Abstract
The recruitment of mesenchymal stem cells (MSCs) is a vital step in the bone healing process, and hence the functionalization of osteogenic biomaterials with chemotactic factors constitutes an important effort in the tissue engineering field. Previously we determined that bone-mimetic electrospun scaffolds composed of polycaprolactone, collagen I and nanohydroxyapatite (PCL/col/HA) supported greater MSC adhesion, proliferation and activation of integrin-related signaling cascades than scaffolds composed of PCL or collagen I alone. In the current study we investigated the capacity of bone-mimetic scaffolds to serve as carriers for delivery of an MSC chemotactic factor. In initial studies, we compared MSC chemotaxis toward a variety of molecules including PDGF-AB, PDGF-BB, BMP2, and a mixture of the chemokines SDF-1α, CXCL16, MIP-1α, MIP-1β, and RANTES. Transwell migration assays indicated that, of these factors, PDGF-BB was the most effective in stimulating MSC migration. We next evaluated the capacity of PCL/col/HA scaffolds, compared with PCL scaffolds, to adsorb and release PDGF-BB. We found that significantly more PDGF- BB was adsorbed to, and subsequently released from, PCL/col/HA scaffolds, with sustained release extending over an 8-week interval. The PDGF-BB released was chemotactically active in transwell migration assays, indicating that bioactivity was not diminished by adsorption to the biomaterial. Complementing these studies, we developed a new type of migration assay in which the PDGF-BB-coated bone-mimetic substrates were placed 1.5 cm away from the cell migration front. These experiments confirmed the ability of PDGF-BB-coated PCL/col/HA scaffolds to induce significant MSC chemotaxis under more stringent conditions than standard types of migration assays. Our collective results substantiate the efficacy of PDGF-BB in stimulating MSC recruitment, and further show that the incorporation of native bone molecules, collagen I and nanoHA, into electrospun scaffolds not only enhances MSC adhesion and proliferation, but also increases the amount of PDGF-BB that can be delivered from scaffolds.
Highlights
Bone has a dramatic capacity for regeneration following injury, and undergoes constant remodeling during homeostasis
Platelet-Derived Growth Factor (PDGF)-BB is a Potent Chemotactic Factor for mesenchymal stem cells (MSCs) The migration capacity of MSCs is influenced by a large range of growth factors, cytokines, and chemokines [8,36,37]
These results are consistent with a growing literature suggesting that PDGF-BB is more effective than BMP-2 or CC/CXC chemokines in stimulating chemotactic activity of human bone marrow-derived MSCs
Summary
Bone has a dramatic capacity for regeneration following injury, and undergoes constant remodeling during homeostasis This remarkable regenerative process is initiated by recruitment and differentiation of progenitor cells of mesenchymal origin along with inflammatory cells in order to first form granulation tissue, followed by hyaline cartilage, endochondral ossification and the restoration of normal bone structure during remodeling. These activities are coordinated and controlled by an intricate system of growth factors and cytokines/chemokines, such as TGF-b, PDGF, FGF-2, and BMP-2 [1]. The identification of chemotactic factors for MSCs is crucial in this regard, there is less known concerning optimal chemoattractants for MSCs when compared with other cell types such as vascular or immune cells
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