臺灣博碩士論文加值系統

肥胖是全球性的重要議題，台灣人口十大死因也與肥胖直接或間接相關。間葉幹細胞 (Mesenchymal stem cells; MSCs)透過體外培養形成棕色(brown)或米色(beige)脂肪細胞後，移植回人體是具潛力的肥胖治療。研究顯示，MSC會維持細胞內pH值較鹼，但未有human adipose tissue derived stem cells (hADSC)其分化過程其細胞內部pHi改變的研究。此外小鼠不論是棕色或白色脂肪細胞分化的過程monocarboxylate transporters (MCT)和Na+/HCO3- cotransporters (NBC) mRNA皆有上調的趨勢，這說明pHi regulators在脂肪分化的過程扮演重要角色。乳酸(Lactate)會與細胞外的氫離子透過MCT同向運輸進入細胞，降低胞內氧化壓力，進而提升粒線體非偶合蛋白 (UCP1:uncoupling protein 1) 的蛋白表現，同時增加培養液乳酸濃度或酸化細胞外液，都可促進兔子間葉幹細胞白色脂肪新生並增加其分化的潛力，然而卻没有研究觀察細胞外液酸鹼變化對於棕色脂肪新生之影響。
因此本研究目的為: (1)了解hADSC pHi，排酸蛋白的蛋白表現及功能性。(2)了解hADSC其分化成脂肪細胞過程pHi，排酸蛋白的蛋白表現及功能性之變化。探討hADSC脂肪分化過程加入乳酸或細胞外液酸鹼變化對於brown adipocyte脂肪新生及UCP1, PPARγ, FABP4等蛋白表現量的影響。
材料與方法
實驗材料取自於三軍總醫院抽脂手術之病人脂肪組織純化而來的脂肪幹細胞，hADSCs (標本取得符合臨床實驗規範並經核准 IRB: No. 100-05-251)，以貼片法進行培養並以免疫螢光染色法(Immunocytochemistry)及流式細胞技術(Flow cytometry)鑑定細胞，運用西方墨點法(Western blot)進行排酸蛋白的蛋白質含量、其isoform測定及脂肪新生路徑相關蛋白之測定，利用顯為螢光技術 (Microspectrofluorimetry)配合氫離子敏感性螢光染劑2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl Ester (BCECF-AM)，透過氯化銨預灌流技術(Ammonium chloride NH4Cl pre-pulse technique)及乳酸灌流技術(Lactate pulse technique)誘導細胞內酸化後，觀察pHi值恢復的變化情形及幹細胞脂肪分化過程中各排酸蛋白之活性，最後以油紅染色法(Oil Red O staining)探討細胞外酸鹼環境及乳酸對於棕色脂肪新生的影響。
實驗結果
1. 首先以免疫螢光染色成功染出間葉幹細胞的positive markers，如:CD90 及CD73 。
2. 同時以流式細胞技術測定帶有positive markers及negative markers的細胞所占比例，其中表現出positive marker染色抗原CD73、CD105、CD90之細胞表現量分別為99.33％、95.41％、97.74%，表現出negative marker染色抗原CD45為9.95％，證明取的實驗材料實為脂肪來源的間葉幹細胞。
3. 首次證明hADSC上有NHE1, NBCe1, MCT1, MCT2及MCT4分生性蛋白表現。
4. hADSC在HEPES緩衝系統中穩定態pHi 約為6.97, 在Bicarbonate緩衝系統中穩定態pHi 約為7.17，不同於其他幹細胞/癌細胞的在HEPES下較鹼(~7.4)及一般成體細胞的pHi (~7.2)。
5. 在HEPES緩衝系統中，NH4Cl誘導酸化後替換為無鈉溶液，pHi值回復速率完全抑制，這證明了hADSCs細胞排酸機制為鈉依賴性。
6. 在HEPES緩衝系統中，NH4Cl誘導酸化後替換為含有30 μM Hoe 694溶液，其回復速率也幾乎抑制，這證明了NHE1參與hADSCs細胞排酸機制。
7. 在HCO3-/CO2緩衝系統中，NH4Cl誘導酸化後分別替換為含有30 μM S0859溶液及30 μM Hoe694溶液，其回復速率分別為抑制30％及70％，這證明了NBC及NHE共同參與hADSCs細胞排酸機制30％及70％。
8. 在HEPES緩衝系統中，透過灌注而後去除15mM乳酸後使細胞內快速酸化和鹼化證明MCT在hADSCs中功能性存在。另外以添加3μM ARC-155858（MCT1 / 2抑制劑）抑制乳酸轉運蛋白，藥理性證明hADSCs中MCT的存在。
9. hADSC分化成棕色脂肪細胞過程第14、21天出現CD36 marker的表現及Oil Red O明顯呈色，證明成功分化出脂肪細胞。
10. hADSC分化成棕色脂肪細胞過程，NHE1的蛋白表現量漸增而第14天最高，此外 NBCe1及MCT1的蛋白表現量於不同時間點表現一致；然而，MCT4蛋白表現量則呈biphasic現象於第0及14天蛋白表現量最高。
11. 在HEPES-buffer系統，hADSC分化成棕色脂肪細胞過程pHi上升0.2個pH單位，而在Bicarbonate-buffer系統下整體pHi也有增加的趨勢約增加0.1個pH單位。
12. hADSC分化成棕色脂肪細胞第7, 21天過程中，NHE活性於第14及21天顯著提升，NBC活性隨天數增加有增加趨勢，而MCT influx活性維持一定而efflux活性則顯著提升。
13. 由Oil Red O染色發現分化第14天，hADSC在弱鹼環境(pH 7.8)脂肪新生情形較佳;相較弱酸組(pH 6.8)抑制脂肪新生，額外投與lactate則沒有影響。

結論
本研究成功由人類脂肪幹細胞分化形成棕色脂肪細胞，首次證實到脂肪組織來源的間葉幹細胞其存在著鈉依賴性排酸蛋白:NHE、NBC及雙向調控蛋白MCT，此外我們首次證明在HEPES緩衝系統下人類脂肪幹細胞內穩定態pH值為6.97而在Bicarbonate緩衝系統下人類脂肪幹細胞內穩定態pH值為7.17，且隨著分化天數拉長細胞內穩定態pH值會增加，NHE、NBC及MCT efflux隨分化天數增加，其功能性活性也隨之增加，同時在較鹼性的培養環境有利幹細胞棕色脂肪新生，本研究揭示著細胞內外pH值調節對於棕色或米色脂肪新生是十分重要的且具有未來臨床應用之潛力。

Abstract
Backgrounds
Obesity is an important global issue, and the top ten causes of death in Taiwan are directly or indirectly related to obesity. The thermogenic capacity of brown or beige adipocyte makes it an attractive therapeutic target for inducing weight loss through energy expenditure. Nowadays, mesenchymal stem cells (MSCs) have gained interests on cell-based therapy by forming brown or beige adipocytes for transplantation to against obesity. Studies showed that keeping higher intracellular pH is important for MSCs to keep the stemness and proliferation; however, there is no study about changes of pHi in human adipose tissue derived stem cells (hADSCs) during its differentiation process. Besides, upregulation of net acid/lactate flux and the expression of intracellular acid-extruders, such as Na+/H+ exchanger, monocarboxylate transporters (MCTs) and Na+/HCO3− cotransporters (NBC), play important roles during adipocyte differentiation in animal model. Increasing of intracellular lactate concentration has been found to induces the expression of thermogenic protein, i.e. uncoupling protein 1 (UCP1). Moreover, decreasing extracellular pH promotes the potential of white adipocyte adipogenesis of rabbit MSCs. However, there is no report about the correlation among intracellular lactate concentration, extracellular pH, and activity of intracellular acid-extruders during brown adipocyte adipogenesis and UCP1 expression in human MSCs.

Materials and Methods
The human adipose tissue and human derived stem cells (hADSCs) were derived from human liposuction surgery with the approval of the institutional review committee (IRB number: No 100-05-251) that provided by Dr. NT Dai in Tri-Service general hospital, National Defense Medical Center, Taipei, Taiwan. The identification of mesenchymal stem cells was examined by immunocytochemistry and flow cytometry. The protein expression of acid-extruders and adipogenesis related proteins were examined by Western blot. The change of pHi and activities of acid extruders during brown adipogenetic differentiation in stem cells were detected by microspectrofluorometry method with a pH sensitive fluorescent dye, BCECF. Oil Red O technique was used to determine the production of lipid droplets.

Results
1. In the identification experiments, positive markers of mesenchymal stem cells, such as CD90 and CD73, were successfully stained in hADSCs by using immunofluorescence staining technique.
2. In hADSCs, the percentage of positive markers of staining antigens CD73, CD105, and CD90 was 99.33%, 95.41%, and 97.74%, respectively, and the negative marker of staining antigen CD45 was 9.95%, by using flow cytometry, which proved that the hADSCs used in my study is human adipose tissue derived stem cells.
3. We demonstrated the co-existence of protein expression of NHE1 (SLC9A1), NBCe1 (SLC4A4), MCT1 (SLC16A1), MCT2 (SLC16A17) and MCT4 (SLC16A3) in hADSCs by using the molecular biologically method of Western blot.
4. In HEPES-buffered system, the resting pHi of hADSCs was found to be 6.86 and 7.17 under bicarbonate-buffered system which is different from that of other stem cells/cancer cells (~7.4) and many mature cells (~7.2).
5. In HEPES buffered system, the pHi recovery following NH4Cl induced-acidosis was entirely block by removing extracellular Na+, which physicological demonstrates the involvement of Na+-dependent acid-extruding mechanism in hADSCs.
6. In the HEPES-buffered system, the pHi recovery following NH4Cl induced-acidosis was almost inhibited by adding 30 μM Hoe694, which pharmacological demonstrates the existence of NHE1 in hADSCs.
7. In the HCO3-/CO2-buffered system, the pHi recovery following NH4Cl induced-acidosis was inhibited up 30% and 70% by adding 30 μM S0859 (a specific NBC inhibitor) and 30 μM Hoe694 (a specific NHE inhibitor), respectively, which pharmacological demonstrates the co-exist of NHE and NBC in acid extruding mechanism in hADSCs.
8. In the HEPES-buffered system, rapidly intracellular acidification and alkalization were induced following superfusion and removal of 15mM lactate, respectively, which physicological demonstrates that MCT functionally exist in hADSCs. Adding 3μM ARC-155858 (MCT1/2 inhibitor) inhibited the lactate transporter either in the direction of influx and exflus that pharmacological demonstrates the existence of MCT1 in hADSCs.
9. The appearance of CD36 marker has been demonstrated during the process of differentiation into brown adipocytes from hADSCs, detecting by the method of immunocytochemistry. Moreover, by using method of Oil Red O, the lipid accumulation was increased significantly on the 14th and 21st day, indicates that the adipocytes were successfully differentiated into brown adipocytes.
10. In the HEPES-buffer system, the value of pHi was increased (+0.3 pH units) during process of differentiation into brown adipocytes from hADSCs. The similar change on pHi also found under the bicarbonate-buffer system.
11. During the differentiation into brown adipocytes from hADSCs, the protein expression of NHE1 increased gradually and was the highest on the 14th day ; besides, the protein expressions of NBCe1 and MCT1 were consistent at different time points; however, the MCT4 protein expression was biphasic and the protein expression was the highest on the 0 and the 14 th day.
12. During the differentiation into brown adipocytes from hADSCs, the NHE activity promoted obviously on the 14th and 21st day and the activity of NBC gradually increased. Besides, the influx activity of MCT didn’t change significantly while efflux activity enhanced markedly.
13. On the 14th day of brown adipogenetic differentiation, detecting by Oil Red O staining, hADSCs increased fat regeneration in a weak alkaline environment (~pH 7.8), while inhibited fat regeneration in a weak acid condition (~pH 6.8). Moreover, the addition of lactate had no effect on the fat regeneration.

Conclusion
In conclusion, we have, for the first time, demonstrated that the protein expression and functional activity of sodiumdependent acid-extruding proteins, i.e. NHE and NBC, and bidirectional regulatory protein MCT in human adipose tissue-derived mesenchymal stem cells. In addition, we have demonstrated, under the HEPES-buffer system, the steady state pHi value of hADSCs is as low as 6.97, and 7.17 under bicarbonate-buffer system. Moreover, the pHi value is getting increased during the brown adipogenetic progress of differentiation . Besides, the functional activity of NHE、NBC and MCT efflux is also increased following the adipogenetic differentiation. In addition, the alkaline culture environment is favorable for stem cell brown or beige adipogenetic differentiation. Our present study demonstrated that pHi regulation is important to brown adipogenesis of hADSCs, and it implies that the pHi regulators are potential targets for clinical application on obesity-related diseases.

目錄

第一章、緒論
第一節、肥胖簡介與脂肪組織相關研究
壹、肥胖的定義及流行病學
貳、現今肥胖治療
參、脂肪組織分類
肆、脂肪細胞的發展與調控
第二節、 細胞內酸鹼恆定之重要性
壹、細胞內 pH 值之恆定
貳、被動緩衝能力（Buffering power, β）
參、主動調控蛋白（active pHi regulators）
第三節、 幹細胞與細胞內pH值的關聯
壹、幹細胞
貳、人類間葉幹細胞 (Human mesenchymal stem cell)
參、人類脂肪幹細胞 (Human adipose tissue derived stem cell, hADSC)
肆、幹細胞中pH值的特性
伍、幹細胞分化與細胞內pH值的相關性
陸、細胞內外pH值調節對於間葉幹細胞脂肪新生及分化之影響
第四節、 研究目的
第二章、材料與方法
第一節、 實驗材料
第二節、 實驗藥品、試劑及溶液
壹、藥品
貳、抗體
參、溶液
第三節、實驗裝置
壹、細胞培養及鑑定裝置
貳、細胞活性實驗裝置
參、顯微螢光技術實驗裝置
肆、西方點墨法實驗裝置
伍、流式細胞儀實驗裝置
第四節、實驗方法
壹、細胞培養
貳、間葉幹細胞之鑑定(Identification)
參、顯微螢光技術（Microspectrofluorimetry）
肆、西方點墨法(Western blot)
伍、油紅染色法 (Oil Red O staining assay)
第五節、統計方法
第三章、結果
第一節、脂肪來源成體幹細胞之鑑定
第二節、細胞內 pH 值校正
第三節、人類脂肪幹細胞內pH值平衡狀態
壹、HEPES緩衝系統下之細胞內pH值平衡狀態
貳、HCO3-/CO2緩衝系統下之細胞內pH值平衡狀態
第四節、排酸蛋白分生性及功能性之證實
壹、pH值調控蛋白之異構體證實
貳、NHE (Na+-H+ exchanger)之生理與藥理性之證實
參、NBC (Na+-HCO3- cotransporter)藥理性證實以及NHE 與NBC在排酸機制中的協同作用
肆、MCT (Monocarboxylate transporter)之生理與藥理性之證實
第五節、幹細胞棕色脂肪分化之鑑定
第六節、幹細胞棕色脂肪分化過程細胞內pH值平衡狀態之變化
壹、HEPES緩衝系統下幹細胞棕色脂肪分化過程之細胞內pH值平衡狀態
貳、Bicarbonate緩衝系統下幹細胞棕色脂肪分化過程細胞內pH值平衡狀態
第七節、幹細胞棕色脂肪分化過程各排酸蛋白活性改變
壹、 幹細胞棕色脂肪分化過程pH值調控蛋白之變化
貳、排酸蛋白NHE在分化時序中功能活性之改變
參、排酸蛋白NBC在分化時序中功能活性之改變
肆、雙向控蛋白MCT在分化時序中功能活性之改變
第八節、細胞外微環境對棕色脂肪新生之影響
第四章、討論
第一節、成體幹細胞之鑑定
第二節、人類脂肪幹細胞及棕色脂肪分化過程之細胞內 pH值平衡調節
第三節、人類脂肪幹細胞之細胞內主動排酸機制
第四節、細胞外微環境對棕色脂肪新生之影響
第五節、臨床應用
第五章、結論
表
Table 1. The definition of adult obesity
Table 2. SLC9 family
Table 3. SLC4 Family
Table 4、SLC16 family
圖
Figure 1. Distribution of global obesity prevalence rate in 2014
Figure 2. The top 10 causes of death in Taiwan in 2017
Figure 3. The prevalence of overweight and obesity in adults over 19 years old in 82-85, 94-97 and 102-105 years of the Republic of China.
Figure 4. Three types of adipose tissue
Figure 5. A model of intracellular pH regulators on the guinea pig myocardium.
Figure 6. Autologous cell therapy and its clinical application
Figure 7. Stem cell adipogenetic differentiation pathway
Figure 8. Energy metabolism pattern of stem cell differentiation
Figure 9. The consent form of Institutional Review Board (the IRB number is 100-05-251)
Figure 10. BCECF Fluorescent Dye has pH-dependent excitation spectroscopy.
Figure 11. Schematic diagram of equipment
Figure 12. The principle of loading BCECF fluorescent dye into cells
Figure 13. The mechanism of the weak base, NH4Cl pre-pulse technique.
Figure 14. The mechanism of lactate superfusion technique.
Figure 15. Immunocytochemistry staining of adipose-tissue derived stem cells.
Figure 16. Flow cytometry analysis of cell markers on hADSC
Figure 17. Intracellular pH calibration curve in cultured hADSCs
Figure 18. Physiological intracellular pH experiment of hADSCs under HEPES-buffered system and Bicarbonate-buffered system.
Figure 19. Molecular expression of pH regulators on adipose-tissue derived stem cells.
Figure 20. Effects of 30μM Hoe694 and Na+-free on pHi recovery in hADSCs superfused with HEPES-buffered Tyrode solution.
Figure 21. Effects of 30μM S0859 and 30μM Hoe694 on pHi recovery in hADSCs superfused with Bicarbonate-buffered Tyrode solution.
Figure 22. Effects of 15mM lactate and 3μM ARC-155858 on pHi recovery in hADSCs superfused with MCT-buffered solution.
Figure 23. Identification of hADSCs during adipogenetic differentiation
Figure 24. The change of resting pHi of hADSC during adipogenetic differentiation under HEPES.
Figure 25. The change of resting pHi of hADSC during adipogenic differentiation under Bicarbonate-buffered system.
Figure 26. The molecular expression of pH regulators on hADSC during adipogenetic differentiation.
Figure 27. The change of functional NHE activity during adipogenetic differentiation in hADSC.
Figure 28. The change of functional NBC activity during adipogenic differentiation in hADSC
Figure 29. The change of functional MCT influx activity during adipogenetic differentiation in hADSC
Figure 30. The change of functional MCT efflux activity during adipogenetic differentiation in hADSC
Figure 31. Oil Red O staining during brown adipogenetic differentiation under different culture conditions in hADSC
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