進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-2801201916213100
論文名稱(中文) 脂肪幹細胞與分化後之特定導向細胞用於神經系統再生之治療方法
論文名稱(英文) Therapeutic approach of ASCs and differentiated lineage cells for the regeneration of nervous system
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 107
學期 1
出版年 108
研究生(中文) 黃家葳
研究生(英文) Chia-Wei Huang
學號 S58021179
學位類別 博士
語文別 英文
論文頁數 126頁
口試委員 指導教授-吳佳慶
口試委員-許桂森
口試委員-郭余民
口試委員-蔡曜聲
口試委員-林天南
口試委員-顏伶汝
中文關鍵字 細胞治療  脂肪幹細胞  微環境線索  胞外體  神經系統 
英文關鍵字 Cell-based therapy  Adipose-derived stem cells  Microenvironmental cue  Extracellular vesicle  Nervous system 
學科別分類
中文摘要 細胞治療已經被廣泛的應用於促進組織修復與再生,特別是退化性、缺血性以及發炎的組織。脂肪幹細胞 (Adipose-derived stem cells, ASCs) 具有在適當的刺激下分化為多種譜系細胞之潛能,因此可以作為細胞治療理想的細胞來源。本研究致力於探討微環境對於誘導脂肪幹細胞分化、細胞-細胞互動與細胞與宿主互動中並促進神經系統再生的重要性。在第一部分中,我們評估機械性的剪力於誘導脂肪幹細胞分化為內皮導向細胞 (Endothelial lineage cells, ELCs) 的效果,以及細胞治療對於保護新生鼠缺血缺氧性腦損傷之可能的機制。增加內皮細胞標誌與內皮細胞功能證明利用合併化學以機械力刺激能成功的將脂肪幹細胞誘導成內皮導向細胞。植入之內皮導向細胞能爬行並嵌入腦組織中,特別是植入的細胞能在血管中促進血管新生。透過 Neuropilin 1 (NRP1) 以及 Vascular endothelial growth factor receptor 2 (VEGFR2) 所活化的Akt 對於內皮導向細胞爬行及其在動物模型中的治療效果中極具重要性。在第二部分中,我們利用甲殼素塗佈的培養皿培養脂肪幹細胞使其形成細胞球,能誘導脂肪幹細胞分化為混合種類的神經導向細胞 (Neural lineage cells, NLCs)。而 Fibroblast growth factor 9 (FGF9) 為胚胎發育中神經細胞命運重要的調控因素,本研究於形成細胞球的同時加入 FGF9 胜肽測試其對於 NLCs 神經譜系命運的調控效果,發現 FGF9 能刺激細胞分化為許旺細胞 (Schwann cells) 並表現 S100β 以及 Glial fibrillary acidic protein (GFAP)。特定抑制 Fibroblast growth factor receptor 2 (FGFR2) 減少 FGF9 誘發之 Akt 磷酸化以及許旺細胞分化。在神經導管中植入之 FGF9-NLCs 能增加坐骨神經截斷損傷後神經軸突再生以及參與髓鞘形成,並促進功能性回復。此部分研究顯示 FGF9 於許旺細胞命運決定中的重要性,並證明了 FGF9-NLCs 的治療性效果。第三部分,我們同時將 ELCs 與 NLCs 植入缺血缺氧的腦中,進一步探討 ELCs 與 NLCs 間以及植入的細胞與宿主間的互動。合併 ELCs + NLCs (E+N) 治療顯著的減少大腦損傷程度與細胞凋亡、維持神經血管單元 (neurovascular unit) 的完整性,並達到認知與動作功能的進步。研究亦發現 ELCs 的 NRP1 以及 NLCs 的 C-X-C chemokine receptor 4 (CXCR4) 與 fibroblast growth factor receptor 1 (FGFR1) 參與在兩細胞於體外缺氧微環境中的協同性互動並增進細胞移行能力。在最後一部分的研究中,我們探討不同細胞與特定導向細胞之分泌性的因子,如胞外體 Extracellular vesicle (EV),並了解其治療機轉。由共同培養的 ELCs 與 NLCs 所分離出之胞外體最具有抑制細胞發炎及凋亡的效果。共同培養之 ELCs 與 NLCs 的協同作用增加了其胞外體中 microRNA-126 的含量,並使胞外體能增加目標細胞中 Akt 磷酸化且抑制 Vascular cell adhesion protein (VCAM) 表現量。此外,在缺血缺氧性腦傷的動物中植入 E+N 胞外體與 E+N 細胞治療對於減少神經受損具有相似的效果。總結,本研究證明微環境線索與胞外體於 ASC 分化、ELC-NLC互動及細胞-宿主互動中所扮演的角色,並最終能達到較好的再生與功能性回復。
英文摘要 Cell-based therapy has been widely applied to promote tissue regeneration and repair, especially for degeneration, ischemic, and inflammatory tissues. Adipose-derived stem cells (ASCs) hold the potential for differentiation into multiple lineages under appropriate cytokine and growth factor stimulation and can serve as cell source for cell therapy. Our study aimed to investigate the microenvironment for ASCs induction, cell-cell interaction, and cell-host interaction for promoting regeneration, especially nervous system. First, we evaluated the beneficial effect of mechanical shear stress in the differentiation of endothelial lineage cells (ELCs) from ASCs and the possible intracellular signals to protect hypoxic-ischemic (HI) injury using cell-based therapy in the neonatal rats. The successful induction of ASCs into ELCs by combined chemical and mechanical stimulation was demonstrated by increasing endothelial marker and endothelial function. The transplanted ELCs can migrate and engraft into the brain tissue, especially in vessels, where they promoted the angiogenesis. The activation of Akt by neuropilin 1 (NRP1) and vascular endothelial growth factor receptor 2 (VEGFR2) were important for ELC migration and following in vivo therapeutic outcomes. Second, sphere formation of ASCs on chitosan-coated microenvironment promoted differentiation of ASCs into a mixed population of neural lineage-like cells (NLCs). The effect of FGF9, a key regulator of neural cell fate during embryo development, was tested by adding FGF9 peptide and discovered the switch of NLCs (FGF9-NLCs) toward Schwann cells (SCs) with expressing of S100β and GFAP. Specific silencing FGFR2 diminished the FGF9-induced Akt phosphorylation and inhibited the SCs differentiation. The transplanted FGF9-NLCs in nerve conduit participated in myelin sheath formation, enhanced the axon regrowth, and promoted the functional regeneration after sciatic nerve transection injury. This study reveals the importance of FGF9 in SCs fate determination via the FGF9-FGFR2-Akt pathway and demonstrates the therapeutic benefit of FGF9-NLCs. Third, we further revealed the interaction between ELC and NLC as well as transplanted cell and host by cotransplanting ELCs and NLCs (E+N) into HI injured brain. The E+N combination produced significant reduction of brain damage and cell apoptosis and the most comprehensive restoration in neurovascular unit. Improvements in cognitive and motor functions were also achieved in the injured rats with E+N therapy. Synergistic interactions to facilitate transmigration under in vitro hypoxic microenvironment were discovered with involvement of the NRP1 signal in ELCs and the C-X-C chemokine receptor 4 (CXCR4) and fibroblast growth factor receptor 1 (FGFR1) signals in NLCs. Finally, we revealed the secretory factors, particularly the extracellular vesicle (EV), among different stem/progenitor cells and investigated their therapeutic mechanism. The EV isolated from coculture of ELCs and NLCs (E+N) showed best effects to inhibit inflammation and cell apoptosis which is further boosted by in vitro hypoxia. The miR-126 was enriched in EV by the synergistic effect of E+N increased the Akt phosphorylation and inhibited the VCAM expression in target cells. The EV injection showed comparable protection with E+N cell transplantation to prevent neuronal loss in HI injury model. Therefore, we showed the characterization of EV profiles in different stem/progenitor cells and illustrated the ELC-NLC interactions and hypoxia to enrich miR-126 for better therapeutic EV which may benefit the future clinical EV therapy. Taken together, current study demonstrated the roles of microenvironmental cue and EV in ASC differentiation, ELC-NLC interaction, cell-host interaction, and finally resulted in better regeneration and functional outcome.
論文目次 摘要....................................................I
Abstract..............................................III
Chapter 1: Introduction.................................1
Adipose-derived stem cells as a potential candidate for regenerative medicine...................................1
Neural lineage and endothelial lineage differentiation..1
Potential signal and therapeutic mechanism..............3
Chapter 2: Hypothesis & Aims............................5
Chapter 3: The application of ELCs for HI brain injury..6
3.1 Introduction........................................6
3.2 Materials and methods...............................8
3.2.1 Isolation of human adipose derived stem cells.....8
3.2.2 Induction of endothelial differentiation and functional assessments..................................9
3.2.3 Animal model of neonatal HI brain injury and cell therapy.................................................9
3.2.4 Brain damage and neurovascular structure measurements...........................................10
3.2.5 In vitro hypoxia and Boyden chamber migration assay..................................................11
3.2.6 Statistical analyses.............................12
3.3 Results............................................12
3.3.1 Inducing endothelial differentiation from ASCs...12
3.3.2 ELCs transplantation protects brain against HI injury.................................................13
3.3.3 Promoting migration ability of ELCs under hypoxic condition..............................................14
3.3.4 Interplays of NRP1 and VEGFR2 signaling in migration and differentiation..........................15
Chapter 4: The application of NLCs in peripheral nervous system.................................................17
4.1 Introduction...........................................17
4.2 Materials and methods..............................20
4.2.1 Primary Culture of Adipose-derived Stem Cells and Neurosphere Formation..................................20
4.2.2 Determine Gene and Protein Expressions...........21
4.2.3 Rat Sciatic Nerve Injury and Cell Applications...23
4.2.4 Histological Assessments.........................23
4.2.5 Statistical Analyses.............................24
4.3 Results............................................24
4.3.1 Changes of FGFRs profile during sphere formation of ASCs...................................................24
4.3.2 FGF9 guides spheres differentiation toward Schwann cell lineage...........................................25
4.3.3 FGF9 transiently phosphorylated Akt in NLCs and promoted the SCs differentiation via FGFR2-Akt axis....26
4.3.4 FGF9-induced NLCs participate the re-myelination of injured sciatic nerve..................................28
Chapter 5: Combined ELCs and NLCs for protecting neurovascular unit in HI brain.........................32
5.1 Introduction.......................................32
5.2 Materials and methods..............................34
5.2.1 Isolation of ASCs................................34
5.2.2 Induction of endothelial and neural differentiation........................................35
5.2.3 HI animal model and cell-based therapies.........36
5.2.4 Assessments of Brain Damage......................36
5.2.5 Immunofluorescent staining of NVU structures.....37
5.2.6 Cell tracing.....................................38
5.2.7 Functional assessments...........................38
5.2.8 Transmigration Assay.............................39
5.2.9 Statistical analyses.............................39
5.3 Results............................................40
5.3.1 Inducing ASCs to differentiate into ELCs and NLCs...................................................40
5.3.2 Protecting the brain from infarction after HI injury.................................................40
5.3.3 Preserving the NVU structure with various cell treatments.............................................41
5.3.4 Cell engraftment and contributions in neurovascular structure..............................................42
5.3.5 Recovery of motor and memory function............43
5.3.6 Synergistic interactions between ELCs and NLCs...44
Chapter 6: The involvement of extracellular vesicles in E+N synergistic effect.................................46
6.1 Introduction.......................................46
6.2 Materials and methods..............................49
6.2.1 hASCs culture and differentiation into lineage specific cells.........................................49
6.2.2 In vitro cell damage model in endothelial and neuronal cells.........................................50
6.2.3 EVs purification and characterizations...........51
6.2.4 Vesicle uptake assay.............................52
6.2.5 Boyden chamber migration assay...................53
6.2.6 Animal model for neonatal HI brain injury and therapy................................................53
6.2.7 Brain damage measurements........................53
6.2.8 Statistical analyses.............................54
6.3 Results............................................54
6.3.1 ELCs and NLCs produce abundant EVs with specialized characteristics than ASCs..............................54
6.3.2 Therapeutic cell-derived EVs exerting anti-inflammation and anti-apoptosis effects on inflamed endothelial and neuronal cells.........................55
6.3.3 Coculture and hypoxia enhanced the interactions of NLCs and ELCs on EVs cargo proteins and miR-126 encapsulation..........................................57
6.3.4 Interplays of hypoxia on NLC-ELC interactions and therapeutic targets on secreted EVs....................58
6.3.5 Essential roles of EVs in E+N combine therapy to prevent brain from neonatal brain HI injury............59
Chapter 7: Discussion..................................61
7.1 Discussion for chapter 3...........................64
7.2 Discussion for chapter 4...........................67
7.3 Discussion for chapter 5...........................70
7.4 Discussion for chapter 6...........................72
Chapter 8: Conclusion..................................77
Reference..............................................79
Appendix...............................................95

參考文獻 1. Bourin, P., et al., Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy, 2013. 15(6): p. 641-8.
2. Gimble, J.M., A.J. Katz, and B.A. Bunnell, Adipose-derived stem cells for regenerative medicine. Circulation research, 2007. 100(9): p. 1249-1260.
3. Safford, K.M., et al., Neurogenic differentiation of murine and human adipose-derived stromal cells. Biochemical and Biophysical Research Communications, 2002. 294(2): p. 371-9.
4. Zuk, P.A., et al., Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue engineering, 2001. 7(2): p. 211-228.
5. Bertolini, F., et al., Adipose tissue cells, lipotransfer and cancer: a challenge for scientists, oncologists and surgeons. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 2012. 1826(1): p. 209-214.
6. Frese, L., P.E. Dijkman, and S.P. Hoerstrup, Adipose tissue-derived stem cells in regenerative medicine. Transfusion Medicine and Hemotherapy, 2016. 43(4): p. 268-274.
7. Marconi, S., et al., Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush. Tissue Engineering Part A, 2012. 18(11-12): p. 1264-72.
8. Kim, J.-M., et al., Systemic transplantation of human adipose stem cells attenuated cerebral inflammation and degeneration in a hemorrhagic stroke model. Brain Research, 2007. 1183: p. 43-50.
9. Schwerk, A., et al., Adipose-derived human mesenchymal stem cells induce long-term neurogenic and anti-inflammatory effects and improve cognitive but not motor performance in a rat model of Parkinson's disease. Regenerative Medicine, 2015. 10(4): p. 431-46.
10. Cao, Q., R.L. Benton, and S.R. Whittemore, Stem cell repair of central nervous system injury. Journal of Neuroscience Research, 2002. 68(5): p. 501-10.
11. Schwarz, S.C. and J. Schwarz, Translation of stem cell therapy for neurological diseases. Translational Research, 2010. 156(3): p. 155-160.
12. Jin, K., et al., Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiology of Disease, 2005. 18(2): p. 366-74.
13. Jin, K., et al., Effect of human neural precursor cell transplantation on endogenous neurogenesis after focal cerebral ischemia in the rat. Brain Research, 2011. 1374: p. 56-62.
14. Liu, S., et al., Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proceedings of the National Academy of Sciences of the USA, 2000. 97(11): p. 6126-31.
15. D'Aiuto, L., et al., Large-scale generation of human iPSC-derived neural stem cells/early neural progenitor cells and their neuronal differentiation. Organogenesis, 2014. 10(4): p. 365-77.
16. Hu, B.Y., et al., Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proceedings of the National Academy of Sciences of the USA, 2010. 107(9): p. 4335-40.
17. Morizane, A., et al., Direct comparison of autologous and allogeneic transplantation of iPSC-derived neural cells in the brain of a non-human primate. Stem Cell Reports, 2013. 1(4): p. 283-92.
18. Gutierrez-Aranda, I., et al., Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection. Stem Cells, 2010. 28(9): p. 1568-70.
19. Kang, S.K., et al., Neurogenesis of Rhesus adipose stromal cells. Journal of Cell Science, 2004. 117(Pt 18): p. 4289-99.
20. Salehi, H., et al., An Overview of Neural Differentiation Potential of Human Adipose Derived Stem Cells. Stem Cell Reviews and Reports, 2016. 12(1): p. 26-41.
21. Radtke, C., et al., Peripheral glial cell differentiation from neurospheres derived from adipose mesenchymal stem cells. International Journal of Developmental Neuroscience, 2009. 27(8): p. 817-23.
22. Shimotake, J., et al., Vascular endothelial growth factor receptor-2 inhibition promotes cell death and limits endothelial cell proliferation in a neonatal rodent model of stroke. Stroke, 2010. 41(2): p. 343-9.
23. Hristov, M., W. Erl, and P.C. Weber, Endothelial progenitor cells: mobilization, differentiation, and homing. Arteriosclerosis, Thrombosis, and Vascular Biology, 2003. 23(7): p. 1185-9.
24. Kawamoto, A., et al., Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation, 2001. 103(5): p. 634-7.
25. Oswald, J., et al., Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells, 2004. 22(3): p. 377-84.
26. Choi, K.D., et al., Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells, 2009. 27(3): p. 559-67.
27. Metallo, C.M., et al., The response of human embryonic stem cell-derived endothelial cells to shear stress. Biotechnology and Bioengineering, 2008. 100(4): p. 830-7.
28. Yamamoto, K., et al., Proliferation, differentiation, and tube formation by endothelial progenitor cells in response to shear stress. Journal of Applied Physiology (1985), 2003. 95(5): p. 2081-8.
29. Wu, C.-C., et al., Synergism of biochemical and mechanical stimuli in the differentiation of human placenta-derived multipotent cells into endothelial cells. Journal of biomechanics, 2008. 41(4): p. 813-821.
30. McCloskey, K.E., et al., Embryonic stem cell-derived endothelial cells may lack complete functional maturation in vitro. Journal of vascular research, 2006. 43(5): p. 411-421.
31. Gimble, J.M., A.J. Katz, and B.A. Bunnell, Adipose-derived stem cells for regenerative medicine. Circulation Research, 2007. 100(9): p. 1249-60.
32. Wynn, R.F., et al., A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood, 2004. 104(9): p. 2643-2645.
33. Karp, J.M. and G.S.L. Teo, Mesenchymal stem cell homing: the devil is in the details. Cell stem cell, 2009. 4(3): p. 206-216.
34. Schwarz, S.C. and J. Schwarz, Translation of stem cell therapy for neurological diseases. Translational Research, 2010. 156(3): p. 155-60.
35. Hao, L., et al., Stem cell-based therapies for ischemic stroke. BioMed research international, 2014. 2014.
36. Cui, G.H., et al., Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB Journal, 2018. 32(2): p. 654-668.
37. Annabi, B., et al., Hypoxia promotes murine bone‐marrow‐derived stromal cell migration and tube formation. Stem cells, 2003. 21(3): p. 337-347.
38. de Couto, G., et al., Exosomal microRNA Transfer into Macrophages Mediates Cellular Postconditioning. Circulation, 2017.
39. Huang, C.-W., et al., Shear stress induces differentiation of endothelial lineage cells to protect neonatal brain from hypoxic-ischemic injury through NRP1 and VEGFR2 signaling. BioMed research international, 2015. 2015.
40. Ferriero, D.M., Neonatal brain injury. N Engl J Med, 2004. 351(19): p. 1985-95.
41. Johnston, M.V., et al., Treatment advances in neonatal neuroprotection and neurointensive care. The Lancet Neurology, 2011. 10(4): p. 372-382.
42. Hawkins, B.T. and T.P. Davis, The blood-brain barrier/neurovascular unit in health and disease. Pharmacological reviews, 2005. 57(2): p. 173-185.
43. Chern, C.-M., et al., 2-Methoxystypandrone ameliorates brain function through preserving BBB integrity and promoting neurogenesis in mice with acute ischemic stroke. Biochemical pharmacology, 2014. 87(3): p. 502-514.
44. Sobrino, T., et al., The increase of circulating endothelial progenitor cells after acute ischemic stroke is associated with good outcome. Stroke, 2007. 38(10): p. 2759-64.
45. Yoon, C.H., et al., Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation, 2005. 112(11): p. 1618-27.
46. Asahara, T., et al., VEGF contributes to postnatal neovascularization by mobilizing bone marrow‐derived endothelial progenitor cells. The EMBO journal, 1999. 18(14): p. 3964-3972.
47. Rabbany, S.Y., et al., Molecular pathways regulating mobilization of marrow-derived stem cells for tissue revascularization. Trends in molecular medicine, 2003. 9(3): p. 109-117.
48. Kalka, C., et al., Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proceedings of the National Academy of Sciences of the USA, 2000. 97(7): p. 3422-7.
49. Kawamoto, A., et al., Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation, 2003. 107(3): p. 461-8.
50. Werner, N., et al., Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury. Circulation Research, 2003. 93(2): p. e17-24.
51. Assmus, B., et al., Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation, 2002. 106(24): p. 3009-17.
52. Fan, Y., et al., Endothelial progenitor cell transplantation improves long-term stroke outcome in mice. Annals of Neurology, 2010. 67(4): p. 488-97.
53. Wu, C.C., et al., Human umbilical vein endothelial cells protect against hypoxic-ischemic damage in neonatal brain via stromal cell-derived factor 1/C-X-C chemokine receptor type 4. Stroke, 2013. 44(5): p. 1402-9.
54. Rafii, S. and D. Lyden, Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nature Medicine, 2003. 9(6): p. 702-12.
55. Wu, C.-C., et al., Synergism of biochemical and mechanical stimuli in the differentiation of human placenta-derived multipotent cells into endothelial cells. Journal of biomechanics, 2008. 41(4): p. 813-821.
56. Zuk, P.A., et al., Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Engineering, 2001. 7(2): p. 211-28.
57. Miranville, A., et al., Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation, 2004. 110(3): p. 349-55.
58. Hsueh, Y.Y., et al., Spheroid formation and neural induction in human adipose-derived stem cells on a chitosan-coated surface. Cells Tissues Organs, 2012. 196(2): p. 117-28.
59. Wu, C.-C., et al., Human Umbilical Vein Endothelial Cells Protect Against Hypoxic-Ischemic Damage in Neonatal Brain via Stromal Cell-derived Factor 1/CXC Chemokine Receptor Type 4. Stroke, 2013. 44(5): p. 1402-1409.
60. Yager, J.Y., et al., Effect of insulin-induced and fasting hypoglycemia on perinatal hypoxic-ischemic brain damage. Pediatric research, 1992. 31(2): p. 138-142.
61. Paxinos, G. and C. Watson, The rat brain in stereotaxic coordinates 1998: Academic press.
62. Hung, H.-S., et al., The behavior of endothelial cells on polyurethane nanocomposites and the associated signaling pathways. Biomaterials, 2009. 30(8): p. 1502-1511.
63. Brugger, V., et al., Delaying histone deacetylase response to injury accelerates conversion into repair Schwann cells and nerve regeneration. Nature Communication, 2017. 8: p. 14272.
64. Arthur-Farraj, P.J., et al., c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron, 2012. 75(4): p. 633-47.
65. Mosahebi, A., et al., Retroviral labeling of Schwann cells: in vitro characterization and in vivo transplantation to improve peripheral nerve regeneration. Glia, 2001. 34(1): p. 8-17.
66. Haastert, K., et al., Autologous adult human Schwann cells genetically modified to provide alternative cellular transplants in peripheral nerve regeneration. Journal of Neurosurgery, 2006. 104(5): p. 778-86.
67. Schaarschmidt, G., et al., A new culturing strategy improves functional neuronal development of human neural progenitor cells. Journal of neurochemistry, 2009. 109(1): p. 238-247.
68. Vierbuchen, T., et al., Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 2010. 463(7284): p. 1035-1041.
69. Venkataramana, N.K., et al., Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson's disease. Translational Research, 2010. 155(2): p. 62-70.
70. Hsueh, Y.Y., et al., Functional recoveries of sciatic nerve regeneration by combining chitosan-coated conduit and neurosphere cells induced from adipose-derived stem cells. Biomaterials, 2014. 35(7): p. 2234-44.
71. Turner, N. and R. Grose, Fibroblast growth factor signalling: from development to cancer. Nature Reviews Cancer, 2010. 10(2): p. 116-29.
72. Mason, I., Initiation to end point: the multiple roles of fibroblast growth factors in neural development. Nature Reviews Neuroscience, 2007. 8(8): p. 583-96.
73. Mertens, J., et al., Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience. Nature Reviews Neuroscience, 2016. 17(7): p. 424-37.
74. Cho, M.S., D.Y. Hwang, and D.W. Kim, Efficient derivation of functional dopaminergic neurons from human embryonic stem cells on a large scale. Nature Protocols, 2008. 3(12): p. 1888-94.
75. Chambers, S.M., et al., Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nature Biotechnology, 2009. 27(3): p. 275-80.
76. Denham, M., et al., Multipotent caudal neural progenitors derived from human pluripotent stem cells that give rise to lineages of the central and peripheral nervous system. Stem Cells, 2015. 33(6): p. 1759-70.
77. Lin, Y., et al., Neuron-derived FGF9 is essential for scaffold formation of Bergmann radial fibers and migration of granule neurons in the cerebellum. Developmental Biology, 2009. 329(1): p. 44-54.
78. Bertrand, V., et al., Neural tissue in ascidian embryos is induced by FGF9/16/20, acting via a combination of maternal GATA and Ets transcription factors. Cell, 2003. 115(5): p. 615-27.
79. Nakamura, S., et al., Fibroblast growth factor (FGF)-9 immunoreactivity in senile plaques. Brain Research, 1998. 814(1-2): p. 222-5.
80. Huang, J.Y., Y.T. Hong, and J.I. Chuang, Fibroblast growth factor 9 prevents MPP+-induced death of dopaminergic neurons and is involved in melatonin neuroprotection in vivo and in vitro. Journal of Neurochemistry, 2009. 109(5): p. 1400-12.
81. Hodges, A., et al., Regional and cellular gene expression changes in human Huntington's disease brain. Human Molecular Genetics, 2006. 15(6): p. 965-77.
82. Chuang, J.I., et al., FGF9-induced changes in cellular redox status and HO-1 upregulation are FGFR-dependent and proceed through both ERK and AKT to induce CREB and Nrf2 activation. Free Radical Biology and Medicine, 2015. 89: p. 274-86.
83. Hecht, D., et al., Identification of fibroblast growth factor 9 (FGF9) as a high affinity, heparin dependent ligand for FGF receptors 3 and 2 but not for FGF receptors 1 and 4. Growth Factors, 1995. 12(3): p. 223-33.
84. Huang, C.W., et al., Shear Stress Induces Differentiation of Endothelial Lineage Cells to Protect Neonatal Brain from Hypoxic-Ischemic Injury through NRP1 and VEGFR2 Signaling. BioMed Research International, 2015. 2015: p. 862485.
85. Huang, C.F., et al., Assembling Composite Dermal Papilla Spheres with Adipose-derived Stem Cells to Enhance Hair Follicle Induction. Scientific Reports, 2016. 6: p. 26436.
86. Hsueh, Y.Y., et al., Synergy of endothelial and neural progenitor cells from adipose-derived stem cells to preserve neurovascular structures in rat hypoxic-ischemic brain injury. Scientific Reports, 2015. 5: p. 14985.
87. Hsueh, Y.-Y., et al., Spheroid formation and neural induction in human adipose-derived stem cells on a chitosan-coated surface. Cells Tissues Organs, 2012. 196(2): p. 117-128.
88. Lu, J., et al., Effect of fibroblast growth factor 9 on the osteogenic differentiation of bone marrow stromal stem cells and dental pulp stem cells. Molecular Medicine Reports, 2015. 11(3): p. 1661-8.
89. Low, J.A., Determining the contribution of asphyxia to brain damage in the neonate. Journal of Obstetrics and Gynaecology Research, 2004. 30(4): p. 276-86.
90. Badve, C.A., P.C. Khanna, and G.E. Ishak, Neonatal ischemic brain injury: what every radiologist needs to know. Pediatric radiology, 2012. 42(5): p. 606-619.
91. Baburamani, A.A., et al., Vulnerability of the developing brain to hypoxic-ischemic damage: contribution of the cerebral vasculature to injury and repair? Frontiers in physiology, 2012. 3: p. 424.
92. Chang, Y.-C. and C.-C. Huang, Perinatal brain injury and regulation of transcription. Current opinion in neurology, 2006. 19(2): p. 141-147.
93. Gidday, J.M., Cerebral preconditioning and ischaemic tolerance. Nature Reviews Neuroscience, 2006. 7(6): p. 437-448.
94. Castillo-Melendez, M., et al., Stem cell therapy to protect and repair the developing brain: a review of mechanisms of action of cord blood and amnion epithelial derived cells. Frontiers in Neuroscience, 2013. 7: p. 194.
95. Park, K.J., et al., Bone marrow-derived endothelial progenitor cells protect postischemic axons after traumatic brain injury. Journal of Cerebral Blood Flow and Metabolism, 2014. 34(2): p. 357-66.
96. Yamashita, J., et al., Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature, 2000. 408(6808): p. 92-96.
97. Oswald, J., et al., Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem cells, 2004. 22(3): p. 377-384.
98. Martínez-Estrada, O.M., et al., Human adipose tissue as a source of Flk-1+ cells: new method of differentiation and expansion. Cardiovascular research, 2005. 65(2): p. 328-333.
99. Lee, H., et al., Directed differentiation and transplantation of human embryonic stem cell‐derived motoneurons. Stem cells, 2007. 25(8): p. 1931-1939.
100. Lefort, N., et al., Human embryonic stem cells reveal recurrent genomic instability at 20q11.21. Nature Biotechnology, 2008. 26(12): p. 1364-6.
101. Wei, X., et al., IFATS collection: The conditioned media of adipose stromal cells protect against hypoxia-ischemia-induced brain damage in neonatal rats. Stem Cells, 2009. 27(2): p. 478-88.
102. Takahashi, M., et al., Adipose tissue-derived stem cells inhibit neointimal formation in a paracrine fashion in rat femoral artery. American Journal of Physiology-Heart and Circulatory Physiology, 2010. 298(2): p. H415-H423.
103. Hsueh, Y.-Y., et al., Functional recoveries of sciatic nerve regeneration by combining chitosan-coated conduit and neurosphere cells induced from adipose-derived stem cells. Biomaterials, 2014. 35(7): p. 2234-2244.
104. Wu, C.-C., et al., Directional shear flow and Rho activation prevent the endothelial cell apoptosis induced by micropatterned anisotropic geometry. Proceedings of the National Academy of Sciences, 2007. 104(4): p. 1254-1259.
105. Zhang, F. and J. Chen, Infarct Measurement in Focal Cerebral Ischemia: TTC Staining, in T Animal Models of Acute Neurological Injuries II. p. 93-98.
106. Théry, C., et al., Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. Journal of Extracellular Vesicles, 2018. 7(1): p. 1535750.
107. Booth, A.M., et al., Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. The Journal of Cell Biology, 2006. 172(6): p. 923-35.
108. Raposo, G. and W. Stoorvogel, Extracellular vesicles: exosomes, microvesicles, and friends. The Journal of Cell Biology, 2013. 200(4): p. 373-83.
109. Batrakova, E.V. and M.S. Kim, Using exosomes, naturally-equipped nanocarriers, for drug delivery. Journal of Controlled Release, 2015. 219: p. 396-405.
110. Hata, A., Functions of microRNAs in cardiovascular biology and disease. Annual Review of Physiology, 2013. 75: p. 69-93.
111. Ameres, S.L. and P.D. Zamore, Diversifying microRNA sequence and function. Nature Reviews Molecular Cell Biology, 2013. 14(8): p. 475-88.
112. Neth, P., et al., MicroRNAs in flow-dependent vascular remodelling. Cardiovascular Research, 2013. 99(2): p. 294-303.
113. Xu, B., et al., Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity. Cell Research, 2017. 27(7): p. 882-897.
114. Amado, L.C., et al., Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proceedings of the National Academy of Sciences, 2005. 102(32): p. 11474-11479.
115. Blurton-Jones, M., et al., Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proceedings of the National Academy of Sciences, 2009: p. pnas. 0901402106.
116. Phinney, D.G., et al., Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nature Communcations, 2015. 6: p. 8472.
117. Ibrahim, A.G., K. Cheng, and E. Marban, Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Reports, 2014. 2(5): p. 606-19.
118. Xin, H., et al., Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells, 2012. 30(7): p. 1556-64.
119. de Jong, O.G., et al., Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. Journal of extracellular vesicles, 2012. 1(1): p. 18396.
120. Eldh, M., et al., Exosomes communicate protective messages during oxidative stress; possible role of exosomal shuttle RNA. PLoS One, 2010. 5(12): p. e15353.
121. Chen, J., et al., Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke, 2001. 32(4): p. 1005-11.
122. Chang, Y.H., et al., Exosomes and Stem Cells in Degenerative Disease Diagnosis and Therapy. Cell Transplant, 2018. 27(3): p. 349-363.
123. Nakano, M., et al., Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes. Scientific Reports, 2016. 6: p. 24805.
124. Xin, H., et al., MicroRNA cluster miR-17-92 Cluster in Exosomes Enhance Neuroplasticity and Functional Recovery After Stroke in Rats. Stroke, 2017. 48(3): p. 747-753.
125. Luo, Q., et al., Exosomes from MiR-126-Overexpressing Adscs Are Therapeutic in Relieving Acute Myocardial Ischaemic Injury. Cellular Physiology and Biochemistry, 2017. 44(6): p. 2105-2116.
126. Hu, J., et al., miR-126 promotes angiogenesis and attenuates inflammation after contusion spinal cord injury in rats. Brain Research, 2015. 1608: p. 191-202.
127. Hsueh, Y.-Y., et al., Synergy of endothelial and neural progenitor cells from adipose-derived stem cells to preserve neurovascular structures in rat hypoxic-ischemic brain injury. Scientific Reports, 2015. 5: p. 14985.
128. Harris, T.A., et al., MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proceedings of the National Academy of Sciences, 2008. 105(5): p. 1516-21.
129. Miranti, C.K. and J.S. Brugge, Sensing the environment: a historical perspective on integrin signal transduction. Nature cell biology, 2002. 4(4): p. E83.
130. Dekker, R.J., et al., KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. Blood, 2006. 107(11): p. 4354-4363.
131. Dekker, R.J., et al., Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Krüppel-like factor (KLF2). Blood, 2002. 100(5): p. 1689-1698.
132. Wynn, R.F., et al., A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood, 2004. 104(9): p. 2643-5.
133. Rosova, I., et al., Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells, 2008. 26(8): p. 2173-82.
134. Yang, J., et al., Exosome mediated delivery of miR-124 promotes neurogenesis after ischemia. Molecular Therapy-Nucleic Acids, 2017. 7: p. 278-287.
135. Zhuang, X., et al., Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Molecular Therapy, 2011. 19(10): p. 1769-1779.
136. Nakano, M., et al., Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes. Scientific Reports, 2016. 6: p. 24805.
137. Wang, Y., et al., The release and trans-synaptic transmission of Tau via exosomes. Molecular neurodegeneration, 2017. 12(1): p. 5.
138. Quaegebeur, A., C. Lange, and P. Carmeliet, The neurovascular link in health and disease: molecular mechanisms and therapeutic implications. Neuron, 2011. 71(3): p. 406-24.
139. Tam, S.J. and R.J. Watts, Connecting vascular and nervous system development: angiogenesis and the blood-brain barrier. Annual review of neuroscience, 2010. 33: p. 379-408.
140. Lee, H.-T., et al., VEGF-A/VEGFR-2 signaling leading to cAMP response element-binding protein phosphorylation is a shared pathway underlying the protective effect of preconditioning on neurons and endothelial cells. Journal of Neuroscience, 2009. 29(14): p. 4356-4368.
141. Tu, Y.-F., et al., Moderate dietary restriction reduces p53-mediated neurovascular damage and microglia activation after hypoxic ischemia in neonatal brain. Stroke, 2012. 43(2): p. 491-498.
142. Hur, J., et al., Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 2004. 24(2): p. 288-293.
143. Rehman, J., et al., Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation, 2003. 107(8): p. 1164-1169.
144. Asahara, T., et al., Isolation of putative progenitor endothelial cells for angiogenesis. Science, 1997. 275(5302): p. 964-966.
145. Zhang, Z.G., et al., Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circulation Research, 2002. 90(3): p. 284-288.
146. Urbich, C. and S. Dimmeler, Endothelial progenitor cells characterization and role in vascular biology. Circulation Research, 2004. 95(4): p. 343-353.
147. Zlokovic, B.V., The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron, 2008. 57(2): p. 178-201.
148. Breier, G., et al., Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development, 1992. 114(2): p. 521-532.
149. Shen, Q., et al., Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science, 2004. 304(5675): p. 1338-1340.
150. Teng, H., et al., Coupling of angiogenesis and neurogenesis in cultured endothelial cells and neural progenitor cells after stroke. Journal of Cerebral Blood Flow and Metabolism, 2008. 28(4): p. 764-771.
151. Leventhal, C., et al., Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Molecular and Cellular Neuroscience, 1999. 13(6): p. 450-464.
152. Byrne, A.M., D. Bouchier‐Hayes, and J. Harmey, Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). Journal of cellular and molecular medicine, 2005. 9(4): p. 777-794.
153. Qi, J.H. and L. Claesson-Welsh, VEGF-induced activation of phosphoinositide 3-kinase is dependent on focal adhesion kinase. Experimental cell research, 2001. 263(1): p. 173-182.
154. Rousseau, S., et al., p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene, 1997. 15(18): p. 2169-2177.
155. Herzog, B., et al., VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation. Molecular biology of the cell, 2011. 22(15): p. 2766-2776.
156. Hong, T.-M., et al., Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clinical Cancer Research, 2007. 13(16): p. 4759-4768.
157. Islam, M.R., et al., Is there a pAkt between VEGF and oral cancer cell migration? Cell Signalling, 2014. 26(6): p. 1294-302.
158. Engler, A.J., et al., Matrix elasticity directs stem cell lineage specification. Cell, 2006. 126(4): p. 677-89.
159. Morrison, S.J. and A.C. Spradling, Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell, 2008. 132(4): p. 598-611.
160. Caddick, J., et al., Phenotypic and functional characteristics of mesenchymal stem cells differentiated along a Schwann cell lineage. Glia, 2006. 54(8): p. 840-9.
161. Kingham, P.J., et al., Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro. Experimental neurology, 2007. 207(2): p. 267-274.
162. Mung, K.L., et al., Rapid and efficient generation of neural progenitors from adult bone marrow stromal cells by hypoxic preconditioning. Stem Cell Research and Therapy, 2016. 7(1): p. 146.
163. Cheng, N.C., et al., Short-term spheroid formation enhances the regenerative capacity of adipose-derived stem cells by promoting stemness, angiogenesis, and chemotaxis. Stem Cells Translational Medicine, 2013. 2(8): p. 584-94.
164. Hermann, A., et al., Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells. Journal of Cell Science, 2004. 117(Pt 19): p. 4411-22.
165. Fu, L., et al., Derivation of neural stem cells from mesenchymal stemcells: evidence for a bipotential stem cell population. Stem Cells and Development, 2008. 17(6): p. 1109-21.
166. Luo, L., et al., EID3 directly associates with DNMT3A during transdifferentiation of human umbilical cord mesenchymal stem cells to NPC-like cells. Scientific Reports, 2017. 7: p. 40463.
167. Maury, Y., et al., Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes. Nature Biotechnology, 2015. 33(1): p. 89-96.
168. Boyer, L.F., et al., Dopaminergic differentiation of human pluripotent cells. Current Protocols in Stem Cell Biology, 2012. Chapter 1: p. Unit1H 6.
169. Dimos, J.T., et al., Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 2008. 321(5893): p. 1218-21.
170. Davidson, K.C., E.A. Mason, and M.F. Pera, The pluripotent state in mouse and human. Development, 2015. 142(18): p. 3090-9.
171. Krencik, R., et al., Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nature Biotechnology, 2011. 29(6): p. 528-34.
172. Cohen, M.A., P. Itsykson, and B.E. Reubinoff, The role of FGF-signaling in early neural specification of human embryonic stem cells. Developmental Biology, 2010. 340(2): p. 450-8.
173. Su, H.-L., Neural Differentiation of Embryonic Stem Cells: Role of FGFs, in Stem Cells and Cancer Stem Cells, Volume 5. 2012, Springer. p. 249-256.
174. Falcone, C., et al., Emx2 expression levels in NSCs modulate astrogenesis rates by regulating EgfR and Fgf9. Glia, 2015. 63(3): p. 412-22.
175. Cohen, R.I. and K.J. Chandross, Fibroblast growth factor-9 modulates the expression of myelin related proteins and multiple fibroblast growth factor receptors in developing oligodendrocytes. Journal of Neuroscience Research, 2000. 61(3): p. 273-87.
176. Tagashira, S., et al., Localization of fibroblast growth factor-9 mRNA in the rat brain. Molecular Brain Research, 1995. 30(2): p. 233-41.
177. Lum, M., et al., Fibroblast growth factor-9 inhibits astrocyte differentiation of adult mouse neural progenitor cells. Journal of Neuroscience Research, 2009. 87(10): p. 2201-10.
178. Fortin, D., et al., Distinct fibroblast growth factor (FGF)/FGF receptor signaling pairs initiate diverse cellular responses in the oligodendrocyte lineage. Journal of Neuroscience, 2005. 25(32): p. 7470-9.
179. McKeehan, W.L., F. Wang, and M. Kan, The heparan sulfate-fibroblast growth factor family: diversity of structure and function. Progress in Nucleic Acid Research and Molecular Biology, 1998. 59: p. 135-76.
180. Hough, S.R., et al., Single-cell gene expression profiles define self-renewing, pluripotent, and lineage primed states of human pluripotent stem cells. Stem Cell Reports, 2014. 2(6): p. 881-95.
181. Moignard, V. and B. Gottgens, Dissecting stem cell differentiation using single cell expression profiling. Current Opinion in Cell Biology, 2016. 43: p. 78-86.
182. Vazquez-Valls, E., et al., HIF-1α expression in the hippocampus and peripheral macrophages after glutamate-induced excitotoxicity. Journal of neuroimmunology, 2011. 238(1): p. 12-18.
183. Guo, R., et al., Brain injury caused by chronic fetal hypoxemia is mediated by inflammatory cascade activation. Reproductive Sciences, 2010. 17(6): p. 540-548.
184. Li, Y., P. Gonzalez, and L. Zhang, Fetal stress and programming of hypoxic/ischemic-sensitive phenotype in the neonatal brain: mechanisms and possible interventions. Progress in neurobiology, 2012. 98(2): p. 145-165.
185. Wang, Y., et al., Roles of chemokine CXCL12 and its receptors in ischemic stroke. Current drug targets, 2012. 13(2): p. 166-172.
186. Yamaguchi, J.-i., et al., Stromal cell–derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation, 2003. 107(9): p. 1322-1328.
187. Tajiri, N., et al., Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats. Journal of Neuroscience, 2014. 34(1): p. 313-26.
188. Xin, H., et al., Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. Journal of Cerebral Blood Flow and Metabolism, 2013. 33(11): p. 1711-1715.
189. Braun, R.K., et al., Intraperitoneal injection of MSC-derived exosomes prevent experimental bronchopulmonary dysplasia. Biochemical and biophysical research communications, 2018. 503(4): p. 2653-2658.
190. Khoshnam, S.E., et al., Emerging Roles of microRNAs in Ischemic Stroke: As Possible Therapeutic Agents. Journal of Stroke, 2017. 19(2): p. 166-187.
191. Dharap, A., et al., Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. Journal of Cerebral Blood Flow and Metabolism, 2009. 29(4): p. 675-687.
192. Buller, B., et al., MicroRNA‐21 protects neurons from ischemic death. The FEBS journal, 2010. 277(20): p. 4299-4307.
193. Zhang, L., et al., miR‐21 represses FasL in microglia and protects against microglia‐mediated neuronal cell death following hypoxia/ischemia. Glia, 2012. 60(12): p. 1888-1895.
194. Zheng, L., et al., Overexpression of MicroRNA-145 Ameliorates Astrocyte Injury by Targeting Aquaporin 4 in Cerebral Ischemic Stroke. BioMed research international, 2017. 2017.
195. Lopez-Ramirez, M.A., MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation. FASEB journal, 2014. 28(6): p. 2551-2565.
196. Reijerkerk, A., et al., MicroRNAs regulate human brain endothelial cell-barrier function in inflammation: implications for multiple sclerosis. Journal of Neuroscience, 2013. 33(16): p. 6857-63.
197. Caballero-Garrido, E., In Vivo Inhibition of miR-155 Promotes Recovery after Experimental Mouse Stroke. The Journal of neuroscience, 2015. 35(36): p. 12446-12464.
198. Wang, S., et al., The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Developmental Cell, 2008. 15(2): p. 261-71.
199. Xi, T., et al., MicroRNA-126-3p attenuates blood-brain barrier disruption, cerebral edema and neuronal injury following intracerebral hemorrhage by regulating PIK3R2 and Akt. Biochemical and biophysical research communications, 2017. 494(1): p. 144-151.
200. Nicoli, S., et al., MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature, 2010. 464(7292): p. 1196-200.
201. Luo, Q., et al., Exosomes from MiR-126-Overexpressing Adscs Are Therapeutic in Relieving Acute Myocardial Ischaemic Injury. Cellular Physiology and Biochemistry, 2017. 44(6): p. 2105-2116.
202. Kosaka, N., et al., Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. The Journal of Biological Chemistry, 2013. 288(15): p. 10849-59.
203. Villarroya-Beltri, C., et al., Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nature communications, 2013. 4: p. 2980.
204. Koppers-Lalic, D., et al., Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Reports, 2014. 8(6): p. 1649-1658.
205. Frank, F., N. Sonenberg, and B. Nagar, Structural basis for 5'-nucleotide base-specific recognition of guide RNA by human AGO2. Nature, 2010. 465(7299): p. 818-22.
206. Szatanek, R., et al., Isolation of extracellular vesicles: Determining the correct approach (Review). International Journal of Molecular Medicine, 2015. 36(1): p. 11-7.
207. Théry, C., et al., Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Current protocols in cell biology, 2006. 30(1): p. 3.22. 1-3.22. 29.
208. Vickers, K.C., et al., MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nature Cell Biology, 2011. 13(4): p. 423-33.
209. Lobb, R.J., et al., Optimized exosome isolation protocol for cell culture supernatant and human plasma. Journal of Extracellular Vesicles, 2015. 4: p. 27031.
210. Oliveira-Rodríguez, M., et al., Development of a rapid lateral flow immunoassay test for detection of exosomes previously enriched from cell culture medium and body fluids. Journal of extracellular vesicles, 2016. 5(1): p. 31803.
211. Bukong, T.N., et al., Exosomes from hepatitis C infected patients transmit HCV infection and contain replication competent viral RNA in complex with Ago2-miR122-HSP90. PLoS pathogens, 2014. 10(10): p. e1004424.
212. Witwer, K.W., et al., Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. Journal of extracellular vesicles, 2013. 2(1): p. 20360.

論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2024-01-31起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2024-01-31起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw