Abstract
Human mesenchymal stromal cells (hMSCs) are increasingly used in regenerative medicine for restoring worn-out or damaged tissue. Newly engineered tissues need to be properly vascularized and current candidates for in vitro tissue pre-vascularization are endothelial cells and endothelial progenitor cells. However, their use in therapy is hampered by their limited expansion capacity and lack of autologous sources. Our approach to engineering large grafts is to use hMSCs both as a source of cells for regeneration of targeted tissue and at the same time as the source of endothelial cells. Here we investigate how different stimuli influence endothelial differentiation of hMSCs. Although growth supplements together with shear force were not sufficient to differentiate hMSCs with respect to expression of endothelial markers such as CD31 and KDR, these conditions did prime the cells to differentiate into cells with an endothelial gene expression profile and morphology when seeded on Matrigel. In addition, we show that endothelial-like hMSCs are able to create a capillary network in 3D culture both in vitro and in vivo conditions. The expansion phase in the presence of growth supplements was crucial for the stability of the capillaries formed in vitro. To conclude, we established a robust protocol for endothelial differentiation of hMSCs, including an immortalized MSC line (iMSCs) which allows for reproducible in vitro analysis in further studies.
Highlights
Human mesenchymal stromal cells, referred to as colony forming unit-fibroblasts (CFU-F), mesenchymal stem cells, or mesenchymal progenitor cells were first identified as a subpopulation of bone marrow cells by Friedenstein [1]
Myoblasts can be obtained from MSCs after applying basic fibroblast growth factor and forskolin [14,15,16]
Proper vascularization is essential for maintaining tissue wellbeing and functionality. It is crucial for engineering of bone graft constructs, liver and many other tissues used for transplantation [63,64,65]
Summary
Human mesenchymal stromal cells (hMSCs), referred to as colony forming unit-fibroblasts (CFU-F), mesenchymal stem cells, or mesenchymal progenitor cells were first identified as a subpopulation of bone marrow cells by Friedenstein [1]. Their abundance among other bone marrow cells was estimated to be 0.01% to 0.001% [1,2,3]. Platelet-derived growth factor (PDGF) together with forskolin and glial growth factor (GGF-2) stimulation results in differentiation of MSCs into cells with a Schwann cell-like phenotype [17]. Other clinical trials with MSCs are performed to improve cardiac functions after myocardial infarction [22,23] and to restore liver and kidney function after failure [24,25]
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