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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 江伯倫(Bor-Luen Chiang) | |
| dc.contributor.author | Chien-Chia Liao | en |
| dc.contributor.author | 廖建嘉 | zh_TW |
| dc.date.accessioned | 2023-03-19T22:58:18Z | - |
| dc.date.copyright | 2022-10-03 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-07-26 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/85333 | - |
| dc.description.abstract | 幹細胞/前驅幹細胞 (Stem/progenitor cells) 具備有自我更新以及可分化出多種細胞型態的能力，因此於再生醫學領域中備受關注。在過往的研究中指出，肺部有一群上皮細胞表現有幹細胞的標誌物 stage-specific embryonic antigen-1 (SSEA-1), 肺SSEA-1+ 細胞 (pulmonary SSEA-1+ cells)。相較於成年 (adult) 小鼠，新生兒 (neonatal) 階段的小鼠蘊含有較多的 pulmonary SSEA-1+ cells 的細胞群體。為探究此間差異，本篇研究進一步探討 neonatal 以及 adult pulmonary SSEA-1+ cells 的差異。透過類器官 (organoid) 的建構，結果顯示 neonatal pulmonary SSEA-1+ cells 具備有較旺盛的幹細胞/前驅幹細胞特性。Neonatal pulmonary SSEA-1+ cells 可發育成結構類似於氣管 (airway)、支氣管肺泡 (bronchoalveolar) 以及肺泡 (alveolar) 的類器官，這結果也顯示 neonatal pulmonary SSEA-1+ cells 同時具備了發育氣管與肺泡上皮細胞的能力。此外研究觀察到 fibroblast growth factor 7 的作用可促進 neonatal pulmonary SSEA-1+ cells 的幹細胞/前驅幹細胞活性，增加類器官的生成並且增加肺泡類器官的發育。進一步地透過無細胞的肺葉或氣管損傷的小鼠…等實驗模式，均可觀察到 neonatal pulmonary SSEA-1+ cells 在肺組織中的貼附、發育與修補。這些結果顯示 neonatal pulmonary SSEA-1+ cells 應用於再生醫學的潛力。此外許多研究指出新生小鼠的肺部微環境偏向於第二型免疫反應，雖然此時過敏原的暴露會增加過敏性氣喘發生的機率，但第二型免疫反應對於新生兒肺部的發育知之甚少。為探討新生兒肺部發育與免疫微環境的關聯性，研究設計在neonatal pulmonary SSEA-1+ cells 發育成類器官的過程中給予 IL-4 與 IL-13 的刺激。實驗結果顯示短暫的 IL-4/IL-13 的作用可增加 neonatal pulmonary SSEA-1+ cells 幹細胞/前驅幹細胞的活性，提高類器官的生成並且發育出正常的氣管類器官。然而當 neonatal pulmonary SSEA-1+ cells 持續地受到 IL-4/IL-13 的刺激，纖毛上皮細胞的分化則會受到抑制，而粘液 (mucus) 的生成反而增加，顯示上皮細胞的發育產生失衡。進一步研究顯示，IL-4/IL-13 透過 STAT6 訊息傳遞途徑刺激 neonatal pulmonary SSEA-1+ cells 的細胞增生與細胞分化反應。因此在新生兒階段，短暫誘發的第二型免疫反應有助於肺的生長，然而當此發炎反應未受到完善的調控，反而會造成肺部上皮細胞的發育失衡。本篇研究果驗證 neonatal pulmonary SSEA-1+ cells 具備有幹細胞/前驅幹細胞的能力，而肺部免疫微環境的變化更進一步地調控 neonatal pulmonary SSEA-1+ cells的幹細胞/前驅幹細胞能力，引導著肺部上皮細胞的發育。 | zh_TW |
| dc.description.abstract | Stem/progenitor cells, because of their self-renewal and multiple cell type differentiation abilities, have good potential in regenerative medicine. We previously reported a lung cell population that expressed the stem cell marker SSEA-1 was abundant in neonatal but scarce in adult mice. The current study further characterized the stem/progenitor property of neonatal and adult mouse lung-derived SSEA-1+ cells. The results showed that the neonatal pulmonary SSEA-1+ cells exhibited enhanced ability in organoid generation compared to those of adult cells, suggesting the stem/progenitor activity is increased in the neonatal stage. The neonatal pulmonary SSEA-1+ cells generated airway-like, bronchoalveolar-like, and alveolar-like organoids that suggested the multilineage cell differentiation ability. In addition, fibroblast growth factor 7 facilitated the activity of neonatal pulmonary SSEA-1+ cells in organoid generation with increased alveolar cell differentiation. Furthermore, neonatal pulmonary SSEA-1+ cells could colonize and develop in the decellularized and injured lungs. These results demonstrated the stem/progenitor property of lung-derived neonatal-stage SSEA-1+ cells that suggested the potential for regenerative medicine. In addition, studies have revealed that the type 2 immunity is transiently increased in neonatal lungs. However, little is known about the effect of type 2 immunity on postnatal lung development. For this purpose, the neonatal lung-derived SSEA-1+ cells were cultured with IL-4/IL-13 during the organoid development. Results showed that short-term exposed the cells with IL-4/IL-13 could enhance the stem/progenitor activity for the organoid generation with normal epithelium development. However, extended IL-4/IL-13 stimulation resulted in decreased ciliated cell differentiation and increased mucus accumulation, suggesting the impairment of epithelial homeostasis. The IL-4 and IL-13 were signaled through STAT6 to mediate the cell proliferation and cell differentiation of the neonatal pulmonary SSEA-1+ cells. The results suggested that the transiently higher type 2 immunity in postnatal lungs plays a role to facilitate neonatal lung growth, but the excessive inflammation leads to abnormal epithelium development. Collectively, we observed the cell population and the stem/progenitor activity of pulmonary SSEA-1+ cells are enriched in the neonatal stages. Moreover, the IL-4/IL-13 further enhanced the stem/progenitor activity of neonatal pulmonary SSEA-1+ cells. Our results suggested the interactions of the pulmonary stem/progenitor cells with their immune environment to mediate neonatal lung growth and development. | en |
| dc.description.provenance | Made available in DSpace on 2023-03-19T22:58:18Z (GMT). No. of bitstreams: 1 U0001-2107202215282900.pdf: 20769012 bytes, checksum: c39305cfc2a2c0505263d576d4085177 (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | 致謝 i 中文摘要 iii ABSTRACT v ABBREVIATIONS vii TABLE OF CONTENTS viii LIST OF FIGURES xiii I. INTRODUCTION 1 1. The respiratory system 2 2. The lung development 4 3. The stem/progenitor cells in mature lungs 7 3.1 Basal cells 8 3.2 Club cells and variant club cells 8 3.3 Type 2 and type 1 alveolar epithelial cells 9 3.4 Bronchioalveolar stem cells 9 4. Growth factors in lung development and regeneration 10 5. Lung organoids 11 6. The immunity in neonatal lungs 12 7. The SSEA-1 molecule 14 8. Previous studies and research aims 15 II. MATERIALS AND METHODS 17 1. Experimental animals 18 2. Antibodies 18 3. Preparation of pulmonary single-cell suspensions and enrichment of the SSEA-1+ cells 19 4. Trachea epithelial and alveolar cell differentiation 19 5. Organoid assay 20 6. Decellularized lung scaffold preparation and incubation with neonatal pulmonary SSEA-1+ cells 21 7. Naphthalene-induced airway injury mouse model 22 8. Flow Cytometry analysis 23 9. Library preparation, RNA sequencing, and data analysis 23 10. Quantitative polymerase chain reaction (qPCR) 24 11. Immunohistochemical staining 25 12. Immunofluorescence staining of the organoids 26 13. Statistical analysis 26 III. RESULTS 28 1. The stem cell marker SSEA-1-expressing lung epithelial cell population, the pulmonary SSEA-1+ cells 29 2. Neonatal and adult pulmonary SSEA-1+ cells shared similar lung epithelial cell-associated markers 29 3. The neonatal pulmonary SSEA-1+ cells expressed Sox2 and Sox9, the transcription factors for lung epithelium development 31 4. Transcriptome analysis revealed the developmental potential of the pulmonary SSEA-1+ cells was increased in the neonatal stage 32 5. Neonatal pulmonary SSEA-1+ cells exhibited increased stem/progenitor cell activity in organoid development 32 6. The neonatal pulmonary SSEA-1+ cells developed into organoids with multiple cell type differentiation 34 7. Neonatal lung-derived SSEA-1+ cells efficiently developed into airway-like, bronchoalveolar-like, and alveolar-like organoids 35 8. FGF7 regulated neonatal pulmonary SSEA-1+ cell activity by increasing organoid generation and AT2 cell development 36 9. Neonatal pulmonary SSEA-1+ cells self-renewed during the organoid development 38 10. The neonatal pulmonary SSEA-1+ cell-derived organoids could be induced to airway and alveolar epithelial cell differentiation 39 11. Neonatal pulmonary SSEA-1+ cells colonized and developed in the decellularized lungs 40 12. Neonatal pulmonary SSEA-1+ cells participated the tissue regeneration in mice with naphthalene-induced airway injury 41 13. The neonatal lung-derived SSEA-1+ cells exhibited greater stem/progenitor activity for the airway and alveolar epithelium development 41 14. IL-4/IL-13 and IFN-γ exerted the opposite effects on the developmental activity of neonatal pulmonary stem/progenitor cells 42 15. Extended IL-4/IL-13 stimulation induced abnormal epithelium development of the neonatal pulmonary stem/progenitor cells 44 16. IFN-γ stimulation suppressed the developmental activity of the neonatal pulmonary stem/progenitor cells 45 17. Short-term IL-4 and IL-13 exposure was sufficient to exert neonatal pulmonary stem/progenitor activity 46 18. Short-term IL-4 and IL-13 exposure maintained the normal developmental characteristic of the neonatal pulmonary stem/progenitor cells 47 19. IL-4 and IL-13 signaled through STAT6 to exert the stem/progenitor cell activity of neonatal pulmonary SSEA-1+ cells 48 20. The pulmonary stem/progenitor cell activity could be regulated by type 1 and type 2 immune responses 49 IV. DISCUSSION 51 V. CONCLUSION AND PROSPECTS 64 VI. FIGURES 67 VII. REFERENCES 129 VIII. APPENDIX 141 | |
| dc.language.iso | en | |
| dc.subject | 第二型免疫 | zh_TW |
| dc.subject | 組織修復 | zh_TW |
| dc.subject | 類器官 | zh_TW |
| dc.subject | 粘膜纖毛清除 | zh_TW |
| dc.subject | 肺前驅幹細胞 | zh_TW |
| dc.subject | mucociliary clearance | en |
| dc.subject | pulmonary stem/progenitor cells | en |
| dc.subject | organoids | en |
| dc.subject | tissue repair | en |
| dc.subject | type 2 immunity | en |
| dc.title | 探討新生肺SSEA-1+前驅幹細胞之特徵及與免疫微環境之互動關係 | zh_TW |
| dc.title | Study on the characteristics of neonatal lung-derived SSEA-1+ stem/ progenitor cells and their interaction with immune microenvironment | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 朱清良(Ching-Liang Chu),林泰元(Thai-Yen Ling),曹伯年(Po-Nien Tsao),周秀慧(Shiu-Huey Chou) | |
| dc.subject.keyword | 肺前驅幹細胞,類器官,組織修復,第二型免疫,粘膜纖毛清除, | zh_TW |
| dc.subject.keyword | pulmonary stem/progenitor cells,organoids,tissue repair,type 2 immunity,mucociliary clearance, | en |
| dc.relation.page | 177 | |
| dc.identifier.doi | 10.6342/NTU202201610 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2022-07-27 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 免疫學研究所 | zh_TW |
| dc.date.embargo-lift | 2022-10-03 | - |
| 顯示於系所單位： | 免疫學研究所 | |
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