Embriyonik Kök Hücrelerde Wnt Sinyal Yolağı

Gelişim ve farklılaşmada, aynı genetik bilgiye sahip hücrelerden farklı hücrelerin oluşumunu sağlayan önemli mekanizmalardan biri hücreler arası sinyal iletimidir. Bu yolaklarının başında ise Wnt gelmektedir. Wnt yolağı embriyonik kök hücrelerdeki etkileri ile embriyonik gelişimde çeşitli süreçlerde rol oynamaktadır. Wnt yolağının embriyonik kök hücreler üzerine olan etkileri, oldukça karmaşık bir mekanizmanın parçasıdır. Hücrelerin içinde bulunduğu mikroçevrenin sağladığı etkileşimler aynı sinyale farklı yanıtlar oluşturabilmektedir. Rejeneratif tıp alanında pluripotent kök hücreler büyük önem taşımaktadır. Bu hücrelerin en önemli kaynağı, embriyonik kök hücrelerdir. Ancak etik sorunlar bu hücrelerin kullanımını engellemektedir. Alternatif olarak görülebilecek indüklenmiş pluripotent kök hücreler ise; üretim tekniklerinde zorluklar ve gen müdahalesine bağlı sorunlar taşımaktadır. Bu bakımdan gen müdahalesine gerek duymayacak veya azaltacak arayışlar sürmektedir. Burada özellikle, çeşitli hücresel mekanizmaları etkileyen küçük moleküller dikkat çekmektedir. Bu moleküllerin hedefinde yer alan mekanizmalardan biri de Wnt sinyal yolağıdır. Ancak bu yolak ile geliştirilmiş, hücresel yeniden programlama açısından güvenli ve başarılı bir yöntem henüz bulunmamaktadır.

Anahtar Kelimeler:

Wnt, Embriyonik kök hücreler, Rejeneratif tıp

Wnt Sıgnaling Pathway In Embryonic Stem Cells

One of the major mechanisms for the formation of different cells from the cells with the same genetic information during the development and differentiation, is intracellular signal transmission. One of the most important of these signaling pathways is Wnt. Wnt pathway plays roles in various processes in the embryonic development by the effects on embryonic stem cells. The effects of Wnt pathway on embryonic stem cells seem to be a part of very complex mechanism. The interactions provided by the microenvironment within the cells can generate different answers to the same signal. Pluripotent stem cells have a great importance in regenerative medicine. The most important source of these cells are embryonic stem cells. However, ethical problems hinder the use of these cells. The induced pluripotent stem cells which can be seen as an alternative; have difficulties in the production techniques and carries some problems related to the gene intervention. In this regard quests to reduce or eliminate the need for gene intervention are ongoing. Here in particular, a variety of small molecules that can affect cellular mechanism draws attention. One of the target mechanisms of these molecules is the Wnt signaling pathway. However, a safe and successful method for cellular reprogramming with this pathway has not yet been developed.

Keywords:

Wnt, Embryonic stem cells, Regenerative medicine,

PDF

___

Referans1 Clevers H. Wnt/beta-catenin signaling in development and disease. Cell 2006;127(3):469-480.
Referans2 Paratore C, Sommer L. Stem Cells. In: Unsicker K., Krieglstein K (Eds). Cell Signaling and Growth Factors in Development: From Molecules to Organogenesis. Weinheim; Wiley-VCH;2006. p.1-37.
Referans3 Lustig B and Behrens J. The Wnt signaling pathway and its role in tumor development. Journal of Cancer Research and Clinical Oncology 2003;129(4):199-221.
Referans4 Jager M et al., Evidence for involvement of Wnt signalling in body polarities, cell proliferation, and the neuro-sensory system in an adult ctenophore. PloS One 2013;8(12).
Referans5 Lien, WH, Fuchs E. Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling. Genes & Development 2014;28(14):1517-1532.
Referans6 Dönmez HG, Demirezen Ş, Beksaç MS. WNT/Beta-Katenin Sinyal Yolunun Sitoplazmik Biyomolekülleri. Deu Med J. 2011;25(3): 189-199
Referans7 Can A. Moleküler Hücre Biyolojisine Kısa Bakış. Can A, Editor. Kök Hücre Biyolojisi, Türleri ve Tedavide Kullanımları. Ankara: Akademisyen Tıp Kitapevi; 2014.
Referans8 Nusse R. Wnt signaling in disease and in development. Cell Research 2005;15(1):28-32.
Referans9 Nusse R. Wnt signaling. Cold Spring Harbor Perspectives in Biology 2012;4(5).
Referans10 Gordon M, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. The Journal of Biological Chemistry 2006;281(32):22429-22433.
Referans11 Berridge MJ. Cell Signaling Biology, 2012 http://www.auburn.edu/academic/classes/biol/6190/CellSignalingBiology/csb001.pdf
Referans12 Cruciat, CM and Niehrs C. Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harbor Perspectives in Biology 2013;5(3):1-26.
Referans13 Sharma G, Sharma AR, Seo EM, Nam JS. Genetic Polymorphism in Extracellular Regulators of Wnt Signaling Pathway. BioMed Research International 2015;2015:847529.
Referans14 Pohl S, Scott R, Arfuso F, Perumal V, Dharmarajan A. Secreted frizzled-related protein 4 and its implications in cancer and apoptosis. Tumor Biology 2014;1-10.
Referans15 Matsuda K and Kondoh H. Dkk1-dependent inhibition of Wnt signaling activates Hesx1 expression through its 5' enhancer and directs forebrain precursor development. Genes to Cells 2014;19(5):374-85.
Referans16 Mii Y, Taira M. Secreted Wnt "inhibitors" are not just inhibitors: regulation of extracellular Wnt by secreted Frizzled-related proteins. Development, Growth & Differentiation 2011;53(8):911-923.
Referans17 Barker N, Clevers H. Mining the Wnt pathway for cancer therapeutics. Nature reviews. Drug Discovery 2006;5(12):997-1014.
Referans18 Zhang X, Lou Y, Zheng X et al. Wnt blockers inhibit the proliferation of lung cancer stem cells. Drug Design, Development and Therapy 2015;9:2399.
Referans19 Madan B, Virshup DM. Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs. Molecular Cancer Therapeutics 2015;14(5):1087-1094.
Referans20 Lu D, Carson D. Inhibition of Wnt signaling and cancer stem cells. Oncotarget 2011;2(8):587.
Referans21 Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Medicine 2004;10(1):55-63.
Referans22 Tan F, Qian C, Tang K, Abd-Allah SM, Jing N. Inhibition of TGF-β Signaling can Substitute for Oct4 in Reprogramming and Maintain Pluripotency. J Biol Chem 2015;290(7):4500-11.
Referans23 Sokol S. Maintaining embryonic stem cell pluripotency with Wnt signaling. Development (Cambridge, England), 2011;138(20):4341-4350.
Referans24 Fernandez A, Huggins IJ, Perna L et al., The WNT receptor FZD7 is required for maintenance of the pluripotent state in human embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America 2014;111(4):1409-1414.
Referans25 Singla DK, Schneider DJ, LeWinter MM, Sobel BE. wnt3a but not wnt11 supports self-renewal of embryonic stem cells. Biochemical and Biophysical Research Communications 2006;345(2):789-795.
Referans26 ten Berge D, Kurek D, Blauwkamp T et al., Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells. Nature Cell Biology 2011;13(9):1070-1075.
Referans27 Walsh J, Andrews P. Expression of Wnt and Notch pathway genes in a pluripotent human embryonal carcinoma cell line and embryonic stem cell. APMIS 2003;111(1):197.
Referans28 Dravid G, Ye Z, Hammond H et al., Defining the role of Wnt/beta-catenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells. Stem Cells 2005;23(10):1489-1501.
Referans29 McCrea PD, Maher MT, Gottardi CJ. Chapter Five-Nuclear Signaling from Cadherin Adhesion Complexes. Current Topics in Developmental Biology 2015;112:129-196.
Referans30 Huang TS, Li L, Moalim-Nour L, et al. A Regulatory Network Involving β-Catenin, E-Cadherin, PI3K/Akt, and Slug Balances Self-Renewal and Differentiation of Human Pluripotent Stem Cells in Response to Wnt Signaling. Stem Cells 2015;33(5):1419-33.
Referans31 Sinev GS, Pospelov VA. β-Catenin in pluripotency: adhering to self-renewal or Wnting to differentiate? International Review of Cell and Molecular Biology, 2014;312:53-78.
Referans32 Marucci L, Pedone E, Di Vicino U, et al. β-catenin pluripotent fluctuates in mouse ESCs and is essential for Nanog-mediated reprogramming of somatic cells to pluripotency. Cell Reports 2014;8(6):1686-1696.
Referans33 Davidson KC, Adams AM, Goodson JM, et al. Wnt/-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4. Proceedings of the National Academy of Sciences 2012;109(12):4485-90.
Referans34 Turner DA, Trott J, Hayward P, Rué P, Martinez Arias A. An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells. Biology Open 2014;3(7):614-626.
Referans35 Schlupf J, Steinbeisser H. IGF antagonizes the Wnt/β-Catenin pathway and promotes differentiation of extra-embryonic endoderm. Differentiation; Research in Biological Diversity 2014;87(5):209-219.
Referans36 Raggioli A, Junghans D, Rudloff S, Kemler R. Beta-catenin is vital for the integrity of mouse embryonic stem cells. PloS One 2014. 9(1):e86691.
Referans37 Hao J, Li TG, Qi X, Zhao DF, Zhao GQ. WNT/beta-catenin pathway up-regulates Stat3 and converges on LIF to prevent differentiation of mouse embryonic stem cells. Developmental Biology 2006;290(1):81-91.
Referans38 Ogawa K, Nishinakamura R, Iwamatsu Y, Shimosato D, Niwa H. Synergistic action of Wnt and LIF in maintaining pluripotency of mouse ES cells. Biochemical and Biophysical Research Communications 2006;343(1):159-166.
Referans39 Anton R, Kestler H, Kühl M. Beta-catenin signaling contributes to stemness and regulates early differentiation in murine embryonic stem cells. FEBS Letters 2007;581(27):5247-5254.
Referans40 Tavernier G, Mlody B, Demeester J, Adjaye J, De Smedt SC. Current methods for inducing pluripotency in somatic cells. Advanced Materials 2013;25(20):2765-2771.
Referans41 Jung DW, Kim WH, Williams DR. Reprogram or reboot: small molecule approaches for the production of induced stem cells and direct cell reprogramming. ACS Chemical Biology 2014;9(1):80-95.
Referans42 Cooper, GM, Hausman RE. Hücre: moleküler yaklaşım. İzmir Tıp Kitabevi;2006.
Referans43 Ross J, Busch J, Mintz E, et al. A rare human syndrome provides genetic evidence that WNT signaling is required for reprogramming of fibroblasts to induced pluripotent stem cells. Cell Reports 2014;9(5):1770-1780.
Referans44 Ho R, Papp B, Hoffman JA, Merrill BJ, Plath K. Stage-specific regulation of reprogramming to induced pluripotent stem cells by Wnt signaling and T cell factor proteins. Cell Reports 2013;3(6):2113-2126.
Referans45 Aulicino F, Theka I, Ombrato L, Lluis F, Cosma MP. Temporal perturbation of the Wnt signaling pathway in the control of cell reprogramming is modulated by TCF1. Stem Cell Reports 2014;2(5):707-20.
Referans46 Murayama H, Masaki H, Sato H, Hayama T, Yamaguchi T, Nakauchi H. Successful Reprogramming of Epiblast Stem Cells by Blocking Nuclear Localization of β-Catenin. Stem Cell Reports 2015;4(1):103-113. Referans 47 Serio RN. Wnt of the two horizons: putting stem cell self-renewal and cell fate determination into context. Stem Cells and Development 2014;23(17):1975-1990.