Differentiation-Dependent Secretion of Proangiogenic Factors by Mesenchymal Stem Cells

Abstract

Mesenchymal stem cells (MSCs) are a promising cell population for cell-based bone repair due to their proliferative potential, ability to differentiate into bone-forming osteoblasts, and their secretion of potent trophic factors that stimulate angiogenesis and neovascularization. To promote bone healing, autogenous or allogeneic MSCs are transplanted into bone defects after differentiation to varying degrees down the osteogenic lineage. However, the contribution of the stage of osteogenic differentiation upon angiogenic factor secretion is unclear. We hypothesized that the proangiogenic potential of MSCs was dependent upon their stage of osteogenic differentiation. After 7 days of culture, we observed the greatest osteogenic differentiation of MSCs when cells were cultured with dexamethasone (OM+). Conversely, VEGF protein secretion and upregulation of angiogenic genes were greatest in MSCs cultured in growth media (GM). Using conditioned media from MSCs in each culture condition, GM-conditioned media maximized proliferation and enhanced chemotactic migration and tubule formation of endothelial colony forming cells (ECFCs). The addition of a neutralizing VEGF165/121 antibody to conditioned media attenuated ECFC proliferation and chemotactic migration. ECFCs seeded on microcarrier beads and co-cultured with MSCs previously cultured in GM in a fibrin gel exhibited superior sprouting compared to MSCs previously cultured in OM+. These results confirm that MSCs induced farther down the osteogenic lineage possess reduced proangiogenic potential, thereby providing important findings for consideration when using MSCs for bone repair.

Lysophosphatidic Acid and Sphingosine-1-Phosphate: A Concise Review of Biological Function and Applications for Tissue Engineering

“…79 In addition to direct contributions to bone formation, MSCs promote the necessary angiogenic contributions to bone repair and homeostasis by secreting trophic factors that recruit and stabilize endothelial cells. 80 LPA potentiates this behavior by stimulating MSCs to increase secretion of proangiogenic and other cytokines, including VEGF and stromal cell derived factor-1. 81 Furthermore, LPA protects MSCs against apoptosis induced by ischemic conditions, likely through a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Aktmediated pathway.…”

Concise Review: Optimizing Expansion of Bone Marrow Mesenchymal Stem/Stromal Cells for Clinical Applications

“…Mesenchymal stem/stromal cells (MSCs) are nonhematopoietic cells with tremendous potential for use in cell-based therapies because of their proliferation, multilineage potential, homing, proangiogenic capabilities, immunosuppression, and relative lack of ethical concerns compared with embryonic stem cells [1][2][3]. Although the community still lacks one specific identification marker for MSCs, minimal criteria have been universally used in its stead: adherence to plastic; specific surface antigen expression (including but not limited to CD105 + , CD73 + , CD90 + , and CD45…”

Enhancing Osteoconductivity of Fibrin Gels with Apatite-Coated Polymer Microspheres

“…29 hMSCs produce trophic factors to recruit other cell populations to drive tissue repair and enhance angiogenesis and neovascularization, critical processes for nutrient transport in the early stages of regeneration. 41,42 Thus, the MIN group may demonstrate increased utility at the early stages of bone formation by increasing blood vessel counts, particularly when used as a delivery vehicle for hMSCs or other progenitor cell populations.…”