Abstract
ObjectivesThe aim of the study was to investigate the effect of matrix stiffness on arteriovenous differentiation of endothelial progenitor cells (EPCs) during vasculogenesis in nude mice.Materials and methodsDextran hydrogels of differing stiffnesses were first prepared by controlling the crosslinking reaction to generate different thioether bonds. Hydrogels with stiffnesses matching those of the arterial extracellular matrix and venous extracellular matrix were separately combined with mouse bone marrow‐derived EPCs and subcutaneously implanted on either side of the backs of nude mice. After 14 days, artery‐specific marker Efnb2 and vein‐specific marker Ephb4 in the neovasculature were detected to determine the effect of matrix stiffness on the arteriovenous differentiation of EPCs in vivo.ResultsFourteen days after the implantation of the EPC‐loaded dextran hydrogels, new blood vessels were observed in both types of hydrogels. We further verified that matrix stiffness regulated the arteriovenous differentiation of EPCs during vasculogenesis via the Ras/Mek pathway.ConclusionsMatrix stiffness regulates the arteriovenous differentiation of EPCs during vasculogenesis in nude mice through the Ras/Mek pathway.
Highlights
The establishment of functional vascularization is key for tissue re‐ generation and represents one of the major challenges to the broad implementation of tissue engineering in clinical practice.[1]
Late endothelial progenitor cells (EPCs) exhibit higher proliferative potential in culture and survive be‐ yond 2 weeks. Both cell types contribute to neovasculogenesis in vivo; early EPCs secrete various angiogenic cytokines, and late EPCs differentiate into specific endothelial cells (ECs).[4]
Treatment with the inhibitor farnesylthiosalicylic acid (FTS) eliminated the effect of matrix stiffness on both arterial and venous phenotypes, demonstrating the important role of Ras/Mek in the matrix stiff‐ ness‐regulated arteriovenous differentiation of EPCs
Summary
The establishment of functional vascularization is key for tissue re‐ generation and represents one of the major challenges to the broad implementation of tissue engineering in clinical practice.[1]. The functional prop‐ erties of EPCs and the molecular mechanisms of their specialized differentiation into arterial and venous subtypes are still unknown This limitation negatively affects the practical use of EPCs. Previous. In order to design matrices to the specific requirements of diverse tissues, it is nec‐ essary to develop well‐defined biomaterials that mimic the matri‐ ces of the vasculature and enable the reliable control of functional vascularization. With this in mind, we first developed a stiffness‐adjustable dex‐ tran hydrogel model. Our work provides a potential method for adapting EPC‐based vascularization to the spe‐ cific requirements of a diverse range of tissues, representing a substantial advancement in regenerative medicine
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