博碩士論文 982404003 詳細資訊




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姓名 彭凱彥(Kai-Yen Peng)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 間質幹細胞治療潛力運用在缺血性心臟疾病及神經退化性疾病- 自胎兒階段及多功能幹細胞之新來源間質幹細胞
(Therapeutic Potential of Mesenchymal Stem Cells (MSCs) for Application in Ischemia Heart Disease (IHD) and Neurodegenerative Disease - New Mesenchymal Stem Cell Sources From Fetal-stage Tissue (F) and Pluripotent Stem Cells (PSCs))
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摘要(中) 缺血性心臟病與神經退化性疾病發生率隨年齡增加而增加。 當組織受 損時,由於心肌細胞及神經細胞具較弱的再生能力,因此自我修復損傷區 域是非常困難的。 近年,幹細胞治療提供缺血性心臟病及神經退化性疾病 新的治療策略。 幹細胞藉由自我更新,分化與旁分泌作用等能力,修復和 改善受損組織。 幹細胞治療方面,常用分離自初始器官或組織的人類間質 幹細胞。 然而,為了達到治療需求量,間質幹細胞在體外培養會面臨複製 時造成的細胞衰老。 這限制自體移植的幹細胞數量。 再者,缺血性與神 經退化疾病發生率隨年齡增加,病人年齡過大,降低了自體間質幹細胞治 療效率。 因此改變幹細胞來源是非常需要‧新的間質幹細胞來源可以來自 胎兒時期組織或是多功能性幹細胞。 依照細胞特性的不同,我們分別探討 胎盤幹細胞(一種源自胎兒時期幹細胞)用於缺血性心臟病及多功能性間質 幹細胞用於神經退化疾病的治療。 我們發現胎盤幹細胞能透過旁分泌作 用,促進心肌細胞存活及降低細胞凋亡。 更進一步發現,藉由調節體外培 養環境,可以加強幹細胞旁分泌作用。 在另一方面,我們也發現源自多功 能性之間質幹細胞,利用細胞骨架重組作用,可以更進一步往神經分化途 徑。 透過我們的發現,胎盤幹細胞及源自多功能性間質幹細胞可提供缺血 性心臟病及神經退化性疾病細胞治療上,新的幹細胞來源。
摘要(英) The incidences of ischemic heart disease (IHD) and neurodegenerative disease increase with age. When tissue injury occurs, cardiomyocytes and neural cells are unable to undergo repair due to poor regenerative capacity. In recent years, stem cell therapy appears to provide a new therapeutic strategy for both IHD and neurodegenerative diseases. Recipient-derived stem cells have been shown to repair and improve damaged tissue through many modalities, including self-renewal, differentiation, and paracrine effects. Human mesenchymal stem cells (MSCs) are an attractive stem cell type, which have been isolated from many adult organs and tissues. However, these adult MSCs undergo replicative senescence during in vitro expansion to reach the cell volumes needed for therapeutic use. This especially limits the number of autologous stem cells, which are usually isolated from older adult patients. Moreover, the incidence of ischemic and degenerative diseases increase with age, thus the use of any type of autologous adult MSCs would lose efficacy as the patient ages. Hence, alternative sources of MSCs are likely necessary. New sources of highly renewable MSCs can be derived from fetal-stage tissue (F) and pluripotent stem cells (PSCs). We therefore explored the application of F- MSCs on IHD, as well as MSCs derived from human PSCs, including human embryonic stem cells (ES) and induced pluripotent stem cells (iPS), on neurodegenerative diseases. Our results showed that PDMCs could promote survival and decrease apoptosis in cardiomyocytes through the paracrine function of secreted factors. Furthermore, these paracrine functions could be enhanced by modulation of extracellular matrix proteins. On the other hand, we also found that PSC-derived MSCs (PSC-MSCs) had potent capacity to undergo more committed neural differentiation through standard neural differentiation in conjunction with cytoskeletal rearrangement. Our findings give support to the use of PDMCs and PSC-MSCs as possible candidate stem cells for therapeutic application towards the respective areas of IHD and neurodegenerative disease.
關鍵字(中) ★ 缺血性心臟病
★ 間質幹細胞
★ 胎盤幹細胞
★ 神經退化性疾病
★ 源自多功能幹細胞之間質細胞
★ 神經分化
關鍵字(英) ★ Ischemic Heart Disease
★ Mesenchymal Stem Cells
★ Placenta-Derived Multipotent Stem Cells
★ Neurodegenerative disease
★ PSC-derived MSCs
★ Neural differentiation
論文目次 Publications arising from this thesis.................................................. I
中 文 摘 要 ...................................................................................II Abstract...................................................................... . .........III
Acknowledgements.....................................................................V
Table of contents......................................................................VI
List of figures.........................................................................IX
List of tables............................................................................X Abbreviation...........................................................................XI
Chapter I - Overall introduction.......................................................1
Ischemic heart disease (IHD) and stem cell therapy..............................1 Neurodegenerative disease and stem cells therapy................................3 Mesenchymal stem cells (MSCs).....................................................4 Fetal-stage MSCs (F-MSCs) and Placenta-derived multipotent stem cells (PDMCs)................................................................................5
Human pluripotent stem cell-derived mesenchymal stem cells (PSC-MSCs) ...........................................................................................7 Figures...................................................................................8
Figure I-1. Ischemic heart disease (IHD) is most commonly caused by myocardial infarction (MI).........................................................8
Figure I-2. The mechanisms of stem cells therapy involved in cardiac regeneration...........................................................................9
Figure I-3. Stem therapy for neurodegenerative disease......................10
Chapter II – Extracellular matrix protein laminin enhances mesenchymal stem cell (MSC) paracrine function through αvβ3/CD61 integrin receptor to reduce cardiomyocyte apoptosis..................................... 11
Abstract...........................................................................12 Introduction..........................................................................14 Materials and methods..............................................................17
Cell culture and related experiments...........................................17 Apoptosis assay...................................................................19
Enzyme Linked Immunosorbent Assay (ELISA)............................19 Reactive Oxygen Species (ROS) measurement..............................20 Western blotting..................................................................20
RNA isolation and Reverse transcription polymerase chain reaction (RT-PCR)......................................21
RNA interference.................................................................21
Statistical analysis................................................................22
Results.................................................................................23
PDMC-CM reduces the number of apoptotic cardiomyocytes..............23 High levels of GRO-α, HGF and IL-8 but not IL-6 secreted by PDMCs are involved in reducing TNF-α-induced apoptosis in cardiomyocyte.....23 GRO-α, HGF, and IL-8 reduce the level of TNF-α-induced ROS..........25 Laminin enhances PDMC secretion of GRO-α, HGF and IL-8.............26 Laminin enhances the anti-apoptotic effects of PDMC-CM on cardiomyocytes.....................................................................26
PDMC secretion of GRO-α, HGF and IL-8 but not IL-6 can be modulated by laminin through αvβ3 integrin..............................................27 Laminin promotes PDMC secretion of multiple factors through JNK for GRO-α and IL-8 secretion and PI3K/AKT for HGF secretion.........28
Discussion...............................................................................29 Figures..................................................................................33
Figure II-1. Identification of mouse cardiomyocytes..........................33 Figure II-2. Placenta-derived multipotent cell (PDMC)-conditioned medium (CM) decreases the percentage of apoptotic cardiomyocytes.34
Figure II-3. GRO-α, HGF and IL-8 decreased the percentage of apoptotic cardiomyocytes.................................. 36 Figure II-4. GRO-α, HGF, and IL-8 decreased the levels of TNF-α-induced ROS in mCardio.....................................................................38 Figure II-5. PDMCs cultured on laminin demonstrate enhanced secretion of GRO-α, HGF and IL-8......................................................... 40
Figure II-6. CM of laminin-cultured PDMCs demonstrates enhanced capacity to suppress mCardio apoptosis.........................................41 Figure II-7. Laminin enhances PDMC paracrine functions through αvβ3 integrin /CD61.......................................................................43
Figure II-8. Laminin promotes paracrine factors secretion from PDMCs with specific involvement of the signaling pathways of p38 for GRO-α and IL-8 secretion and PI3K/AKT for HGF secretion. ........................ 45 Figure II-9. Schematic diagram on the suppression of cardiomyocyte apoptosis and ROS production by PDMCs.....................................47
Chapter III - Human pluripotent stem cell (PSC)-derived mesenchymal stem cells (MSCs) show potent neurogenic capacity which is enhanced with cytoskeletal rearrangement..................................48
Abstract................................................................................49 Introduction............................................................................51 Materials and methods...............................................................53
Cell culture.........................................................................53 Differentiation studies............................................................54 Immunofluorescent (IF) staining................................................54
Real-time quantitateive polymerase chain reaction (real-time PCR)...54
Statistical analysis................................................................55 Results.................................................................................56
PSC-MSCs express higher levels of NSC-associated genes at baseline than BM-MSCs...................................................................56
PSC-MSCs acquired an early-stage neural cell phenotype through inhibition of Rho a kinase-myosin II pathway...............................57 ROCK inhibition of iPS-MSCs cultured in NDM induce further neural Commitment......................................................................58
PSC-MSCs express NRP-associated proteins after ROCK inhibition in SF conditions.........................................................................59 Discussion............................................................................61 Figures.................................................................................64
Figure III-1. Human pluripotent stem cell-derived mesenchymal stem cells (PSC-MSCs) express higher level of neural stem cell-associated genes than bone marrow mesenchymal stem cells (BM-MSCs).............64
Figure III-2. PSC-MSCs express early neural markers after RhoA kinase (ROCK) inhibition....................................................66 Figure III-3. ROCK inhibition in serum-free (SF) conditions induces further neural lineage commitment of PSC-MSCs. ...........................68 Figure III-4. PSC-MSCs express committed neural lineage proteins after ROCK inhibition in SF conditions......................................... 70
Figure III-5. PSC-MSCs have differentiation capacity of neural lineage more than BM-MSCs....................................................71 Table...................................................................................73
Table III-1. Primer list.............................................................73
Chapter IV - Overall discussion......................................................74 PDMCs for therapeutic application in IHD........................................75 PSC-MSCs-derived NRP could support the clinical use for neurodegenerative diseases..........................................................78 Figure...................................................................................81
Figure IV-1. Therapeutic potentiall of PDMCs and PSC-MSCs for application in IHD and neurodegenerative disease.............................81
References................................................................................82
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指導教授 顏伶汝 陳盛良(B. L.J, Yen) 審核日期 2017-1-20
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