we present several bioreactor setups that are suitable for such an innovative cocultivation approach. Bioprocess engineering of the cocultivation processes is necessary to achieve successful beta cell therapy.

Figure 1

Therapeutic effect of human mesenchymal stem/stromal cells (hMSCs) in the context of beta cell engraftment. Human MSCs modulate the host immune systems, for example, by secreting various trophic factors. Therefore, they prevent rejection of allogenic beta cell grafts and improve the survival of the graft by promoting neoangiogenesis at the transplant site and prevent apoptosis and fibrosis. ┤ inhibition, → improvement. Abbreviations: VEGF: vascular endothelial growth factor; IGF-1: insulin-like growth factor 1; PDGF: platelet-derived growth factor; CCL2: monocyte chemoattractant protein-1; FGF-2: basic fibroblast growth factor; IL-5/6/10: interleukins 5, 6, and 10; HGF: hepatocyte growth factor; GM-CSF: granulocyte macrophage colony-stimulating factor; TGF-β: transforming growth factor beta; PGE2: prostaglandin E2; IDO: indoleamine 2,3-dioxygenase; HO-1: heme oxygenase 1; NO: nitrogen monoxide; HLA-G5: human leukocyte antigen-G5.

Figure 2

Bioreactor concepts for the cocultivation of human mesenchymal stem/stromal cells (hMSCs) and beta cells. Beta cells and hMSCs can be cocultivated using either a direct mode or an indirect mode. Therefore, the cells can be present as aggregates or as encapsulated cells or attached to a carrier. In direct cocultivation, one medium and one aeration rate must be chosen for both cells, whereas indirect cocultivation allows each cell type to be supplied with a cell-specific medium and aeration rate. Abbreviations: STR: stirred tank reactor; FBR: fixed-bed reactor; FLBR: fluidized-bed reactor.