從細胞活性改善到組織再生：間質幹細胞在個人化應用之研究探索

Abstract

間質幹細胞（Mesenchymal stem cells, MSCs）是維持體內器官穩定性的重要細胞群。然而，隨著年齡的增長，體內 MSCs 的活性和數量逐漸下降，這不僅影響健康，還限制了細胞療法的應用。雖然亞精胺（Spermidine, Spd）等多胺被認為有助於器官保護和延長生物體壽命，但它們對 MSCs 的影響仍不明確。本研究顯示，Spd 透過活化 AMPK 來促進自噬作用，並調節 MSCs 的增殖、遷移和分化。在氧化壓力下，Spd 能減少 MSCs 中的活性氧和炎症。In Vivo 結果顯示，給予 Spd 可以提升小鼠體內 MSCs 的活性，並開啟自噬作用改善老化。為了解決 MSCs 的來源問題，本研究透過化學再程序化(Chemical reprogramming)獲得了人類化學誘導多能幹細胞（hCiPSCs），並將其分化為類似於人類臍帶間質幹細胞（hUC-MSCs）和脂肪來源的間質幹細胞（hADSCs）的人類誘導間質幹細胞(hiMSCs)，這些細胞具有更好的增生和穩定性。組織工程是再生醫學的重要組成部分，利用支架和特定細胞組裝功能性仿生結構。本研究透過胰蛋白酶去細胞化得到豬主動脈的細胞外基質（ECM），以促進生物廢棄物的再利用。此外，本研究成功將 hiMSCs 移植至豬主動脈 ECM 中，使其分化為成熟的軟骨層，並展現出良好的生物相容性。綜上所述，Spd 對於提升 MSCs 的活性有顯著益處，為健康老化提供了新的保健選擇。此外，本研究確立了豬主動脈 ECM 的可用性，並與個人化 hiMSCs 流程相結合，為未來的組織工程提供了全新的方案。

Mesenchymal stem cells (MSCs) are regarded as a crucial cell population for maintaining organ homeostasis. However, with aging, the activity and quantity of MSCs are progressively reduced, impacting overall health and limiting cell therapy application. Although polyamines such as spermidine (Spd) have been suggested to contribute to organ protection and lifespan extension, their effects on MSCs remain unclear. This study demonstrated that Spd promotes autophagy through AMPK activation and regulates the proliferation, migration, and differentiation of MSCs. Under oxidative stress, Spd was shown to reduce reactive oxygen species (ROS) and inflammation in MSCs. In Vivo results showed that administration of Spd could enhance the activity of MSCs in mice and activate autophagy to improve aging. To address the issue of MSC sourcing, human chemically induced pluripotent stem cells (hCiPSCs) were obtained through chemical reprogramming and subsequently differentiated into human-induced MSCs (hiMSCs) resembling human umbilical cord MSCs (hUC-MSCs) and adipose-derived MSCs (hADSCs). These hiMSCs exhibited superior proliferation and stability. Tissue engineering, a critical component of regenerative medicine, involves assembling functional biomimetic structures using scaffolds and specific cells. In this study, extracellular matrix (ECM) from porcine aorta was obtained through trypsin-based decellularization, facilitating the reutilization of biological waste. Furthermore, hiMSCs were successfully implanted into the porcine aorta ECM, where they differentiated into mature cartilage layers and demonstrated excellent biocompatibility. In conclusion, Spd was shown to significantly enhance MSC activity, offering a novel option for promoting healthy aging. Additionally, the usability of porcine aorta ECM was established, and its integration with the personalized hiMSCs process provides an innovative approach for future tissue engineering.