小鼠肺臟幹源細胞之疾病模型研究

Abstract

肺泡主要由第一型與第二型肺泡上皮細胞組成。其中，第一型肺泡上皮細胞（AT1）覆蓋約 95% 的肺泡表面面積，是肺部氣體交換的主要結構。儘管AT1細胞在肺部功能中扮演關鍵角色，但由於其在體外難以分離與培養，導致對其功能特性的研究仍十分有限。間質幹／間質基質細胞（mesenchymal stem/stromal cells, MSCs）因具備自我更新能力與多向分化潛能，近年來在再生醫學領域備受關注，並於多種疾病中展現出具前景的治療應用。 本研究使用本實驗室自行開發的專利技術，成功分離出肺部前驅細胞（mPSCs），並誘導其分化為AT1細胞。同時，我們探討不同培養基材對mPSCs形態與分化潛能的影響，發現在不同培養條件下，細胞展現出顯著差異的特性。此外，本研究也評估了mPSCs衍生之AT1細胞對脂多醣（lipopolysaccharide, LPS）刺激的反應，並進一步驗證由人類胎盤絨毛膜基底層來源的間質基質細胞（pcMSCs）對細胞損傷的修復潛力；此外，我們亦透過動物模式進行療效驗證。本研究突顯pcMSCs在肺部治療應用上的潛力，並證實以mPSCs衍生AT1細胞作為肺部相關研究模型的可行性。同時，我們的發現亦提供了關於培養條件如何影響mPSCs命運與功能的新見解，為未來肺部細胞模型的優化提供重要參考。

The alveoli are primarily composed of type I and type II alveolar epithelial cells. Type I alveolar epithelial cells (AT1) cover approximately 95% of the alveolar surface area and serve as the primary structure for gas exchange in the lungs. Despite their crucial role, AT1 cells are notoriously difficult to isolate and maintain in vitro, resulting in limited research on their functional characteristics. Mesenchymal stem/stromal cells (MSCs) are well known for their self-renewal capacity and multi-lineage differentiation potential. In recent years, MSCs have garnered significant attention in regenerative medicine due to their promising therapeutic applications across various diseases. This study was conducted using a proprietary technique developed in our laboratory to isolate lung progenitor cells (mPSCs) and induce their differentiation into AT1 cells. Additionally, we investigated the effects of different culture substrates on mPSCs morphology and differentiation potential, revealing distinct cellular characteristics under varying culture conditions. We further examined the response of mPSCs-derived AT1 cells to lipopolysaccharide (LPS) stimulation and assessed the therapeutic potential of human placenta choriodecidual-derived mesenchymal stromal cells (pcMSCs) in mitigating cellular damage. Moreover, the efficacy of pcMSCs was validated using an in vivo animal model. The study underscores the therapeutic potential of pcMSCs and highlights the feasibility of utilizing mPSCs-derived AT1 cells as a valuable tool for future lung-related research. Additionally, our findings provide new insights into how culture conditions influence mPSCs fate and function, offering valuable guidance for optimizing in vitro lung cell models.