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研究生：	林子翔 Lin, Tzu-Hsiang
論文名稱：	探討利用間葉幹細胞或內皮前驅細胞結合幾丁聚醣之溫感型水膠與軟骨化誘導因子於關節軟骨再生之效應 Effects of mesenchymal stem cells or endothelial progenitor cells combined thermoresponsive chitosan-based hydrogel and chondrogenic inducing factors in cartilage regeneration
指導教授：	葉明龍 Yeh, Ming-Long
學位類別：	博士 Doctor
系所名稱：	工學院 - 生物醫學工程學系 Department of BioMedical Engineering
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	108
中文關鍵詞：	溫感型、髕下脂肪墊幹細胞、內皮前驅細胞、高濃度血小板血漿、軟骨再生
外文關鍵詞：	Thermosensitive, Infrapatellar fat pad-derived stem cells, Endothelial progenitor cells, Platelet-rich plasma, Cartilage regeneration
相關次數：	點閱：112 下載：4
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由於關節軟骨自我修復的能力有限，故現今研究提出組織工程和細胞治療來作為軟骨缺損修復的潛力性療法。軟骨化生長因子，其可調節軟骨細胞增生和分化。而在不同的生長因子中，轉化生長因子β-1(TGF-β1)顯示在幹細胞分化上扮演著重要的調節者。另一方面，研究發現TGF-β1所引導的內皮細胞轉變間質幹細胞(EndMT)機制可轉化內皮細胞(EC)形成間質幹細胞(MSC)，並且可被進一步誘導成軟骨細胞。除了TGF-β1外，高濃度血小板血漿(PRP)也匯聚了許多的生長因子，其研究指出可誘導MSC增生與軟骨分化。另外，在眾多的MSC中，髕下脂肪墊幹細胞 (IFPSC)其軟骨化能力近似於關節滑膜幹細胞。除了傳統的MSC外，內皮前驅細胞 (EPC)具有高度的再生與血管新生能力，可幫助關節軟骨再生。先前研究指出聚異丙基丙烯醯胺接枝幾丁聚醣之溫感水膠 (CSPN)，可促進幹細胞之存活和軟骨分化，並進一步發展軟骨組織。本研究包含兩部份:第一部份是探討PRP豐富的微環境對於IFPSC的軟骨和硬骨分化之效應與骨軟骨再生的促進作用。結果顯示，含有PRP之CSPN水膠可促進IFPSC之骨軟骨分化並在短期內有效修復骨軟骨缺損。第二部份，探討TGF-β1誘導後的EPC之幹細胞特性和軟骨分化潛力，並進一步研究其搭配CSPN之軟骨再生能力。研究顯示，EPC藉由TGF-β1引發EndMT機制並獲得幹細胞特性，再經由軟骨化誘導後，分化為似軟骨細胞，其過程參予了TGF-β/Smad訊號路徑。長期活體研究顯示CSPN種植軟骨化EPC可有效再生全層骨軟骨缺損。總結來說，將EPC或IFPSC和CSPN與軟骨化生長因子結合，其對於軟骨組織工程具有加成之助益，尤其是PRP與IFPSC之組合。

Adult articular cartilage shows a poor self-repair ability after injury. Tissue engineering and stem cell therapies are attractive alternative treatments with potential for cartilage defect repair. Chondrogenic growth factors regulate chondrocyte growth and differentiation. TGF β-1 plays a crucial role as a potent regulator of mesenchymal stem cell (MSC) differentiation. Several studies have found that TGF β-1-induced endothelial-mesenchymal transition (EndMT) converts endothelial cells (ECs) into MSCs, and then differentiates into chondrocytes. Additionally, platelet-rich plasma (PRP) is a reservoir of some critical growth factors, which promote MSC proliferation and chondrogenic differentiation. MSCs derived from infrapatellar fat pad (IFPSCs) show good chondrogenic potential similar to that of synovial MSCs. Apart from adult tissue-derived MSCs, endothelial progenitor cells (EPCs) provide a high tissue regeneration and vasculogenesis capacity for promoting cartilage repair. Chitosan-graft-poly(N-isopropylacrylamide) (CSPN) scaffold reportedly enhances cell viability and chondrogenic differentiation of stem cells, and further produces good cartilage formation. This study was conducted in two parts: in the first, the regenerative potential of IFPSCs cultured in a novel CSPN hydrogel with PRP in an osteochondral defect and on the enhancing effect of PRP-enriched microenvironment on chondrogenesis and osteogenesis of IFPSCs was investigated. Results showed that CSPN-PRP scaffold provided a favorable microenvironment, inducing IFPSCs to differentiate into osteochondral lineages in vitro and enhancing in vivo osteochondral repair in a short-term. Based on these findings, in part II, EPCs and an inducing factor (TGF-β1) were used to further investigate stem cell-like properties and chondrogenic potential of TGF-β1-stimulated EPCs and to examine the regenerative potential of CSPN seeded with chondrogenic EPCs (CEPC-CSPN) in osteochondral repair. Results showed that EPCs presented a stem cell phenotype by TGF-β1-driven EndMT, and subsequently redifferentiated into chondrogenic-like cells, which were mainly mediated by TGF-β/Smad signaling pathway. Long-term in vivo study demonstrated that CEPC-CSPN scaffold had great potential in the regeneration of osteochondral defects. Overall, these results highlight the synergic effects of EPCs or IFPSCs and CSPN hydrogel with chondrogenic factors, which may be beneficial in articular cartilage tissue engineering, particularly in PRP/IFPSC combination.

中文摘要	I
Abstract	II
誌謝	IV
Table of Content	V
List of Tables	IX
List of Figures	X
Chapter I. Introduction	1
I.1 Composition and Structure of Articular Cartilage	2
I.2 Articular Cartilage Lesions	6
I.3 Current Strategies for Articular Cartilage Repair and Tissue Engineering	7
I.4 Endothelial Progenitor Cells and Infrapatellar Fat Pad-derived Stem Cells as Cell Sources	8
I.5 Transforming Growth Factor-β and Platelet-Rich Plasma as A Microenvironmental Factor	9
I.6 Novel Thermoresponsive Chitosan-g-Poly(N-isopropylacrylamide) Copolymer Hydrogel as Cell Delivery Vehicles for Cartilage Repair	10
I.7 Study Aim of This Thesis	11
Chapter II. The parts of thesis	12
II.1 Part I. The Regenerative Effect of Thermoresponsive CSPN Hydrogel Combined IFPSCs and PRP for Osteochondral Lesion Repair	13
II.1.1 Introduction and Hypothesis	13
II.1.2 Materials and Methods	20
II.1.2.1 Instruments	20
II.1.2.2 Materials	21
II.1.2.3 Synthesis of PNIPAAm (PN) and chitosan-g-PNIPAAm (CSPN) polymers	23
II.1.2.4 Characterization of chitosan-g-PNIPAAm hydrogels	23
II.1.2.5 In vitro cell culture using rabbit IFPSC (rIFPSC)	24
II.1.2.6 Cell culture in PNIPAAm and chitosan-g-PNIPAAm hydrogels	24
II.1.2.7 Autologous PRP preparation	25
II.1.2.8 Preparation of PRP composite hydrogel	25
II.1.2.9 Cell viability test in various hydrogels	26
II.1.2.10 In vitro chondrogenic and osteogenic differentiation	26
II.1.2.11 Creation of in vivo rabbit knee joint osteochondral defect model and histopathology examinations	29
II.1.2.12 Macroscopic evaluations	30
II.1.2.13 Micro-CT evaluations	31
II.1.2.14 Histological and immunohistochemical processing	31
II.1.2.15 Statistical analysis	32
II.2 Part II. Chondrogenic Differentiation Potential of EPCs Encapsulated In A Novel Thermoresponsive CSPN Hydrogel for Cartilage Regeneration	33
II.2.1 Introduction and Hypothesis	33
II.2.2 Materials and Methods	36
II.2.2.1 Instruments	36
II.2.2.2 Materials	36
II.2.2.3 In vitro cell culture using rabbit EPC (rEPC)	37
II.2.2.4 Induction of EndMT and cell differentiation in cultured rEPCs	37
II.2.2.5 In vitro chondrogenic differentiation and signal molecules of TGF-β pathway in the EndMT	39
II.2.2.6 Preparation of chitosan-g-PNIPAAm (CSPN) scaffolds	43
II.2.2.7 Cell culture in chitosan-g-PNIPAAm (CSPN) scaffolds	43
II.2.2.8 Creation of in vivo rabbit knee joint osteochondral defect model and histopathology examinations	43
II.2.2.9 Macroscopic evaluations	44
II.2.2.10 Micro-CT evaluations	44
II.2.2.11 Histological and immunohistochemical processing	45
II.2.2.12 Statistical analysis	45
Chapter III. Results	46
III.1 Part I. The Regenerative Effect of Thermoresponsive CSPN Hydrogel Combined IFPSCs and PRP for Osteochondral Lesion Repair	47
III.1.1 Enzymatic Degradation of The CSPN hydrogel	47
III.1.2 Cell Viability of RIFPSCs Cultured In The PN or CSPN05 Hydrogel or The CSPN05 Hydrogel With PRP	49
III.1.3 Chondrogenesis and Osteogenesis of RIFPSCs In Hydrogels	49
III.1.4 Signaling Cascade and ECM In RIFPSCs after PRP treatment	53
III.1.5 Tissue Regeneration of RIFPSC-Scaffolds In Rabbit Osteochondral Defects	56
III.2 Part II. Chondrogenic Differentiation Potential of EPCs Encapsulated In A Novel Thermoresponsive CSPN Hydrogel for Cartilage Regeneration	61
III.2.1 Cultivation of Rabbit EPCs	61
III.2.2 Characterization of Transdifferented EPCs	62
III.2.3 Chondrogenic Differentiation of Transdifferented EPCs	65
III.2.4 The Signaling Molecules and Protein Synthesis Involved In EndMT Process of EPC and Chondrogenic EPC Development	67
III.2.5 Using Rabbit Model for In Vivo Evaluation of The Regenerative Potential of Cell-Scaffold Constructs In Osteochondral Defects	69
Chapter IV. Discussion	79
IV.1 Part I. The Regenerative Effect of Thermoresponsive CSPN Hydrogel Combined IFPSCs and PRP for Osteochondral Lesion Repair	80
IV.2 Part II. Chondrogenic Differentiation Potential of EPCs Encapsulated In A Novel Thermoresponsive CSPN Hydrogel for Cartilage Regeneration	85
IV.3 The Comparison of Experimental Results Between Part I and II	89
Chapter V. Conclusion	90
References	92

                                    

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