Russo Valentina, Mauro Annunziata, Peserico Alessia, Di Giacinto Oriana, Khatib Mohammad El, Citeroni Maria Rita, Rossi Emanuela, Canciello Angelo, Mazzotti Eleonora, Barboni Barbara
Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy.
Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise "Giuseppe Caporale", 64100 Teramo, Italy.
Biomedicines. 2022 May 19;10(5):1177. doi: 10.3390/biomedicines10051177.
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.
肌腱病处于应对健康挑战和部门政策目标的前沿。基于细胞的疗法在解决肌腱疾病方面具有巨大潜力。为了验证羊膜上皮干细胞（AECs）逐步转分化在肌腱再生中的作用，在本研究中，将三种不同的呈现上皮（eAECs）、间充质（mAECs）和肌腱样（tdAECs）表型的AEC亚群同种异体移植到经过验证的实验性绵羊跟腱损伤模型中。在两个早期愈合终点（14天和28天）采用比较方法分析组织愈合情况。所有三个移植细胞亚群都能够加速再生：总组织学评分（TSH）总结表明，mAECs的加速程度低于eAECs和tdAECs，在第28天时，与mAECs处理的肌腱相比，eAECs和tdAECs的评分显著更好（p < 0.0001）。此外，第14天的免疫调节反应显示，与mAECs和tdAECs相比，eAECs移植的肌腱中促再生M2巨噬细胞上调（p < 0.0001）。此外，与对照组相比，所有同种异体移植肌腱中的IL10/IL12均呈良性（p < 0.001）。eAECs和tdAECs在肌腱中表现出两种不同的潜在再生机制。eAECs主要通过其更强的能力在宿主组织中传递从促炎反应到促再生反应的转变，从而积极影响再生，导致有序的细胞外基质（ECM）沉积和血管重塑。另一方面，tdAECs的移植主要作用于增殖期，通过影响ECM密度并支持快速恢复，诱导宿主细胞区室的低细胞密度和角度排列。这些结果支持了AECs为产生不同细胞表型奠定基础的观点，这些细胞表型可通过与宿主组织的相互作用来引导肌腱再生。特别是，获得的证据表明eAECs是治疗急性肌腱病的一种可行且有效的策略，从而加强了将其应用于临床实践的依据。
