設計熱敏感表面塗佈細胞外間質用於 人羊水幹細胞的分化

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黃于茹(Yu-Ru Huang) 查詢紙本館藏

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化學工程與材料工程學系

論文名稱

設計熱敏感表面塗佈細胞外間質用於人羊水幹細胞的分化
(Design of Thermoresponsive Surface Immobilized with ECM for Differentiation of Human Amniotic Fluid Stem Cells)

相關論文

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★ 羊水間葉幹細胞培養於接枝細胞外間質寡肽與環狀肽具有最佳表面硬度的生醫材料,其增殖能力及多能性之研究	★ 人類體細胞從組成誘導型多能性幹細胞培養在無飼養層上

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摘要(中)

人羊水幹細胞（hAFSCs）是多能胚胎細胞，它能夠分化成多個譜系。分離的hAFSCs貼附和增殖取決於所使用的基質。微環境在hAFSCs的分化和基因表達中扮演著關鍵的角色。因此，在本研究中，我們設計了hAFSCs的培養方法，其中將不同的基質（細胞外間質或熱敏感聚合物）塗覆被在組織培養聚苯乙烯（TCPS）培養皿上，可以在成骨細胞和軟骨細胞獲得更高的細胞增殖和分化能力。我們培養了使用不同基質的hAFSCs，例如TCPS以及TCPS塗有（a）基質膠，（b）Synthemax II，（c）人類重組-玻璃粘連蛋白（rVN），（d）第一型膠原蛋白，（e）纖連蛋白（f）聚（N-異丙基丙烯酰胺）（PolyNIPAAm），（g）聚（N-異丙基丙烯酰胺-丙烯酸丁酯共聚物）（PolyNIPAAm-BA）和（h）用ECM固定的熱敏感聚合物（NIPAAm-ECMs）。
在這些材料中，在rVN，Synthemax II和NIPAAm-ECM上培養的hAFSCs呈現出更高的增殖和分化能力。
此外，我們研究了使用間充質幹細胞（MSCs）衍生為視網膜色素上皮細胞（RPE）的潛力和可行性。先前的研究已經使用人類胚胎幹細胞（hESC）或人類誘導性多能幹細胞（hiPSC）來分化成RPE。然而，這可能導致免疫排斥和畸胎瘤產生的問題。對於使用間充質乾細胞（MSCs），例如hAFSC衍生的自RPE，應該更具前瞻性。
而且我們開發了一種新的細胞培養基，它使用人血小板裂解液（hPL）代替胎牛血清（FBS）作為補充劑，以提高hAFSCs的分化率，並建立更完整的hAFSCs無異種培養條件作為未來的臨床應用。

摘要(英)

Human amniotic fluid stem cells (hAFSCs) are pluripotent fetal cells, which are capable to differentiate into multiple lineages. The isolated hAFSCs adhesion and proliferation depending on the substrates used. Microenvironment plays a key role in differentiation and gene expression for hAFSCs. Therefore, in this study, we designed a culture method of hAFSCs where the different substrates (extracellular matrices or thermoresponsive polymers) were coated on tissue culture polystyrene (TCPS) dishes could get higher cell proliferation and differentiation ability into osteoblasts and chondrocytes. We cultivated the hAFSCs where on different substrates were used such as TCPS and TCPS coated with (a) Matrigel, (b) Synthemax II, (c) human recombinant-vitronectin (rVN), (d) collagen type I, (e) fibronectin, (f) poly(N-isopropylacrylamide) (PNIPAAm), (g) poly(N-isopropylacrylamide-co-butylacrylate) (PNIPAAm-BA) and (h) thermoresponsive polymers immobilized with ECMs (PNIPAAm-ECMs).
Among these materials hAFSCs cultured on rVN, Synthemax II and PNIPAAm-ECMs presented the higher proliferation and differentiation abilities.
Moreover, we investigated the potential and feasibility of mesenchymal stem cells (MSCs) derived into retinal pigment epithelium (RPE). Previous studies have used human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) to differentiate into RPE. However, this may cause immune rejection and teratoma production problems. It should be more prospective for mesenchymal stem cells (MSCs) such as hAFSCs derived into RPE.
Furthermore, a new cell culture medium was developed, which used human platelet lysate (hPL) instead of fetal bovine serum (FBS) as a supplement to improve the differentiation ratio of hAFSCs and built up a more complete hAFSCs with xeno-free culture conditions for clinical application in future.

關鍵字(中)

★ 熱敏感
★ 羊水幹細胞
★ 成骨分化

關鍵字(英)

★ thermoresponsive polymer
★ hAFSCs
★ human amniotic fluid stem cells
★ osteogenic differentiation

論文目次

Index of content
Chapter 1. INTRODUCITON 1
1-1 Regenerative medicine for cell therapy 1
1-2 Stem cells 2
1-2.1 Totipotent stem cells 3
1-2.2 Pluripotent stem cells 3
1-2.3 Multipotent stem cells 5
1-2.4 Unipotent stem cells 7
1-3 Amniotic fluid 7
1-3.1 Definition 7
1-3.2 Developmental diagnosis using amniotic fluid 8
1-3.3 Content of amniotic fluid 8
1-3.4 Clinical significance and potential of amniotic fluid 9
1-3.5 Amniotic fluid cells (AFs) 10
1-3.5.1 AF-type cells 11
1-3.5.2 F-type cells 11
1-3.5.3 Epithelioid E-type cells 12
1-4 Amniotic fluid stem cells (AFSCs) 14
1-4.1 Isolation of amniotic fluid stem cells 14
1-4.2 Characterization of amniotic fluid stem cells 15
1-4.3 Pluripotency of Amniotic fluid stem cells 17
1-5 Stem cell microenvironments 19
1-5.1 Cell-soluble factor interactions 20
1-5.2 Cell-cell interactions 22
1-5.3 Cell-biomaterials interactions 22
1-5.4 Physical factors 23
1-6 ECMs 24
1-6.1 What is ECM? 24
1-6.2 The function of ECM 25
1-6.3 The component of ECM 26
1-6.4 ECM receptors 26
1-6.4.1 Matrigel (M) 29
1-6.4.2 Collagen (Col) 30
1-6.4.3 Fibronectin 31
1-6.4.4 Vitronectin 32
1-7 Human platelet lysate (hPL) 33
1-7.1 Preparation of human platelet lysate 36
1-7.2 Processing of platelet concentrates into hPL 37
1-7.3 Components within human platelet lysate 39
1-8 Thermoresponsive polymer and characteristics 42
1-9 Goal of the study 45
Chapter 2. MATERIALS AND METHODS 46
2-1 Experimental materials 46
2-1.1 Cell source for cultivation 46
2-1.2 Cell culture dishes coated with ECM 47
2-1.3 Materials for thermoresponsive surface 48
2-1.4 Differentiation of hAFSCs 48
2-1.5 Characteristic evaluation of hAFSCs 50
2-2 Experimental instrument 52
2-3 Experimental methods 52
2-3.1 Preparation of the cell culture medium 52
2-3.2 Cell cultivation 53
2-3.3 Passage of the hAFSCs 54
2-3.4 Cell density measurement 55
2-3.5 Preparation of extracellular matrix (EMC) coated dishes 56
2-3.6 Preparation of thermoresponsive polymer coated with extracellular matrix (ECM) dishes 56
2-3.7 Pluripotent gene expression analysis 57
2-3.8 Immunofluorescence staining 59
2-3.9 Flow cytometry analysis 60
2-3.10 Osteogenic differentiation 60
2-3.11 Adipogenic differentiation of hAFSCs 62
2-3.12 Chondrogenic differentiation of hAFSCs 63
2-3.13 Quantitative analysis of differentiation 63
2-3.14 Retinal pigment epithelium (RPE) differentiation of hAFSCs 64
Chapter 3. RESULT AND DISSCUSION 67
3-1 Cultivation of hAFSCs 67
3-1.1 The morphology of hAFSCs on ECMs-coating, polymer-coating, and polymer-ECM-coating dishes 68
3-1.2 The effect of human platelet lysate on hAFSCs culture 76
3-2.1 Osteogenic differentiation of hAFSCs cultured on ECMs, thermoresponsive polymers coating dishes 86
3-2.2 Development of home-made differentiation medium for inducing hAFSCs 94
3-2.3 Materials surface analysis - AFM (atomic force microscope) 108
3-2.4 Retinal pigment epithelium differentiation of hAFSCs 110
Chapter 4. Conclusion 131
Supplementary data 135
S3-2.5 Neural differentiation of hAFSCs cultured on ECMs, thermoresponsive polymers coating dishes 135
S3-2.6 Adipocyte differentiation of hAFSCs cultured on ECMs, thermoresponsive polymers coating dishes 139

Index of figure
Figure 1-1 Outline of Bone Marrow Transplant. 1
Figure 1-2 Classification of stem cells on basis of their potency. 2
Figure 1-3 Derivation and differentiation potential of ESCs. 4
Figure 1-4 Developmental model of cell differentiation and dedifferentiation. 4
Figure 1-5 The mesengenic process. Mesenchymal stem cells are multipotent and possess the ability to proliferate and commit to different cell types based on the environmental conditions. They also may be redirected from one lineage to another. (https://www.frontiersin.org/articles/10.3389/fimmu.2013.00201/full). 7
Figure 1-6 The fetus is surrounded by amniotic fluid. 8
Figure 1-7 Morphological differences in the primary cells. A – The morphology of the AF-type cells. i. A phase-contrast image of a primary AF-type cell colony on the fifth day after seeding the amniotic fluid (magnification: 100x). ii. A typical AF-type cell colony on the eighth day after seeding (magnification: 40x). B – The morphology of the F-type cells. i. A phase-contrast image of a primary F-type cell colony on the seventh day after seeding (magnification: 100x). ii. A typical AF-type cell colony on the ninth day after seeding (magnification: 40x). C – The morphology of the E-type cells. i. A phase-contrast image of a primary E-type cell colony on the fifth day after seeding (magnification: 40x). ii. An enlarged photo of Fig. 1Ci (magnification: 100x). P = passage; D = day; AF = AF-type; F = F-type; E = E-type [58]. 12
Figure 1-8 Extraction of amniotic fluid (Amniocentesis). 13
Figure 1-9 The time line of pregnant period. 14
Figure 1-10 Expression of MSC surface and postmitotic neuron markers by flow cytometry of hAFSCs [69]. 16
Figure 1-11 Microenvironment of stem cells [86]. 20
Figure 1-12 Effects of soluble factors on bone marrow mesenchymal stem cells (MSCs) trilineage differentiation [87]. 21
Figure 1-13 Regulation of cell behavior by ECM [98]. 23
Figure 1-14 Stem cells derive the tissues across that body that vary in stiffness of wide scales [100]. 24
Figure 1-15 Extracellular matrix (ECM). Typical components include collagen, proteoglycans, bronectin, and laminin [101]. 24
Figure 1-16 A model of adhesion between integrins and ECM. 26
Figure 1-17 Molecular structure of fibronectin. The various structural domains as well as binding sites for fibronectin (FN), fibrin, collagen, cells, and heparin are indicated. The amino acid sequences RGD and PHSRN constitute the major binding site for integrin α5β1 and second site that supports RGD-mediated adhesion, respectively [124]. 32
Figure 1-18 The modular structure of vitronectin and its binding domains. 33
Figure 1-19 Platelet derived growth factors in wound healing [129]. 34
Figure 1-20 Different modalities of platelet concentrate preparation [129]. 37
Figure 1-21 Preparation of allogeneic pooled human platelet lysate (pHPL) from platelet concentrates [129]. 38
Figure 1-22 Platelet granule cargo. The various types of platelet granules store a plethora of potent substances including lysosomal enzymes, coagulation factors, immunologic and adhesion molecules, chemokines and growth factors for hemostasis, host defense, angiogenesis and tissue repair [129]. 40
Figure 1-23 Curves showing phase transition phenomenon. (a) Lower critical solution temperature (LCST) and (b) upper critical solution temperature (UCST) phase transition behaviors of thermo-responsive polymers in solution [159]. 43
Figure 1-24 The structures of thermoresponsive polymers. (a) poly(N-isopropylacrylamide) (PNIPAAm). (b) poly (acrylic acid) (PAA). (c) polyacrylamide (PAAm). (d) poly (N-isopropylacrylamide-co-butylacrylate) (PNIPAAm-co-BA) 43
Figure 1-25 The mechanism for the hydrophilicity of PNIPAAm. 44
Figure 2-1 The counting grid pattern. 55
Figure 2-2 The thermoresponsive polymer surface dishes coating procedures 57
Figure 2-3 The timeline of RPE differentiation method I. 65
Figure 2-4 The time line of RPE differentiation method II. 66
Figure 3-1 Morphology of hAFSCs on different substrates-coating dishes at day 4. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm 71
Figure 3-2 The doubling time of hAFSCs on ECM or Polymer-coating dishes at Passage 7 for 4 days. (Seeding density: 2×104 /well). 72
Figure 3-3 Morphology of hAFSCs on different substrates-coating dishes at day 5. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm 74
Figure 3-4 The doubling time of hAFSCs on ECM or Polymer-coating dishes at Passage 7 for 5 days. (Seeding density: 2×104 /well). 75
Figure 3-5 Morphology of hAFSCs on different substrates-coating dishes at day 4. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm 80
Figure 3-6 The doubling time of hAFSCs on ECM or Polymer-coating dishes at Passage 4 for 4 days. (Seeding density: 2×104 /well). 81
Figure 3-7 Morphology of hAFSCs on different substrates-coating dishes at day 4. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm 83
Figure 3-8 The doubling time of hAFSCs on ECM or Polymer-coating dishes at Passage 5 for 4 days. (Seeding density: 2×104 /well). 83
Figure 3-9 Compare doubling time of 20% FBS and 10% hPL culture medium on thermoresponsive surface coated with ECMs 84
Figure 3-10 The mesengenic process. Mesenchymal stem cells are multipotent and possess the ability to proliferate and commit to different cell types based on the environmental conditions. They also may be redirected from one lineage to another (https://www.frontiersin.org/articles/10.3389/fimmu.2013.00201/full). 85
Figure 3-11 The time line of osteogenic differentiation of hAFSCs. 86
Figure 3-12 The morphology of hAFSCs after inducing 14 days with MODM (commercial product) inducing medium differentiation into osteoblast. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm, Passage 7 88
Figure 3-13 ALP activity (early stage marker of osteoblasts) of hAFSCs on several substrates coating dishes after 14 days induction into osteoblast. 89
Figure 3-14 The morphology of hAFSCs after inducing 28 days with MODM (commercial product) inducing medium differentiation into osteoblast. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm, Passage 7 90
Figure 3-15 Osteogenic differentiation of hAFSCs on various substrates coating dishes after 28 days induction into osteoblast. Upper row was top view and lower row was the morphology of the cells stained with Alizarin Red S under microscopy, Scale bar = 500μm. Red color sites indicate calcium deposition. 91
Figure 3-16 The quantification of staining cell ratio of Alizarin Red S staining. 92
Figure 3-17 Osteogenic differentiation of hAFSCs on various substrates coating dishes after 28 days induction into osteoblast. Upper row was top view and lower row was the morphology of the cells stained with von Kossa staining under microscopy, Scale bar = 500μm. Silver black color sites indicate calcium phosphate deposition. 93
Figure 3-18 The quantification of staining cell ratio of von Kossa staining. 94
Figure 3-19 The morphology of hAFSCs after inducing 14 days with 20% FBS (home-made) inducing medium differentiation into osteoblast. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm, Passage 5, 80390. 97
Figure 3-20 ALP activity (early stage marker of osteoblasts) of hAFSCs on several substrates coating dishes after 14 days induction into osteoblast. 97
Figure 3-21 The morphology of hAFSCs after inducing 28 days with 20% FBS (home-made) inducing medium differentiation into osteoblast. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm, Passage 5, 80390. 98
Figure 3-22 Osteogenic differentiation of hAFSCs on various substrates coating dishes after 28 days induction into osteoblast. Upper row was top view and lower row was the morphology of the cells stained with Alizarin Red S under microscopy, Scale bar = 500μm. Red color sites indicate calcium deposition. 99
Figure 3-23 The quantification of staining cell ratio of Alizarin Red S staining. 100
Figure 3-24 Osteogenic differentiation of hAFSCs on various substrates coating dishes after 28 days induction into osteoblast. The top view was the morphology of the cells stained with von Kossa staining. 100
Figure 3-25 The morphology of hAFSCs after inducing 14 days with 10% hPL (home-made) inducing medium differentiation into osteoblast. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm, Passage 5, 80390. 102
Figure 3-26 ALP activity (early stage marker of osteoblasts) of hAFSCs on several substrates coating dishes after 14 days induction into osteoblast. 103
Figure 3-27 The morphology of hAFSCs after inducing 28 days with 10% hPL (home-made) inducing medium differentiation into osteoblast. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm, Passage 5, 80390. 104
Figure 3-28 Osteogenic differentiation of hAFSCs on various substrates coating dishes after 28 days induction into osteoblast. Upper row was top view and lower row was the morphology of the cells stained with Alizarin Red S under microscopy, Scale bar = 500μm. Red color sites indicate calcium deposition. 105
Figure 3-29 The quantification of staining cell ratio of Alizarin Red S staining. 106
Figure 3-30 Osteogenic differentiation of hAFSCs on various substrates coating dishes after 28 days induction into osteoblast. The top view was the morphology of the cells stained with von Kossa staining. 106
Figure 3-31 ALP activity of hAFSCs induced into osteoblasts at 14 days of differentiation in commercial induction medium, home-made induction medium containing 20% FBS, and home-made induction medium containing 10% hPL after hAFSCs cultured on various substrates coating dishes. 107
Figure 3-32 Alizarin Red S staining of hAFSCs induced into osteoblasts at 28 days of differentiation in commercial induction medium, home-made induction medium containing 20% FBS, and home-made induction medium containing 10% hPL after hAFSCs cultured on various substrates coating dishes. 108
Figure 3-33 AFM analysis of ECMs, NIPAAm and NIPAAm-ECM coating dishes. AFM topography images. 109
Figure 3-34 The Rq value (roughness) on these coating substrates dishes. 109
Figure 3-35 The time line of RPE differentiation of hAFSCs (Schwartz., 2012). 110
Figure 3-36 The time line of RPE differentiation of hAFSCs (Osakada., 2009). 110
Figure 3-37 The morphology process of hAFSCs differentiation into RPE (Schwartz., 2012). 40X: Scale bar = 500μm 111
Figure 3-38 The morphology process of hAFSCs differentiation into RPE (Schwartz., 2012). 40X: Scale bar = 500μm 113
Figure 3-39 The morphology process of hAFSCs differentiation into RPE (Schwartz., 2012). 40X: Scale bar = 500μm 116
Figure 3-40 The morphology process of hAFSCs differentiation into RPE (Schwartz., 2012). 40X: Scale bar = 500μm 119
Figure 3-41 The morphology process of hAFSCs differentiation into RPE (Schwartz., 2012). 40X: Scale bar = 500μm 121
Figure 3-42 The morphology process of hAFSCs differentiation into RPE (Osakada., 2009). 40X: Scale bar = 500μm 122
Figure 3-43 RPE65 expression of hAFSCs-derived RPE analyzed by flow cytometry. 123
Figure 3-44 The morphology process of hAFSCs differentiation into RPE (Osakada., 2009). 40X: Scale bar = 500μm. 124
Figure 3-45 RPE65 expression of hAFSCs-derived RPE analyzed by flow cytometry. 124
Figure 3-46 The morphology process of hAFSCs differentiation into RPE (Zhang L et al., 2011) [170]. 40X: Scale bar = 500μm 125
Figure 3-47 RPE65 expression of hAFSCs-derived RPE analyzed by flow cytometry. 126
Figure 3-48 The morphology process of hAFSCs differentiation into RPE (Zhu, J., 2013 & Leach, L. L., 2016). 40X: Scale bar = 500μm 127
Figure 3-49 RPE65 expression of hAFSCs-derived RPE analyzed by flow cytometry. 127
Figure 3-50 The morphology process of hAFSCs differentiation into RPE (Leach LL., 2016) [173]. 40X: Scale bar = 500μm 128
Figure 3-51 RPE65 expression of hAFSCs-derived RPE analyzed by flow cytometry. 129
Figure 4-1. The main idea of developing optimal hAFSCs culture and differentiation. 131
Figure 4-2. The doubling time of hAFSCs cultivated with 20% FBS cultured on ECM, polymers and polymer immobilized with ECM-coating dishes. 132
Figure 4-3. The doubling time of hAFSCs cultivated with 10% hPL cultured on ECMs, polymers and polymer immobilized with ECM-coating dishes. 132
Figure 4-4. The osteogenic differentiation ratio of hAFSCs after culture on ECM-coating dishes, polymer-coating dishes and polymer immobilized with ECM-coating dishes with commercial (5%FBS), 20% FBS, and10% hPL contained in inducing medium. 134

Index of table
Table-1-1 Summary of hMSCs sources, cell surface markers and expansion media with serum supplements [11] 6
Table 1-2 In vitro growth potentials of colony-forming amniotic fluid cell types. 13
Table 1-3 Expression of some markers at varying stem cells. 17
Table 1-4 Lists of markers for AFSCs [12, 61, 81]. 19
Table 1-5 Medium for induction of lineage-specific differentiation [84, 85]. 19
Neurogenic differentiation (Ectoderm) 19
Table 1-6 Ligand-binding specificities of human integrins [111]. 28
Table 1-7 Collagen types, forms and distribution [121]. 31
Table 1-8 Advantages and disadvantages of FBS and hPL [128]. 35
Table 2-1 Probes of pluripotent gene 51
Table 2-2 The formula of ECM-coating dishes. 56
Table 2-3 Composition of RNA/primer solution in PCR reaction 58
Table 2-4 Formula of qRT-PCR reaction. 58
Table 2-5 qRT-PCR step condition. 59
Table 2-6 Formula of home-made osteogenic differentiation medium. 61
Table 3-1 The doubling time of hAFSCs on ECM or Polymer-coating dishes at Passage 7. 72
Table 3-2 The doubling time of hAFSCs on substrates-coating dishes at Passage 7 for 5 days. 75
Table 3-3 The doubling time of hAFSCs on substrates-coating dishes at Passage 4 for 4 days. 81
Table 3-4 The doubling time of hAFSCs on substrates-coating dishes at Passage 5 for 4 days. 84
Table 3-5 The osteogenic induction medium developed in this study. 96
Table 3-6 The results sorting of RPE differentiation method I of hAFSCs. 121
Table 3-7 The results sorting of RPE differentiation method II of hAFSCs. 130

Supplementary data
Figure S3-52 The time line of neural differentiation of hAFSCs. 135
Figure S3-53 The morphology of hAFSCs expansion for 7 days before neural differentiation. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm, Passage 3 136
Figure S3-54 The morphology of hAFSCs after inducing 21 days with HNEU.D. Media-450 (commercial product) inducing medium differentiation into neural. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm, Passage 3 137
Figure S3-55 The immunofluorescence staining of pluripotent proteins detected on hAFSCs cultured on ECMs, thermoresponsive polymers coating dishes passage 4. (A) Hoechst (nuclei) expression, (B) Nestin expression, (C)β-III tubulin expression, and (D) merged pictures. Scale bar = 100μm. 138
Figure S3-56 The time line of adipocyte differentiation of hAFSCs. 139
Figure S3-57 The morphology of hAFSCs after inducing 21 days with StemPro™ Adipogenesis Differentiation Kit (No. A1007001, Gibco™) (commercial product) inducing medium differentiation into adipocyte cells. 40X: Scale bar = 500μm; 100X: Scale bar = 100μm, Passage 6. 140
Figure S3-58 The top view of Oil red staining detected the hAFSCs cultured on ECMs, thermoresponsive polymers coating dishes at passage 6. 141

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指導教授

樋口亞紺(Akon Higuchi)

審核日期

2019-8-20

推文