臺灣博碩士論文加值系統

本研究主要是探討幹細胞相關治療或生物性指標應用於治療漢丁頓舞蹈症 (HD)可能性，我們首先評估以人類骨髓間質幹細胞 (hBM-MSCs) 應用於治療HD小鼠模式的效果。以喹啉酸 (quinolinic acid, QA) 引發的HD小鼠，以hBM-MSCs移殖十週後，HD小鼠的運動能力與存活率均獲得顯著地改善。實驗也證明移殖的hBM-MSCs可以在小鼠腦部紋狀體 (striatum) 內存活並引發神經增生與分化，並誘使microglia、neuroblast以及骨髓內的細胞移動至受到QA損傷的腦部區域附近。另外在基因轉殖HD小鼠品系R6/2-J2作同樣的處理亦可得到相似的結果，但行為並沒有具體改善，而且移殖的hBM-MSCs細胞可嵌入 (integrate) 宿主細胞，並促進laminin、VWF、SDF-1、Cxcr4表現量增加。由近一步之研究結果推論，此治療可能藉由增加p-Erk1/2表現量和減少Bax與caspase-3表現量減緩細胞凋亡 (apoptosis) 而達到改善神經分化、分泌神經支持性 (neurotrophic support) 物質與對抗細胞凋亡的能力，此治療具有可能應用於HD的潛力。
另一方面，我們試著找尋可以診斷HD的幹細胞相關生物性指標 (biomarker)，發現在HD患者血液中一些幹細胞相關因子，如CD133與CD34表現量都較同次實驗中正常人高。在HD基因轉殖小鼠骨髓中，Flt3+/CD34－ 與MPP細胞族群比例均較正常鼠高，轉殖鼠血液中白血球、紅血球與血小板相關參數亦與正常小鼠有顯著地差異，然而我們的CFC實驗結果卻發現骨髓中造血幹細胞數目並無差異。這些研究結果之落差仍有待近一步探討。
最後，G-CSF可誘發紺細胞分化之能力已研究很清楚，我們於是評估G-CSF應用在HD治療之可能性。我們的結果顯示G-CSF治療並無法延長HD小鼠壽命，但在運動能力與行為測試實驗中，包括十字迷宮與平衡木測試結果均證明G-CSF具有稍微改善小鼠行為表現之效果。
綜合我們各項研究結果，hBM-MSCs與G-CSF均有潛力應用於HD治療，雖然幹細胞相關生物性指標之研究尚待探討，未來幹細胞相關治療與應用仍有機會於HD臨床治療扮演重要角色。

In this study, we investigated whether stem cell-related treatments or biomarkers were potential in Huntington’s disease (HD) therapeutic application. We first evaluated the therapeutic potential of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in Huntington’s disease (HD) mouse models. Ten weeks after intrastriatal injection of quinolinic acid (QA), mice that received hBM-MSC transplantation showed a significant reduction in motor function impairment and increased survival rate. Transplanted hBM-MSCs were capable of survival, and inducing neural proliferation and differentiation in the QA-lesioned striatum. In addition, the transplanted hBM-MSCs induced microglia, neuroblasts and bone marrow-derived cells to migrate into the QA-lesioned region. Similar results were obtained in R6/2-J2, a genetically-modified animal model of HD, except for the improvement of motor function. After hBM-MSC transplantation, the transplanted hBM-MSCs may integrate with the host cells and increase the levels of laminin, Von Willebrand Factor (VWF), stromal cell-derived factor-1 (SDF-1), and the SDF-1 receptor Cxcr4. The p-Erk1/2 expression was increased while Bax and caspase-3 levels were decreased after hBM-MSC transplantation suggesting that the reduced level of apoptosis after hBM-MSC transplantation was of benefit to the QA-lesioned mice. Our data suggest that hBM-MSCs have neural differentiation improvement potential, neurotrophic support capability and an anti-apoptotic effect, and may be a feasible candidate for HD therapy.
On the other hand, we tried to identify the candidate stem cell-related biomarkers for HD diagnosis. We found some stem cell markers were higher in HD patients compared to health persons, including CD133 and CD34. The hematopoietic stem / progenitor cells (HSPC) in HD mice were different from their wild-type control littermates. The populations of Flt3+/CD34－ and MPP were higher in the bone marrow of HD mice. Some parameters of leukocyte, erythrocyte, and thrombocyte were found different from wild-type mice although the quantification of hematopoietic progenitors by colony-forming cell (CFC) assay showed no difference between them. Further investigation needs to be conducted to elucidate the inconsistence between these studies.
Finally, the stem cell differentiation-iduction effect of G-CSF has been well studied, therefore we evaluated the therapeutic potential of granulocyte-colony stimulating factor (G-CSF) in HD. Our results show that G-CSF treatment could not prolong the lifespan of HD mice.However, we found G-CSF treatment could slightly improve motor function and behavior of HD mice in elevated plus maze (EPM) and beam test. Modification of G-CSF therapeutic protocol in dosage and frequency may help to obtain a more effective treatment for HD.
According to our studies, hBM-MSC transplantation and G-CSF treatment are possible potential candidates for HD therapy. Although investigation about identify the candidate stem cell-related biomarkers for HD needs to be evaluated, stem cell-related therapy still has chance apply in clinical therapy of HD.

Chinese Abstrate…………………….……………..…………………………………i
English Abstrate…………………………………...………………………………...iii
Contents…………………………………...……………………………………….....v
List of Figures………………………………..……………….……………………viii
List of Tables…………………………………………………...…………...………...x
Abbreviation List……………………………………………………………………xi
Chapter 1 Introduction ……………………………………………………………...1
1.1 Huntington’s disease (HD)…………………………………………………...….1
1.2 Cell transplantation therapy for HD……………………………………………1
1.3 Biomarker candidates for HD…………………………………………………...2
1.4 Granulocyte-colony stimulating factor (G-CSF).................................................4
1.5 Research rationale………………………………..………………………...……5
Chapter 2 Materials and Methods…………………………………………………..6
Chapter 3 Results………………………………………………………………...…15
3.1 Therapeutic potential of hBM-MSC transplantation in HD…………...……15
3.1.1 hBM-MSCs may differentiate and survive in C57/B6 mice………….……15
3.1.2 hBM-MSCs do not cause tumorigenesis………...……………..………......15
3.1.3 hBM-MSC transplantation improves striatum volume after QA-induced excitotoxicity…………………………………………...….………..….…..16
3.1.4 hBM-MSC transplantation improves rotarod Pperformance and survival rates after QA-induced excitotoxicity……….………………….....…….…16
3.1.5 hBM-MSCs improve cell proliferation after transplantation in QA-lesioned mice..………………………………………………………………….……17
3.1.6 hBM-MSCs Iimprove cell differentiation after transplantation in QA-lesioned mice……………………………………………………...…..17
3.1.7 hBM-MSCs sustained for sixteen weeks after transplantation in QA-lesioned mice………………………………………...………….…….18
3.1.8 hBM-MSCs improve survival rates after transplantation into R6/2-J2 HD mice…………………..……………………………………………..…..…18
3.1.9 hBM-MSCs induce cell differentiation after transplantation into R6/2-J2 HD mice……………………..………………………………………..….…….19
3.1.10 Transplanted hBM-MSCs play a trophic role in the HD mouse model…………..…………………………………....………………...……20
3.1.11 hBM-MSC transplantation induces migration of neuroblast cells in HD mouse models...........................................................................................…20
3.1.12 Transplanted hBM-MSCs might integrate with host cells in HD mouse models…………………..……………………………………….…...…….21
3.1.13 Transplanted hBM-MSCs improve angiogenic activity in the damaged striatal region of HD mouse models……………………………..……...…22
3.1.14 Transplanted hBM-MSCs improve chemotactic activity in the damaged Striatal region in HD mouse models………………...……………..…...…22
3.1.15 Transplanted hBM-MSCs reduce apoptosis after transplantation in QA-lesioned mice……………….……………………………….....….….24
3.2 Biomarker candidates for HD………………………………………………….25
3.2.1 Hematopoietic stem / progenitor cell (HSPC) expression distribution were distinct in human peripheral bloods……………………………….…..…...25
3.2.2 Hematopoietic stem / progenitor cell (HSPC) expression pattern were different between wild-type and HD mice………………………............…26
3.2.3 Complete bood count (CBC) sata were altered in R6/2 mouse model…….27
3.2.4 Colony-forming cell (CFC) numbers were unaffected in R6/2 mouse model……………………………………………………..………...……...28
3.3 Therapeutic potential of G-CSF treatment in HD…………………….……...28
3.3.1 The lifespan of R6/2-J2 mice was not prolonged by G-CSF treatment.…...28
3.3.2 G-CSF treatment could not improve the motor function of R6/2-J2 mice...29
3.3.3 G-CSF treatment altered the behavior of R6/2-J2 mice…………………....30
3.3.4 G-CSF treatment did not affect the bodyweight of R6/2 mice………....….31
3.3.5 G-CSF treatment improved the motor function of R6/2 mice……………..31
3.3.6 G-CSF treatment altered the behavior of R6/2 mice……………….……...32
Chapter 4 Discussion……………………………………….…………………..…..34
4.1 Therapeutic potential of hBM-MSC transplantation in HD….......................34
4.1.1 Summary…….……...……………………………………………………...34
4.1.2 Application of mesenchymal stem cells in HD mouse models………..…...34
4.1.3 The role of gliosis after hBM-MSC transplantation.....................................36
4.1.4 The role of intrinsic stem cells after hBM-MSC transplantation………..…36
4.1.5 hBM-MSC transplantation induces angiogenesis and offers neurotrophic support………………..……………………………………………………37
4.1.6 hBM-MSC transplantation alleviates apoptosis……………………………38
4.1.7 hBM-MSC transplantation has potential in HD therapeutic application…..39
4.2 Biomarker candidates for HD……………………………………………….…39
4.2.1 Summary…..………………………………………………………………39
4.2.2 The role of HSCs……………………………………………………….…40
4.3 Therapeutic potential of G-CSF treatment in HD……………………………41
4.3.1 Summary……………………………………………………………….….41
4.3.2 The possible anti-inflammation role of G-CSF in HD………………….42
4.3.3 G-CSF may alter hematopoiesis in HD………………………………….43
4.3.4 Behavior characteristics of R6/2 mice………………………………...…44
Chapter 5 Conclusion and Future Perspectives…………..………………………46
References...................................................................................................................48

List of Figures
Figure 1. Transplanted hBM-MSCs differentiated and survived in wild-type C57/B6 mice………………………………………………….…………………..60
Figure 2. Transplanted hBM-MSCs improved striatal volumes in QA-lesioned mice…………………………………………….………………………..62
Figure 3. Transplanted hBM-MSCs improved motor function and survival rates of QA-lesioned mice..…………………………………….………………..64
Figure 4. Transplanted hBM-MSCs improved cell proliferation in QA-lesioned mice..………………………………………….…………………………66
Figure 5. Transplanted hBM-MSCs improved cell differentiation in QA-lesioned mice..…………………………………….………………………………68
Figure 6. Transplanted hBM-MSCs were alive in QA-lesioned mice..……………..70
Figure 7. Transplanted hBM-MSCs improved animal survival rate in R6/2-J2 mice…………………………………………….………………………..72
Figure 8. Transplanted hBM-MSCs induce cell differentiation in R6/2-J2 mice…...74
Figure 9. Bone marrow replacement mice expressed GFP-positive cells in the peripheral blood……………………………………………..…………...76
Figure 10. Transplanted hBM-MSCs attract GFP-positive cells migration into the striatum..……………………………………………………..…………..78
Figure 11. Transplanted hBM-MSCs attract neuroblast cells migration into the striatum.……….........................................................................................80
Figure 12. hBM-MSCs integrated with host cells in QA-lesioned mice.…………...82
Figure 13. hBM-MSCs improved angiogenic activity in QA-lesioned mice…….....84
Figure 14. hBM-MSCs improved chemotactic activity in QA-lesioned mice……...86
Figure 15. Gene expression levels after transplantation were assessed by qRT-PCR.…………………………………………….………………….88
Figure 16. hBM-MSCs reduced apoptosis in QA-lesioned mice.…………………..90
Figure 17. hBM-MSCs reduced apoptosis may through Erk and Bax pathways in QA-lesioned mice.…………………………………..…………………...92
Figure 18. Gene expression levels after transplantation were assessed by western blot.…………………………………………………..…………………..94
Figure 19.. Quantification of hematopoietic stem cells (HSCs) in human peripheral bloods………………………………………………..…………………...96
Figure 20. The LSK cell population in HD mouse models………………………….98
Figure 21. The HSPC in the bone marrow of HD mouse models.…………………100
Figure 22. The expression of HSPC in the peripheral bloods of R6/2 mice……….102
Figure 23. Results of CBC analysis with leukocyte related parameters from the peripheral bloods of R6/2 mice.……………………………………......104
Figure 24. Results of CBC analysis with erythrocyte related parameters from the peripheral bloods of R6/2 mice……………………………………...…106
Figure 25. Results of CBC analysis with thrombocyte related parameters from the peripheral bloods of R6/2 mice.……………………………………......108
Figure 26. Results of CFC assay from the bone marrow of HD mouse models…...110
Figure 27. The lifespan was not prolonged after G-CSF treatment in R6/2-J2 mice112
Figure 28. G-CSF treatment did not improve motor function of R6/2-J2 mice……114
Figure 29. The elevated plus maze (EPM) results of R6/2-J2 mice………………..116
Figure 30. The locomoter activity results of R6/2-J2 mice.………………………..118
Figure 31. G-CSF did not affect bodyweight of R6/2 mice.………….……..……..120
Figure 32. G-CSF treatment improved motor function of R6/2 mice.……………..122
Figure 33. The elevated plus maze (EPM) results of R6/2 mice.……………….....124
Figure 34. The locomoter activity results of R6/2 mice.………………………......126
Figure 35. The balance beam test results of R6/2 mice.……………...……………128
Figure 36. Summary of possible mechanisms by which hBM-MSCs may alleviate cell damage……………………………………………..………………130

List of Tables
Table 1 Antibodies used in immunofluorescence and Western blot………………..132
Table 2. Primer sequences used in qRT-PCR experiments………………...………133
Table 3 Antibodies used in FACS…………………………………...……………..134
Table 4 The state of leukocyte related parameters from R6/2 mice………………..135
Table 5 The state of erythrocyte related parameters R6/2 mice……………………136
Table 6 The state of thrombocyte related parameters from R6/2 mice………...…..137

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