2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644206摘要：缺氧性心臟病是目前全球主要死因之一，它主要是因為心臟的冠狀動脈阻塞造成心肌缺氧壞死所致。目前雖然知道可以經由控制高血壓及膽固醇來降低它的發生率，但一旦發生大片心肌壞死時，只剩心臟移植方能救命。因此醫學界一直在尋找其它較有效的治療方法。而近年來再生醫學幹細胞的發展似乎為這個疾病帶來了一線曙光。由於胚胎幹細胞有倫理及會長出畸胎瘤的疑慮，因此目前間葉幹細胞似乎是較佳的選擇。現在很多即將或已在進行的人體臨床試驗，是用病患自身的骨髓間葉幹細胞（BM-MSCs），這些自身來的幹細胞雖然不會有免疫排斥的問題，但因為病人本身大多年紀已老邁，其身上的幹細胞也會因繼代老化以致分化能力大為降低。我們之前的研究顯示：胎盤來的間葉幹細胞(P-MSCs)在小鼠模式可以有效治療缺氧性心臟病，它主要的機轉是促進血管新生及保護缺氧的心肌細胞。雖然P-MSCs因為來源較年輕，分化能力佳，但同樣還是會遭遇到容易繼代老化的問題。最近我們實驗室發現：從胚胎幹細胞衍生的間葉幹細胞(ES cell-derived mesenchymalprogenitor－EMPs)，這種細胞株具有與BM-MSCs及P-MSCs一樣的間葉幹細胞特性：具多分化能力、不會長出畸胎瘤、有免疫抑制能力移植時較不會被排斥。但它的增生及更新能力則較像它的母代胚胎幹細胞，遠較BM-MSC好 (Yen et al, Stem Cells 2009；Yen et al,Cell Transplant 2011)。再加上我們實驗室之前對幹細胞分化方向(lineage commitment)的一些研究經驗(Yen et al, Stem Cells 2007；Su et al, J Biol Chem 2010；Tseng et al, JBone Miner Res 2011)，因此我們想要來探討這種新來源，增生與更新能力更好的間葉幹細胞－EMPs，是否在缺氧性心臟病上能有更佳的治療效果。我們的研究目標包括：(1)在小鼠心臟缺氧的小動物模式，確認EMPs的治療效果及其程度(2)解析EMPs治療效果的機轉，看是經由直接分化成心肌細胞、還是分泌保護因子、抑或是促進血管新生所致(3)進行更近似人類的大動物模式－豬心臟缺氧實驗，測量EMPs的治療效果。希望藉由這個研究的進行，我們能夠釐清這種新來源，增生與更新能力更好的間葉幹細胞，它在缺氧性心臟病上的治療效果及機轉，期能讓再生醫學在這種常見重要疾病的治療上有所進展。<br> Abstract: Ischemic heart disease (IHD) has become the primary cause of death worldwide, with themost common cause being acute myocardial infarction (MI) due to compromised coronaryarterial blood flow. Advances have occurred in treating MI risk factors including hypertensionand hypercholesterolemia, but the issue of cardiomyocyte loss is unresolved except throughheart transplantation, which is limited by supply and complicated by immune rejection. Thus,much interest has gathered around exogenous application of stem cells for IHD, and recentstudies have highlighted that mesenchymal stem cells (MSCs) may be the preferred stem celltype for MI treatment.While embryonic stem cells (ESCs) may be the most pluripotent of stem cells, its isolationis ethically problematic and teratoma/tumor formation is a risk. Thus, current human trialsgenerally use autologous bone marrow (BM) stem cells including MSCs. However, theseimmunologically matched stem cells are difficult to expand due to replicative senescence andmay not be therapeutically optimal. We therefore recently turned to using fetal placentalMSCs (P-MSCs), and we found that P-MSCs yield therapeutic effects in a mouse model ofacute MI model by enhancing angiogenesis (manuscript in submission). The mechanismlikely involves paracrine secretion of pro-angiogenic factors by P-MSCs, and may alsoextend to protect ischemic cardiomyocytes.While P-MSCs are developmentally younger than BMMSCs, we have found that withextended ex vivo passaging, P-MSCs will still become senescent. Thus, our goal in thisProposal is to use a non-autologous, renewable source of MSCs to treat IHD. To this end,we have isolated ESC-derived mesenchymal progenitors (EMPs). EMPs are not onlysimilar to BM-MSCs in terms of differentiation capacity, immunosuppressive propertiesand lack of teratoma formation, but have the additional advantage of being highlyproliferative and renewable (Yen et al, Stem Cells 2009; Yen et al, Cell Transplant 2011). Inaddition, with our lab’s work on studying MSC lineage-commitment mechanisms fortherapeutic application (Yen et al, Stem Cells 2007; Su et al, J Biol Chem 2010; Tseng et al, JBone Miner Res 2011), our Specific Aims in this Proposal is to elucidate (1) whetherEMPs are therapeutic for IHD in a small animal mouse model; (2) determine whetherthe mechanisms involve EMP engraftment and/or direct cardiomyocyte differentiation,or EMP-secreted paracrine factor mediated anti-apoptosis and/or angiogenesis; andfinally (3) moving to a large animal pig model for more clinical relevance.We hope our study can reveal mechanistic insights on how EMPs—a renewable,non-tumorigenic source of MSCs—can mediate therapeutic effects for the optimization ofstem cell therapy for IHD.缺氧性心臟病心肌梗塞動物實驗小鼠豬幹細胞治療胚胎幹細胞衍生 的間葉幹細胞ischemic heart disease (IHD)myocardial infarction (MI)animal modelmousepigstem cell therapyembryonic stem cell-derived mesenchymal stem cells