Tendon Healing Response Is Dependent on Epithelial–Mesenchymal–Tendon Transition State of Amniotic Epithelial Stem Cells

Abstract

Tendinopathies are at the frontier of advanced responses to health challenges and sectoral policy targets. Cell-based therapy holds great promise for tendon disorder resolution. To verify the role of stepwise trans-differentiation of amniotic epithelial stem cells (AECs) in tendon regeneration, in the present research three different AEC subsets displaying an epithelial (eAECs), mesenchymal (mAECs), and tendon-like (tdAECs) phenotype were allotransplanted in a validated experimental sheep Achilles tendon injury model. Tissue healing was analyzed adopting a comparative approach at two early healing endpoints (14 and 28 days). All three subsets of transplanted cells were able to accelerate regeneration: mAECs with a lesser extent than eAECs and tdAECs as indicated in the summary of the total histological scores (TSH), where at day 28 eAECs and tdAECs had better significant scores with respect to mAEC-treated tendons (p < 0.0001). In addition, the immunomodulatory response at day 14 showed in eAEC-transplanted tendons an upregulation of pro-regenerative M2 macrophages with respect to mAECs and tdAECs (p < 0.0001). In addition, in all allotransplanted tendons there was a favorable IL10/IL12 compared to CTR (p < 0.001). The eAECs and tdAECs displayed two different underlying regenerative mechanisms in the tendon. The eAECs positively influenced regeneration mainly through their greater ability to convey in the host tissue the shift from pro-inflammatory to pro-regenerative responses, leading to an ordered extracellular matrix (ECM) deposition and blood vessel remodeling. On the other hand, the transplantation of tdAECs acted mainly on the proliferative phase by impacting the density of ECM and by supporting a prompt recovery, inducing a low cellularity and angle alignment of the host cell compartment. These results support the idea that AECs lay the groundwork for production of different cell phenotypes that can orient tendon regeneration through a crosstalk with the host tissue. In particular, the obtained evidence suggests that eAECs are a practicable and efficient strategy for the treatment of acute tendinopathies, thus reinforcing the grounds to move their use towards clinical practice.

The current status of various preclinical therapeutic approaches for tendon repair

“…Ethical considerations and non-invasive procurement render them appealing contenders for regenerative therapies in the context of TIs. Leveraging the regenerative capabilities of AECs presents considerable potential for the progression of tendon repair methodologies and the enhancement of clinical results [ 179 , 180 ].…”

Applications of functionally-adapted hydrogels in tendon repair

“…Multiple types of stem cell sources have been widely investigated in the differentiation toward tenogenic lineage and regeneration of tendon tissues, including TDSCs, MSCs and amniotic epithelial cells (AECs). MSCs, such as bone marrow mesenchymal stem cells (BMSCs) and ADSCs, are regarded as the most studied stem cell type for tissue engineering, while TDSCs and AECs have also attracted considerable interests in tendon repair ( Gulotta et al, 2012 ; Lin et al, 2018 ; Costa-Almeida et al, 2019 ; Citeroni et al, 2020b ; Li et al, 2021a ; Russo et al, 2022b ). Despite the advances in stem-cell-based tendon tissue engineering, the delivery and activation of the transplanted stem cells in the tendon injury site remains unresolved, which would significantly impede the success of transplantation ( Lui, 2015 ).…”

The roles and therapeutic potentialof mesenchymal stem/stromal cells and their extracellular vesicles in tendinopathies

“…On histological assessment there was appropriate parallel arrangement of hypercellular fibroblastic bundles as well as an increased presence of collagen I fibers ( Kwon et al, 2018 ). Amniotic membrane derived MSCs (AMSCs) have also been used in proof-of-concept preclinical studies for the treatment of tendon injuries ( Russo et al, 2022b ). In a comparative study, Lange-Consiglio et al evaluated AMSCs and BMSCs infusion therapeutic capacity in acute tendon injury equine model ( Lange-Consiglio et al, 2013b ).…”