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Using Diffusion-Reaction Equations to Reproduce the Suitable Environment for Stem Cells in Tissues
|關鍵字:||stem cell niche;幹細胞凹陷;diffusion-reaction equations;cancer;擴散反應方程;癌症||出版社:||生物物理學研究所||引用:||1. Schofield R et al; The relationship between the spleen colony forming cell and the haemopoietic stem cell. Blood Cells 1978, 4: 7-25 2. Xie T. et al; A niche maintaining germ line stem cells in the Drosophila ovary. Science 2000, 290: 328-330 3. Vladimir P. Z.; Simulation of proliferation and differentiation of cells in a stem-cell niche; Physica A; 2008; 387:6126-6136 4. Benjamin O. et al; The stem cell niche: theme and variations; Current Opinion in Cell Biology; 2004; 16: 693-699 5. Sean J. Morrison et al; Stem cells and niches: mechanisms that promote stem cell maintenance throughout life; Cell 2008; 132: 598-611 6. Stephan Lindsey et al; The importance of physiologically inspired physicochemical parameters on hematopoietic stem-cell maintenance and lineage-specific differentiation in ex vivo cultures; Stem cells: from mechanisms to technologies; 2011 7. Bruce Alberts et al; Molecular biology of the cell, 5th edition; 2008 8. Jose Manuel C. M. et al; Role of the intracellular ph in the metabolic switch between oxidative phosphorylation and aerobic glycolysis-relevance to cancer; WebmedCentral>Review articles; 2011 9. Petr Jezek et al; Distinctions and similarities of cell bioenergetics and the role of mitochondria in hypoxia, cancer, and embryonic development; The International Journal of Biochemistry and Cell Biology 42; 2010; 604-622 10. J. D. B. Macdougall et al; Diffusion coefficient of oxygen through tissues; Nature 215; 1967; 1173-1174 11. A. V. Hill; The diffusion of oxygen and lactic acid through tissues; Proceedings of the royal society of London. Series B; 728: 39-96; 1928 12. Ruey Tarng L. et al; Turing model for generating biological patterns; 2007 13. Michael H. Ross et al; Ross Histology 5th edition; 2006 14. Peter S. Amenta; Histology and human microanatomy 6th edition; 1991 15. Karel R. et al; Morphometry of human coronary capillaries during normal growth and the effect of age in left ventricular pressure-overload hypertrophy; Journal of the American Heart Association; 1992; 86:38-46 16. Eduard R. et al; Expansion of endothelial surface by an increase of vessel diameter during tumor angiogenesis in experimental hepatocellular and pancreatic cancer; World journal of Gastroenterology; 2004; 10(21): 3171-3174 17. A. K. E. Bonamy et al; Lower skin capillary density, normal endothelial function and higher blood pressure in children born preterm; Journal of Internal Medicine; 2007; 262: 635-642 18. Yamanaka Shinya; Pluripotency and nuclear reprogramming; Philosophical transactions of the royal society B; 2008; 363:2079-2087||摘要:||
幹細胞凹陷是一三維結構, 幹細胞身處其中可分裂和製造前驅細胞, 但前驅細胞若要進一步分化成成熟細胞則必須在離開幹細胞凹陷後才會發生。 幹細胞凹陷已被證明廣泛存在於不同組織中, 且因為其在再生醫學和癌症治療領域的重要性而吸引大量學者投入其中。 然而經過十年以上的努力, 仍未能對幹細胞凹陷的大小和環境有清楚而一致的共識。 這個困境便幫助我們回頭反思當初提出幹細胞凹陷的理由, 我們相信幹細胞凹陷存在的目的是為了提供幹細胞穩定適當的環境, 而現今已有大量證據支持幹細胞和癌細胞偏好處在低氧酸性環境。 於是我們簡化了無氧呼吸和有氧呼吸的反應式並歸納建立出乳酸和氧氣的擴散反應方程, 並應用福傳程式做模擬以試圖複製出組織中乳酸和氧氣的濃度梯度空間分佈。 根據我們的模型, 我們得到的結果如下: (1) 不同的組織具有不同的氧氣閾值已被廣泛認可, 而此項特徵在我們的模型中會自動產生; (2) 若乳酸和氧氣在組織中的行為的確由我們模型中的反應擴散方程所調控, 則低氧酸性環境和高氧鹼性環境本來就自然會交替出現在組織中。 (3) 我們已知濃度梯度在誘導細胞分化扮演極重要角色。 我們提出假設, 幹細胞所適合的環境條件除了已知的酸性低氧外, 還需要加上低濃度梯度。 此外, 在我們的模型中, 乳酸和氧氣濃度梯度在上皮組織中都最小, 此現象或許能解釋為何臨床上上皮組織來源的癌症最常見; 另一方面, 乳酸和氧氣濃度梯度在心肌組織最大, 此現象可能可以解釋為何臨床上幾乎沒有心肌細胞來源的癌症。
The stem cell niche is a 3-dimensional structure in which stem cells reside. The stem cells in niche can divide and produce progenitor cells, however, the further differentiation into mature cells can not occur until the stem cells leave the niche. Now the stem cell niche has been discovered to be broadly distributed in many tissues such as bone marrow, brain, intestine, and skin et al. For the important applications in regeneration and cancer research, there have been many scientists to devote into the area of stem cell niche study. However, the consistent conclusions for the size and environment of stem cell niche are still not obtained. This problem encourages us to think the original purpose of stem cell niche. We believe that the acidic hypoxic environment is the stable environment which should be originally provided by the stem cell niche. Then we simplify the glycolysis and oxphos reactions to build up the diffusion-reaction equations for the lactic acid and oxygen and reproduce the spatial distribution of lactic acid and oxygen in normal tissues. By solving the diffusion-reaction equations in our model, we have obtained the results as follows: (1) There is different oxygen levels for different types of tissue, and this can be reproduced in our model. (2) We found that if the behavior of lactic acid and oxygen in tissues is really regulated by our diffusion-reaction equations, then the hypoxic acidic and normoxic high pH environment would naturally exist. (3) We have known that the gradients of growth factors play an important role in inducing differentiation. We postulated that the stem cells would reside in hypoxic acidic environment where the gradients of both lactic acid and oxygen are low. Moreover, in our model, the gradients of both lactic acid and oxygen are small in skin, which may explain why epithelium-origin cancers are common. On the other hand, the gradients of both lactic acid and oxygen are large in heart which may explain why there is almost no cardiomyocyte-origin cancer noted.
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