2011-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644156摘要： 脊椎損傷會引起脊椎中神經組織之缺損，而可能進一步導致嚴重的永久性感覺與運動功能喪失。脊椎損傷之病理生理變化均包含最初對脊椎的機械性侵害，以及由此而引起的後續細胞及分子變化。研究顯示，基質金屬蛋白酶 （matrix metalloproteinase, MMP）9 與初期傷害後星狀細胞大量移入損傷區域有關，此外，移入的星狀細胞所大量表現的 MMP9，亦會造成腦血障壁之缺損，並進一步引發更嚴重的炎症反應及白血球浸潤等與脊椎損傷預後不良相關的現象。另一方面，損傷區域急性期過後，星狀細胞會表現少量的MMP2，此蛋白酶能夠降解位於膠質疤（glial scar）中的硫酸軟骨蛋白多醣（chondroitin sulfate proteoglycans, CSPGs），進而促使神經軸突之再生。近年來，幹細胞療法成為治療退化性疾病之熱門研究題材，尤其對於諸如脊椎損傷等再生能力不佳之組織缺損來說，更是如此。間質幹細胞由於取得容易，已經被用於多種實驗動物之脊椎損傷之試驗中。而且多項實驗結果顯示，急性脊椎損傷之動物在接受間質幹細胞移殖後，無論在運動功能回復、脊椎神經組織之缺損、軸突再生、軸突再髓鞘或神經傳導等方面，皆有顯著的改善。但是，間質幹細胞移殖再急性脊椎損傷之臨床治療效果，仍屬未知，且其達成療效之分子機制亦需釐清。在本研究計畫中，我們提出以犬隻臨床急性脊椎損傷之病患，進行骨髓間質幹細胞移殖之試驗性治療計畫。此外，也將以小鼠實驗性脊椎損傷為模型，探討間質幹細胞是否藉由抑制脊椎損傷中之MMP9，降低後續炎症反應之傷害，並提升MMP2/3 等能夠降解CSPGs 之酵素含量，促使軸突再生，進而對急性脊椎損傷產生療效。透過本研究計劃，我們希望能夠藉由試驗性治療計畫，探索幹細胞療法在脊椎損傷臨床應用的標準方法，同時也對間質幹細胞對急性脊椎損傷之療效，能有初步的了解。此外，若能對於間質幹細胞療法之分子機轉有更多的瞭解，也許能夠更加改善脊椎神經損傷的治療方法。 Abstract Spinal cord injury (SCI) results in loss of nervous tissue in the spinal cord and can lead to severe, permanent, motor and sensory dysfunction. In dogs, SCI most commonly is due to thoracolumbar disc herniation. Regardless of cause, the pathophyisology of SCI involves an initial mechanical insult to the spinal cord, referred to as the primary injury, followed by the secondary injury, a cascade of cellular and molecular events. Matrix metaloproteinase 9 (MMP9) contributes to the migration of astrocytes to the lesion site and to compromise of the blood-brain barrier, aggravating the level of inflammation and worsening the prognosis, while MMP2 expressed by astrocytes at a later stage can facilitate the clearance of the glial scar and promote axonal regeneration. Recently, stem cell therapy has shown great potential in treating degenerative diseases that have low rates of spontaneous recovery, such as SCI. Transplantation of mesenchymal stem cells (MSCs) has been tested as a therapy for SCI in various experimental animals. These animals showed significant functional recovery with less lesion cyst and scar, more axonal outgrowth, and better myelination and nerve conductivity if MSCs were applied in the acute phase. However, the therapeutic effect of MSCs in clinical applications and the molecular mechanisms of the therapeutic effects in acute SCI remain to be elucidated. We propose to evaluate the effectiveness of MSCs transplantation in clinical cases of canine acute SCI due to disc herniation, and to determine whether the therapeutic effect of MSCs involves inhibition of MMP9 expression and the promotion of CSPG-degrading enzymes such as MMP2 and MMP3. Through this study, we will establish a standard clinical protocol for MSC therapy for acute, severe SCI. Moreover, with more insight into the molecular mechanisms of this therapeutic effect, we may be able to develop better therapeutic targets and methods for treating acute SCI.骨髓間質幹細胞基質金屬蛋白脢幹細胞療法脊椎神經損傷Bone marrow-derived mesenchymal stem cellSpinal cord injuryMatrix metalloproteinaseStem cell therapy