Matos Ana M, Gonçalves Ana I, Rodrigues Márcia T, Miranda Margarida S, Haj Alicia J El, Reis Rui L, Gomes Manuela E
3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Acta Biomater. 2020 Sep 1;113:488-500. doi: 10.1016/j.actbio.2020.07.009. Epub 2020 Jul 8.
Injuries affecting load bearing tendon tissues are a significant clinical burden and efficient treatments are still unmet. Tackling tendon regeneration, tissue engineering strategies aim to develop functional substitutes that recreate native tendon milieu. Tendon mimetic scaffolds capable of remote magnetic responsiveness and functionalized magnetic nanoparticles (MNPs) targeting cellular mechanosensitive receptors are potential instructive tools to mediate mechanotransduction in guiding tenogenic responses. In this work, we combine magnetically responsive scaffolds and targeted Activin A type II receptor in human adipose stem cells (hASCs), under alternating magnetic field (AMF), to synergistically facilitate external control over signal transduction. The combination of remote triggering TGF-β/Smad2/3 using MNPs tagged hASCs, through magnetically actuated scaffolds, stimulates overall expression of tendon related genes and the deposition of tendon related proteins, in comparison to non-stimulated conditions. Moreover, the phosphorylation of Smad2/3 proteins and their nuclear co-localization was also more evident. Overall, biophysical stimuli resulting from magnetic scaffolds and magnetically triggered cells under AMF stimulation modulate the mechanosensing response of hASCs towards tenogenesis, holding therapeutic promise. STATEMENT OF SIGNIFICANCE: The concept of magnetically-assisted tissue engineering may assist the development of innovative solutions to treat tendon disorders upon remote control of biological processes as cell migration or differentiation. Herein, we originally combine a fibrous aligned superparamagnetic scaffold, based on a biodegradable polymeric blend of starch and poly-ɛ-caprolactone incorporating magnetic nanoparticles (MNPs), and human adipose stem cells (hASCs) labelled with MNPs functionalized with anti-activin receptor type IIA (ActRIIA). Constructs were stimulated using alternating magnetic field (AMF), to activate the ActRIIA and subsequent induction of TGF-β signaling, through Smad2/3 phosphorylation cascade, enhancing the expression of tendon-related markers. Altogether, these findings contribute with powerful bio-magnetic approaches to activate key tenogenic pathways, envisioning future translation of magnetic biomaterials into regenerative platforms for tendon repair.
影响承重肌腱组织的损伤是一项重大的临床负担，目前仍缺乏有效的治疗方法。为了解决肌腱再生问题，组织工程策略旨在开发能够重现天然肌腱环境的功能性替代物。具有远程磁响应能力的肌腱模拟支架和靶向细胞机械敏感受体的功能化磁性纳米颗粒（MNPs）是介导机械转导以引导肌腱生成反应的潜在指导性工具。在这项工作中，我们将磁响应支架与人类脂肪干细胞（hASCs）中靶向激活素A II型受体相结合，在交变磁场（AMF）作用下，协同促进对信号转导的外部控制。与未刺激条件相比，通过磁驱动支架使用标记有MNPs的hASCs远程触发TGF-β/Smad2/3，刺激了肌腱相关基因的整体表达和肌腱相关蛋白的沉积。此外，Smad2/3蛋白的磷酸化及其核共定位也更加明显。总体而言，在AMF刺激下，磁支架和磁触发细胞产生的生物物理刺激调节了hASCs对肌腱生成的机械传感反应，具有治疗前景。
磁辅助组织工程的概念可能有助于开发创新解决方案，以在远程控制细胞迁移或分化等生物过程的情况下治疗肌腱疾病。在此，我们首次将基于淀粉和聚ε-己内酯的可生物降解聚合物共混物并掺入磁性纳米颗粒（MNPs）的纤维排列超顺磁支架与用抗激活素受体IIA型（ActRIIA）功能化的MNPs标记的人类脂肪干细胞（hASCs）相结合。使用交变磁场（AMF）刺激构建体，以激活ActRIIA并随后通过Smad2/3磷酸化级联诱导TGF-β信号传导，增强肌腱相关标志物的表达。总之，这些发现为激活关键肌腱生成途径提供了强大的生物磁方法，设想了磁性生物材料未来转化为肌腱修复再生平台的前景。
