General features and molecular mechanisms involved in self-renewal, pluripotency, differentiation, reprogramming of stem cells

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Review Paper 01/06/2017
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General features and molecular mechanisms involved in self-renewal, pluripotency, differentiation, reprogramming of stem cells

Motahhareh Tourchi-Roudsari
Int. J. Biosci.10( 6), 87-100, June 2017.
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Stem cells have identified as biological cells that exist in nearly all multicellular organisms. They are unspecialized which have the ability to self-renew as well as to differentiate into defined cellular subtypes. Moreover, stem cells have ability to return function to damaged cells in the living organism. Moreover, they have the potential to replace or repair damaged cells and or disease tissues to treat a wide spectrum of diseases and injuries. Molecular mechanism that regulate self-renewal and pluripotency is not clear exactly yet. In this review, I will summarize different types of stem cells, some their properties, potency, and applications. Also, in this paper will be focused on currently known molecular mechanism involved in self-renewal, pluripotency, differentiation, and reprogramming of Stem Cells; such as three of signal transduction pathways involving, Transcription factors and their network, cell cycle regulators, microRNA, telomerase enzyme, chromatin, Epigenetic regulators, and chromatin modification in ES cells.


Aladjem MI, Spike BT,Rodewald LW,Hope T J, Klemm M,Jaenisch R, Wahl GM. 1998. ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage. Current Biology 8(3), 145-155.

Austin E, Guttridge M, Pamphilon D, Watt S. 2008. The role of blood services and regulatory bodies in stem cell transplantation. Vox sanguinis, 94(1), 6-17.

Azuara V, Perry P, Sauer S, Spivakov M, Jørgensen HF, John RM, Gouti M, Casanova M, Warnes G, Merkenschlager M. 2006. Chromatin signatures of pluripotent cell lines. Nature cell biology 8(5), 532-538.

Banito A, Rashid ST, Acosta JC, Li S, Pereira CF, Geti I, Pinho S, Silva JC, Azuara V, Walsh M. 2009. Senescence impairs successful reprogramming to pluripotent stem cells. Genes & development, 23(18), 2134-2139.

Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner D D,Rich JN. 2006. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444(7120), 756-760.

Bartek J, Lukas J. 2001. Pathways governing G1/S transition and their response to DNA damage. FEBS letters, 490(3), 117-122.

Becker KA, Ghule PN, Therrien JA, Lian JB, Stein JL, Van Wijnen AJ, Stein GS. 2006. Self‐renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase. Journal of cellular physiology, 209(3), 883-893.

Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K. 2006. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell, 125(2), 315-326.

Bindu H, Srilatha B. 2011. Potency of various types of stem cells and their transplantation. Journal of Stem Cell Research and Therapy, 1(3).

Boyce KJ, Hynes MJ, Andrianopoulos A. 2005. The Ras and Rho GTPases genetically interact to co‐ordinately regulate cell polarity during development in Penicillium marneffei. Molecular microbiology 55(5), 1487-1501.

Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther  G, Kumar RM, Murray HL,Jenner RG. 2005. Core transcriptional regulatory circuitry in human embryonic stem cells. cell, 122(6), 947-956.

Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK. 2006. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature, 441(7091), 349-353.

Burdon T, Smith A, Savatier P. 2002. Signalling, cell cycle and pluripotency in embryonic stem cells. Trends in cell biology, 12(9), 432-438.

Cartwright P, McLean C, Sheppard A, Rivett D, Jones K, Dalton S. 2005. LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development, 132(5), 885-896.

Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A. 2003. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell, 113(5), 643-655.

Chen L,Daley GQ. 2008. Molecular basis of pluripotency. Human molecular genetics, 17(R1), R23-R27.

Dean M, Fojo T, Bates S. 2005. Tumour stem cells and drug resistance. Nature Reviews Cancer 5(4), 275-284.

Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M. 2009. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature, 458(7239), 780-783.

Esteban M A, Wang T, Qin B, Yang J, Qin D, Cai J, Li W, Weng Z, Chen J, Ni S. 2010. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell stem cell, 6(1), 71-79.

Hanna J, Saha K, Pando B, Van Zon J, Lengner CJ, Creyghton MP, Van Oudenaarden A, Jaenisch R. 2009. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature, 462(7273), 595-601.

Heo I, Joo C, Cho J, Ha M, Han J,Kim VN. 2008. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Molecular cell, 32(2), 276-284.

Hima Bindu A, Srilatha B. 2011. Potency of various types of Stem Cells and their transplantation. Journal of Stem Cell Research & Therapy, 1(3), 1-6.

Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M, Okita K, Yamanaka S. 2009. Suppression of induced pluripotent stem cell generation by the p53–p21 pathway. Nature 460(7259), 1132-1135.

Hong Y, Stambrook PJ. 2004. Restoration of an absent G1 arrest and protection from apoptosis in embryonic stem cells after ionizing radiation. Proceedings of the National Academy of Sciences of the United States of America 101(40), 14443-14448.

Jenuwein T, Allis CD. 2001. Translating the histone code. Science, 293(5532), 1074-1080.

Judson RL, Babiarz J, Venere M, Blelloch R. 2009. Embryonic stem cell specific microRNAs promote induced pluripotency. Nature biotechnology, 27(5), 459.

Jung KW. 2009. Perspectives on human stem cell research. Journal of cellular physiology, 220(3), 535-537.

Kang L, Kou Z, Zhang Y, Gao S. 2010. Induced pluripotent stem cells (iPSCs)-a new era of reprogramming. Journal of Genetics and Genomics, 37(7), 415-421.

Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, Wahl GM, Belmonte JCI. 2009. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature, 460(7259), 1140-1144.

Kim NW, Piatyszek MA, Prowse KR,Harley CB. 1994. Specific association of human telomerase activity with immortal cells and cancer. Science, 266(5193), 2011.

Kuroda T, Tada M, Kubota H, Kimura H, Hatano SY, Suemori H, Nakatsuji N, Tada T. 2005. Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression. Molecular and cellular biology 25(6), 2475-2485.

Lee CT, Bendriem RM, Kindberg AA, Worden LT, Williams MP, Drgon T, Mallon BS, Harvey BK, Richie CT, Hamilton RS. 2015. Functional consequences of 17q21. 31/WNT3-WNT9B amplification in hPSCs with respect to neural differentiation. Cell reports, 10(4), 616-632.

Lee JH, Hart SR, Skalnik DG. 2004. Histone deacetylase activity is required for embryonic stem cell differentiation. Genesis, 38(1), 32-38.

Li H, Collado M, Villasante A, Strati K, Ortega S, Cañamero M, Blasco MA, Serrano M. 2009. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature, 460(7259), 1136-1139.

Lin T, Chao C, Saito SI, Mazur SJ, Murphy ME, Appella E, Xu Y. 2005. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nature cell biology, 7(2), 165-171.

Liu N, Lu M, Tian X, Han Z. 2007. Molecular mechanisms involved in self‐renewal and pluripotency of embryonic stem cells. Journal of cellular physiology, 211(2), 279-286.

Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS. 2006. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer research 66(12), 6063-6071.

Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B,Liu J. 2006. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nature genetics 38(4), 431-440.

Loh YH, Zhang W, Chen X, George J, Ng HH. 2007. Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes & development, 21(20), 2545-2557.

Mailand N, Falck J, Lukas C, Syljuåsen RG, Welcker M, Bartek J,Lukas J. 2000. Rapid destruction of human Cdc25A in response to DNA damage. Science, 288(5470), 1425-1429.

Marión RM, Strati K, Li H, Murga M, Blanco R, Ortega S, Fernandez-Capetillo O, Serrano M,Blasco MA. 2009. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature, 460(7259), 1149-1153.

Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T, Johnstone S, Guenther MG, Johnston WK, Wernig M, Newman J. 2008. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell, 134(3), 521-533.

Maye P, Becker S, Siemen H, Thorne J, Byrd N, Carpentino J,Grabel L. 2004. Hedgehog signaling is required for the differentiation of ES cells into neurectoderm. Developmental biology, 265(1), 276-290.

Merrill BJ. 2012. Wnt pathway regulation of embryonic stem cell self-renewal. Cold Spring Harbor perspectives in biology, 4(9), a007971.

Meshorer E, Misteli T. 2006. Chromatin in pluripotent embryonic stem cells and differentiation. Nature reviews Molecular cell biology 7(7), 540-546.

Mimeault M, Hauke R, Batra S. 2007. Stem cells: a revolution in therapeutics—recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies. Clinical Pharmacology & Therapeutics, 82(3), 252-264.

Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S. 2003. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell, 113(5), 631-642.

Miura T, Mattson MP, Rao MS. 2004. Cellular lifespan and senescence signaling in embryonic stem cells. Aging cell 3(6), 333-343.

Na J, Plews J, Li J, Wongtrakoongate P, Tuuri T, Feki A, Andrews PW, Unger C. 2010. Molecular mechanisms of pluripotency and reprogramming. Stem cell research & therapy 1(4), 33.

Niwa H. 2001. Molecular mechanism to maintain stem cell renewal of ES cells. Cell structure and function, 26(3), 137-148.

Pan G, Li J, Zhou Y, Zheng H, Pei D. 2006. A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal. The FASEB Journal 20(10), 1730-1732.

Pasini D, Bracken AP, Jensen MR, Denchi EL, Helin K. 2004. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. The EMBO journal, 23(20), 4061-4071.

Perry A, Linch D. 1996. The history of bone-marrow transplantation. Blood reviews, 10(4), 215-219.

Pick M, Stelzer Y, BarNur O, Mayshar Y, Eden A,Benvenisty N. 2009. Clone‐and Gene‐Specific Aberrations of Parental Imprinting in Human Induced Pluripotent Stem Cells. Stem cells 27(11), 2686-2690.

Prezioso C, Orlando V. 2011. Polycomb proteins in mammalian cell differentiation and plasticity. FEBS letters 585(13), 2067-2077.

Raguz S, Yagüe E. 2008. Resistance to chemotherapy: new treatments and novel insights into an old problem. British journal of cancer 99(3), 387-391.

Ramachandran RP, Yelledahalli LU. 2011. Exploring the Recent Advances in Stem Cell Research. Journal of Stem Cell Research and Therapy 1(3), 113.

Richly H, Aloia L, Di Croce L. 2011. Roles of the Polycomb group proteins in stem cells and cancer. Cell death & disease 2(9), e204.

Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P. 2005. Transcriptional regulation of nanog by OCT4 and SOX2. Journal of Biological Chemistry, 280(26), 24731-24737.

Rosner MH, Vigano MA, Ozato K, Timmons P M,Poirier F. 1990. A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo. Nature, 345(6277), 686.

Roush S, Slack FJ. The let-7 family of microRNAs. Trends in cell biology 18(10), 505-516. 2008.

Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. 2004. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature medicine 10(1), 55-63.

Shojima K, Sato A, Hanaki H, Tsujimoto I, Nakamura M, Hattori K, Sato Y, Dohi K, Hirata M, Yamamoto H. 2015. Wnt5a promotes cancer cell invasion and proliferation by receptor-mediated endocytosis-dependent and-independent mechanisms, respectively. Scientific reports 5, 8042.

Sokol SY. 2011. Maintaining embryonic stem cell pluripotency with Wnt signaling. Development, 138(20), 4341-4350.

Stead E, White J, Faast R, Conn S, Goldstone S, Rathjen J, Dhingra U, Rathjen P, Walker D, Dalton S. 2002. Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities. Oncogene, 21(54), 8320.

Stefani G, Slack FJ. 2008. Small non-coding RNAs in animal development. Nature reviews Molecular cell biology, 9(3), 219-230.

Takahashi K, Yamanaka S. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663-676.

Takeda J, Seino S, Bell GI. 1992. Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues. Nucleic acids research 20(17), 4613-4620.

Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. 1998. Embryonic stem cell lines derived from human blastocysts.Science 282(5391), 1145-1147.

Toma JG, Akhavan M, Fernandes KJ, Barnabé-Heider F, Sadikot A, Kaplan DR, Miller FD. 2001. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nature cell biology 3(9), 778-784.

Urbach A, Bar-Nur O, Daley GQ, Benvenisty N. 2010. Differential modeling of Fragile X syndrome by human embryonic stem cells and induced-pluripotent stem cells. Cell stem cell 6(5), 407.

Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, Khalil A, Rheinwald J G, Hochedlinger K. 2009. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature, 460(7259), 1145-1148.

Van Stijn A, van der Pol MA, Kok A, Bontje P M, Roemen G, Beelen R, Ossenkoppele GJ, Schuurhuis GJ. 2003. Differences between the CD34+ and CD34-blast compartments in apoptosis resistance in acute myeloid leukemia. Haematologica, 88(5), 497-508.

Viswanathan SR, Daley GQ,Gregory RI. 2008.  Selective blockade of microRNA processing by Lin28. Science, 320(5872), 97-100.

Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH. 2006. A protein interaction network for pluripotency of embryonic stem cells. Nature, 444(7117), 364-368.

Wang Y, Medvid R, Melton C, Jaenisch R, Blelloch R. 2007. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nature genetics, 39(3), 380-385.

Watt FM, Driskell RR. 2010. The therapeutic potential of stem cells. Philosophical Transactions of the Royal Society B: Biological Sciences, 365(1537), 155-163.

Wu SM, Choo AB, Yap MG, Chan KKK. 2010. Role of Sonic hedgehog signaling and the expression of its components in human embryonic stem cells. Stem cell research, 4(1), 38-49.

Yeom YI, Fuhrmann G, Ovitt CE, Brehm A, Ohbo K, Gross M, Hubner K,Scholer H. 1996. Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development, 122(3), 881-894.

Yu X, Zou J, Ye Z, Hammond H, Chen G, Tokunaga A, Mali P, Li YM, Civin C, Gaiano N. 2008. Notch signaling activation in human embryonic stem cells is required for embryonic, but not trophoblastic, lineage commitment. Cell Stem Cell2(5), 461-471.

Zhao Y, Yin X, Qin H, Zhu F, Liu H, Yang W, Zhang Q, Xiang C, Hou P, Song Z. 2008. Two supporting factors greatly improve the efficiency of human iPSC generation. Cell stem cell 3(5), 475-479.