臺灣博碩士論文加值系統

由不同人體組織分離間葉幹細胞的研究，為再生醫學的領域帶來很多新的期許。 然而經由不同分離方法所取的細胞，通常由不同種類的細胞所組成。 從近年來對幹細胞的研究中，ABCG2和CD90這兩個分子標誌不但皆能在不同來源的幹細胞中表現，並且和幹細胞在分化相關的原始特性及間葉幹細胞在人體可能存在的位置有極大的相關性。 以人體胎盤做細胞的組織來源，我們分離ABCG2+/CD90+的細胞，並以免疫染色、流式細胞儀及分化實驗進一步對這些細胞進行特性的分析。
以流式細胞儀分析可發現，初始分離的細胞皆有部分細胞表達間葉幹細胞的分子標誌，而ABCG2、CD73、CD90及CD105的表現則偏低。ABCG2的表現低於2%，而CD90的表現則在3-35%的範圍，且在檢體之間有較大的差異性。 有趣的是，表現ABCG2的細胞皆有CD90的表現。 另外，血球細胞及胚胎幹細胞的分子標定表現，也證實了初始分離的細胞包含了混合的細胞族群。
當這些細胞以低密度(1x104 cells/cm2)進行培養時，在第十到十四天會開始有具纖維母細胞型態的細胞聚落形成。 而聚落形成的比例會隨著胎盤檢體的不同，其範圍約在每一萬顆細胞有四到四十顆的前驅細胞。 這些會形成聚落的細胞，皆均一的表現典型間葉幹細胞的分子標誌，如CD29、CD44、CD90、CD105以及HLA-ABC，且不會有血球細胞相關的分子標誌表現。 此外，CD13、CD49a及CD63的表現則較為微弱。 經過不同代數的培養後，其分子標誌的表現及分化能力上都有逐漸增加的趨勢。
在分析聚落形成的細胞時，可發現兩種不同細胞族群(ABCG2+/CD90+ 及ABCG2-/CD90+)。但在這兩群細胞中，間葉幹細胞的分子標誌在表現上並沒有明顯的差異性。 在胚胎幹細胞分子標誌的分析上，也有相同的趨勢。 這些細胞皆會表現Oct-4、E-cadherin、Sox-2、TRA-1-61及TRA-1-80，但在SSEA-3和SSEA-4上則不會有表現。 而在分化誘導的部分，在不同的聚落細胞則具有不同程度的分化能力，且分化能力和ABCG2的表現似乎沒有明顯的相關性。
在我們實驗中可發現，在胎盤絨毛組織的細胞中的確也和造血幹細胞相同，具有表現ABCG2的細胞群。 然而ABCG2在這些間葉幹細胞的真實功能及角色，仍需要進一步的研究，才能有更深入的了解。

Studies of mesenchymal stem cells from various human tissues have brought new promises in regenerative medicine. However, most isolation methods result heterogeneous cell population. From recent studies on stem cells, expressions of ABCG2 (ATP-binding cassette, group 2) had been the key feature associated with a more primitive characteristic in most stem cells, while expression of CD90 was considered as common stem marker associated with stem cell residency in vivo. Therefore, by using human placenta as our tissue source, we isolated ABCG2+/CD90+ cells and characterized these cells by immunohistochemistry, flow cytometry and differentiation potentials.
In our study, flow cytometric analysis of fresh-isolated placental cells showed moderate shift for most MSC markers, except ABCG2, CD73, CD90 and CD105. Expression of ABCG2 was less than 2% while expression of CD90 was between 3-35% with strong individual variation. Interestingly, cells positive with ABCG2 also co-expressed CD90 in most cases. In addition, expression of hematopoietic cell and embryonic stem cell markers demonstrated the heterogeneous nature of placental cells.
When cells were cultured with a low seeding density of 1x104 cells/cm2, colony formation appeared approximately 10-14 days and exhibited a typical fibroblast-like morphology. Colony efficiency was around 4-40 per 10000 cells depending on placenta samples. These colonies uniformly expressed typical MSC markers, such as CD29, CD44, CD90, CD105 and HLA-ABC, and were devoid of hematopoietic cell marker. In addition, CD13, C49a, and CD63, were also weakly expressed in these cells. Furthermore, expressions of MSC markers and differentiation potentials were found to increase through culture.
When analyzing these colony-forming cells, two subpopulations (ABCG2+/CD90+ and ABCG2-/CD90+) were found. No significant difference of MSC marker expressions was found in both subpopulations. Similar results were obtained when expression of ESC markers was analyzed. Both subpopulations expressed Oct-4, Sox-2, E-cadherin, TRA-1-61 and TRA-1-80, but not SSEA-3 and SSEA-4. However, when differentiation potentials were analyzed between these subpopulations, individual variations were found in each colony with no correlation to ABCG2 expression.
In our study, we demonstrated that side population phenotype could also be found in placental chorionic villi similar to hematopoietic stem cells. However, further studies are still required in order to reveal the particular role of ABCG2 in mesenchymal stem cells.

Table of content

Chinese abstract………………………………………………………………..i
Abstract………….…………………………………………………………...iii
Special Thanks…………………………………………………………...…..iv
Table of content……………………………………………………………….v
Figures.............................................................................................................vii
Tables...……………………………………………………………………..viii
Abbreviation list……………………………………………………………...ix


1. Introduction………………..…………………………………………. 1
1.1 Mesenchymal stem/progenitor cells……………………………….. 1
1.1.1 Discovery and definition……………………………………. 1
1.1.2 Isolation and enrichment methods………………………….. 1
1.1.3 Immunophenotypic characteristics………………………..... 2
1.1.4 MSCs from different tissue sources………………………… 3
1.1.5 Possible residence and localization in post-natal organs and
tissues……………………………………………………….
4
1.1.6 MSCs application…………………………………………… 5
1.2 Extra-embryonic tissue/ placenta…………………………………. 6
1.2.1 Extra-embryonic mesoderm from embryogenesis………….. 6
1.2.2 Structure and function of placenta………………………….. 7
1.2.3 Chorionic villi……………………………………………..... 7
1.2.4 Placenta-derived mesenchymal stem cells (PDMSCs)……... 8
1.3 Specific stem cell markers for PDMSCs isolation………………... 9
1.3.1 CD90/ Thy-1………………………………………………... 9
1.3.2 ABCG2/BCRP……………………………………………… 10
1.4 Aim of study……………………………………………………… 11

2. Materials and Methods………………………………………………. 31
2.1 Instruments………………………………………………………... 31
2.2 Chemicals…………………………………………………………. 32
2.3 Experimental methods……………………………………………. 33
2.3.1 Collection of human placentas……………………………… 33
2.3.2 Tissue handling and cell extraction of placenta chorionic
villi………………………………………………………….
33
2.3.3 Primary cell culture and passage…………………………… 34
2.3.4 Colony forming unit fibroblast (CFU-F) assay and colony efficiency (CE)………………………………………………
34
2.3.5 Flow cytometric analysis…………………………………… 34
2.3.6 Growth kinetics analysis……………………………………. 35
2.3.7 Immunocytochemical / immunofluorescent staining……….. 35
2.3.8 Immunohistochemical staining (Frozen section/cytospin)…. 36
2.3.9 Differentiation assay………………………………………... 36
2.3.9.1 Osteogenic differentiation………………………….. 36
2.3.9.2 Adipogenic differentiation…………………………. 37
2.3.9.3 Neural differentiation………………………………. 37
2.3.10 Fluorescence-activated cell sorting……………………….. 37
2.3.11 Colony harvest………………………………………………. 38

3. Results………………………………………………………………… 46
3.1 Isolation and characterization of PDMSCs……………………….. 46
3.1.1 Cell yield……………………………………………………. 46
3.1.2 Immunophenotypic profile of uncultured placental cells…... 46
3.1.3 Colony formation and efficiency (CE)……………………... 46
3.1.4 Immunocytochemical staining of colony forming cells……. 47
3.1.5 Growth kinetics and characteristic of cultured PDMSCs…... 47
3.1.6 Differentiation assay………………………………………... 47
3.1.6.1 Osteogenic induction………………………………. 47
3.1.6.2 Adipogenic induction………………………………. 48
3.1.6.3 Neural induction…………………………………… 48
3.2 Isolation and characterization of ABCG2+/CD90+ cells from PDMSCs………………………………………………………….
48
3.2.1 Fluorescence-activated cell sorting…………………………. 48
3.2.2 Expression of ABCG2 and CD90 on colony forming cells… 49
3.2.3 Expression of MSC markers on ABCG2+/CD90+ cells……. 49
3.2.4 Expression of ESC markers on ABCG2+/CD90+ cells…….. 49
3.2.5 Differentiation potential of ABCG2+/CD90+ cells………… 49
3.2.5.1 Osteogenic induction………………………………. 49
3.2.5.2 Adipogenic induction………………………………. 49
3.2.5.3 Neural induction…………………………………… 50

4. Discussion……………………………………………………….......... 79
4.1 Characteristics of uncultured placental cells……………………... 79
4.2 Characteristics of cultured placental cells…………………………. 79
4.3 ABCG2 and CD90 double positive cells…………………………... 80

5. Reference………………………………………………………........... 83

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