Electrospun
uniaxially aligned ultrafine fibers show great promise
in constructing vascular grafts mimicking the anisotropic architecture
of native blood vessels. However, understanding how the stiffness
of aligned fibers would impose influences on the functionality of
vascular cells has yet to be explored. The present study aimed to
explore the stiffness effects of electrospun aligned fibrous substrates
(AFSs) on phenotypic modulation in vascular smooth muscle cells (SMCs).
A stable jet coaxial electrospinning (SJCES) method was employed to
generate highly aligned ultrafine fibers of poly(l-lactide-co-caprolactone)/poly(l-lactic acid) (PLCL/PLLA)
in shell–core configuration with a remarkably varying stiffness
region from 0.09 to 13.18 N/mm. We found that increasing AFS stiffness
had no significant influence on the cellular shape and orientation
along the fiber direction with the cultured human umbilical artery
SMCs (huaSMCs) but inhibited the cell adhesion rate, promoted cell
proliferation and migration, and especially enhanced the F-actin fiber
assembly in the huaSMCs. Notably, higher fiber stiffness resulted
in significant downregulation of contractile markers like alpha-smooth
muscle actin (α-SMA), smooth muscle myosin heavy chain, calponin, and desmin, whereas upregulated
the gene expression of pathosis-associated osteopontin (OPN) in the huaSMCs. These results allude to the
phenotype of huaSMCs on stiffer AFSs being miserably modulated into
a proliferative and pathological state. Consequently, it adversely
affected the proliferation and migration behavior of human umbilical
vein endothelial cells as well. Moreover, stiffer AFSs also revealed
to incur significant upregulation of inflammatory gene expression,
such as interleukin-6 (IL-6), monocyte chemoattractant
protein-1 (MCP-1), and intercellular adhesion molecule-1
(ICAM-1), in the huaSMCs. This study stresses that
although electrospun aligned fibers are capable of modulating native-like
oriented cell morphology and even desired phenotype realization or
transition, they might not always direct cells into correct functionality.
The integrated fiber stiffness underlying is thereby a critical parameter
to consider in engineering structurally anisotropic tissue-engineered
vascular grafts to ultimately achieve long-term patency.
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