Abstract
Background. The design of tendon biomimetic electrospun fleece with Amniotic Epithelial Stem Cells (AECs) that have shown a high tenogenic attitude may represent an alternative strategy to overcome the unsatisfactory results of conventional treatments in tendon regeneration. Methods. In this study, we evaluated AEC-engineered electrospun poly(lactide-co-glycolide) (PLGA) fleeces with highly aligned fibers (ha-PLGA) that mimic tendon extracellular matrix, their biocompatibility, and differentiation towards the tenogenic lineage. PLGA fleeces with randomly distributed fibers (rd-PLGA) were generated as control. Results. Optimal cell infiltration and biocompatibility with both PLGA fleeces were shown. However, only ha-PLGA fleeces committed AECs towards an Epithelial-Mesenchymal Transition (EMT) after 48 h culture, inducing their cellular elongation along the fibers’ axis and the upregulation of mesenchymal markers. AECs further differentiated towards tenogenic lineage as confirmed by the up-regulation of tendon-related genes and Collagen Type 1 (COL1) protein expression that, after 28 days culture, appeared extracellularly distributed along the direction of ha-PLGA fibers. Moreover, long-term co-cultures of AEC-ha-PLGA bio-hybrids with fetal tendon explants significantly accelerated of half time AEC tenogenic differentiation compared to ha-PLGA fleeces cultured only with AECs. Conclusions. The fabricated tendon biomimetic ha-PLGA fleeces induce AEC tenogenesis through an early EMT, providing a potential tendon substitute for tendon engineering research.
Highlights
In human and animal patients, tendinopathies have a high incidence and are still a persistent orthopedic challenge to be solved due the fact of their high incidence of recurrences as well as their low healing ability
Using ovine AECs (oAECs) that have an epithelial genotype and phenotype in origin as a stem cell model allowed verification of the precocious Epithelial-Mesenchymal Transition (EMT) mechanisms occurring to oAECs when cultured on the PLGA constructs possessing highly aligned fibers
This study demonstrates that an instructive microenvironment for oAECs is provided by the aligned electrospun fibers, since they are trans-differentiated into mesenchymal cells of the teno-lineage
Summary
In human and animal (i.e., equine, canine) patients, tendinopathies have a high incidence and are still a persistent orthopedic challenge to be solved due the fact of their high incidence of recurrences as well as their low healing ability. Current tendinopathy therapeutic strategies foresee the use of conservative approaches or surgical repair using autografts, allografts, and xenografts, which have a limited success [7]. This situation has prompted researchers to find alternative solutions in tendon tissue engineering. Stem Cells (AECs) that have shown a high tenogenic attitude may represent an alternative strategy to overcome the unsatisfactory results of conventional treatments in tendon regeneration. We evaluated AEC-engineered electrospun poly(lactide-co-glycolide) (PLGA) fleeces with highly aligned fibers (ha-PLGA) that mimic tendon extracellular matrix, their biocompatibility, and differentiation towards the tenogenic lineage. AECs further differentiated towards tenogenic lineage as confirmed by the up-regulation of tendon-related genes and Collagen Type 1
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