2011-04-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659277摘要：心衰竭是世人首要的死因，然而目前臨床治療僅能試圖改善心臟 功能及延緩疾病進展。近期研究報告指出人類終其一生心臟約有近50% 細胞更新率。事實上心臟中尚留存的心臟前驅細胞能分生為包括心肌 細胞等多種心臟細胞，顯示心臟並非終極分化。因此，藉由擴增存留 在心臟中的心臟前軀細胞來彌補心臟疾病時損失的心臟細胞應該是項 有前景的心臟再生治療策略。Homeobox proteinNkx2.5是心臟發育的必要因子，胚胎Nkx2.5血 統心臟幹細胞具有分化為心肌細胞及平滑肌細胞雙重潛能，藉由血統 追蹤方法，亦可自出生後Nkx2.5 enhancer-GFP基因轉殖小鼠心臟分離 出一群表現Nkx2.5之未分化細胞。目前尚未瞭解該群細胞如何自我更 新及其命運。我們先前的研究發現TGF-P能導引出生後小鼠心臟 Nkx2.5-GFP+細胞分化為平滑肌細胞。TGFpRI抑制劑可抑制此作用， 擴增細胞量，並促進心肌分化。然而，其詳細之機轉尚未明瞭，並且 需要進一步地研究來釐清抑制TGFPRI是否能對心臟疾病時之心臟再 生有所貢獻。有鑑於此，本研究計晝目標為：[1]研究TGFPRI抑制劑 調控出生後小鼠心臟Nkx2.5-GFP+細胞之生長及分化的訊息傳遞路 徑，[2]評估TGFpRI抑制劑代償心肌梗塞後損失心肌細胞之作用，並 檢驗心臟功能，[3]評估再生心臟細胞功能特性。本計晝結果能提供新穎的心臟再生醫學治療策略與轉譯醫學可行 性之重要資訊。<br> Abstract: Heart failure is the leading cause of death worldwide, and current therapies are intended to improve cardiac function and delay progression of the disease. More recently, the cardiomyocytes renewal in human was reported that fewer than 50% of cardiomyocytes are exchanged during a normal life span. Actually, the resident cardiac progenitors have been shown to differentiate into multiple cell types present in the heart, including cardiac muscle cells, indicating that the heart is not terminally differentiated. Therefore, it might be a promising cardiac regenerative strategy via expanding the residual cardiac progenitors to compensate the loss of cardiomyocytes in heart diseases.Homeobox protein Nkx2.5 is essential for cardiac development. Embryonic Nkx2.5-lineage cardiac stem cells are bipotential to differentiate into cardiomyocytes and smooth muscle cells. By using lineage tracing method, a population of undifferentiated cells express Nkx2.5 can also be isolated from the postnatal hearts of Nkx2.5 enhancer-GFP transgenic mice. It remains unclear in the self-renewal mechanism and the fate of postnatal cardiac Nkx2.5-GFP + cells. Our previous study found that TGF-3 could regulate postnatal cardiac Nkx2.5-GFP+ cells differentiation into smooth muscle cells. TGF^RI inhibitor could attenuate TGF-3 mediated effect, expanded Nkx2.5-GFP+ cells and conducted them into cardiomyogenic differentiation. However, the underlying mechanisms are unclear and it needs further investigation to clarify whether TGF-3 signaling inhibition can contribute to cardiac regeneration in heart diseases. Therefore, the objectives of the present project are [1] to identify the signaling pathways of TGF^RI inhibitors-mediated regulation in the proliferation and differentiation of postnatal cardiac Nkx2.5-GFP+ cells, [2] to assess the effect of TGF^RI inhibitors in the compensation of the loss of cardiac cells in the infarcted hearts and to examine the cardiac function, and [3] to characterize the functional properties of the regenerative cardiac cells in post MI mice with or without TGF^RI inhibitor treatment.The results of the present project can provide the important information for the novel therapeutic strategy of cardiac regenerative medicine and the feasibility in translational medicine.Nkx25TGF-p心肌分化心臟再生心肌梗塞Nkx25TGF-pcardiomyogenic differentiationcardiac regenerationmyocardial infarction