User:L!ttleW0lf/Reprogramming
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In cell culture systems
Reprogramming can also be induced artificially through the introduction of exogenous factors, usually transcription factors. In this context, it often refers to the creation of induced pluripotent stem cells from mature cells such as adult fibroblasts. This allows the production of stem cells for biomedical research, such as research into stem cell therapies, without the use of embryos. It is carried out by the transfection of stem-cell associated genes into mature cells using viral vectors such as retroviruses.
History
The first person to successfully demonstrate reprogramming was John Gurdon, who in 1962 demonstrated that differentiated somatic cells could be reprogrammed back into an embryonic state when he managed to obtain swimming tadpoles following the transfer of differentiated intestinal epithelial cells into enucleated frog eggs.[1] For this achievement he received the 2012 Nobel Prize in Medicine alongside Shinya Yamanaka.[2] Yamanaka was the first to demonstrate (in 2006) that this somatic cell nuclear transfer or oocyte-based reprogramming process (see below), that Gurdon discovered, could be recapitulated (in mice) by defined factors (Oct4, Sox2, Klf4, and c-Myc) to generate induced pluripotent stem cells (iPSCs).[3] Other combinations of genes have also been used, including LIN25 and Homeobox protein NANOG[4].[5]
Phases of reprogramming into iPSC
With the discovery that cell fate could be altered, the question of what progression of events occur to signify a cell reprogramming. As the final product of iPSC reprogramming was similar in morphology, proliferation, gene expression, pluripotency, and telomerase activity was way to determine what phase of reprogramming was needed.[6] Reprogramming is defined into three phase: initiation, maturation, and stabilization.[7]
Initiation
The initiation phase is associated with the downregulation of cell type specific genes and the upregulation of pluripotent genes.[7] As the cells move towards pluripotency, the Telomerase activity is reactivated to extend telomeres. The cell morphology can directly affect the reprogramming process as the cell is modifying itself to prepare for the gene expression of pluripotency.[8] If the cell is directly reprogrammed from one somatic cell to another, the genes associated with each cell type begin to be upregulated and downregulated accordingly.[7] This can either occur through direct cell reprogramming or creating a intermediate, such as a iPSC, and differentiating into the desired cell type.[9]
The initiation phase is completed through one of three pathways: nuclear transfer, cell fusion, or defined factors (MicroRNA, Transcription factor, epigenetic markers, and other small molecules).[9]
Somatic cell nuclear transfer
An oocyte can reprogram an adult nucleus into an embryonic state after somatic cell nuclear transfer, so that a new organism can be developed from such cell.[10]
Reprogramming is distinct from development of a somatic epitype,[11] as somatic epitypes can potentially be altered after an organism has left the developmental stage of life.[12] During somatic cell nuclear transfer, the oocyte turns off tissue specific genes in the Somatic cell nucleus and turns back on embryonic specific genes. This process has been shown through cloning, as seen through John Gurdon with the tadpoles[1] and Dolly (sheep).[13] Notably, these events have shown that cell fate is a reversible process.
Cell fusion
Cell fusion is used to create a multi nucleated cell called a Heterokaryon.[9] The fused cells allow for otherwise silenced genes to become reactivated and expressive. As the genes are reactivated, the cells can re-differentiate.
Defined factors
Unlike nuclear transfer and cell fusion, defined factors do not require a full genome, but only reprogramming factors. These reprogramming factors include MicroRNA, Transcription factor, epigenetic markers, and other small molecules.[9] The original transcription factors, that lead to iPSC development, discovered by Yamanaka include Oct4, Sox2, Klf4, and c-Myc (OSKM factors).[3][6] Although the OSKM factors have been shown to induce and aid in pluripotency, other transcription factors such as Homeobox protein NANOG[14], LIN25[4], TRA-1-60[15], and C/EBPα[16].
Maturation
Stabilization
Variability
The properties of cells obtained after reprogramming can vary significantly, in particular among iPSCs.[17] Factors leading to variation in the performance of reprogramming and functional features of end products include genetic background, tissue source, reprogramming factor stoichiometry and stressors related to cell culture.[17]
References
- ^ a b Gurdon JB (December 1962). "The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles". Journal of Embryology and Experimental Morphology. 10: 622–40. PMID 13951335.
- ^ "The Nobel Prize in Physiology or Medicine – 2012 Press Release". Nobel Media AB. 8 October 2012.
- ^ a b Takahashi K, Yamanaka S (August 2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors" (PDF). Cell. 126 (4): 663–76. doi:10.1016/j.cell.2006.07.024. PMID 16904174. S2CID 1565219.
- ^ a b Magalhães, João Pedro de; Ocampo, Alejandro (2022-06-01). "Cellular reprogramming and the rise of rejuvenation biotech". Trends in Biotechnology. 40 (6): 639–642. doi:10.1016/j.tibtech.2022.01.011. ISSN 0167-7799. PMID 35190201.
- ^ Baker M (2007-12-06). "Adult cells reprogrammed to pluripotency, without tumors". Nature Reports Stem Cells. doi:10.1038/stemcells.2007.124.
- ^ a b Takahashi, Kazutoshi; Tanabe, Koji; Ohnuki, Mari; Narita, Megumi; Ichisaka, Tomoko; Tomoda, Kiichiro; Yamanaka, Shinya (2007-11-30). "Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors". Cell. 131 (5): 861–872. doi:10.1016/j.cell.2007.11.019. ISSN 0092-8674. PMID 18035408.
- ^ a b c David, Laurent; Polo, Jose M. (2014-05-01). "Phases of reprogramming". Stem Cell Research. 12 (3): 754–761. doi:10.1016/j.scr.2014.03.007. ISSN 1873-5061.
- ^ Downing, Timothy L.; Soto, Jennifer; Morez, Constant; Houssin, Timothee; Fritz, Ashley; Yuan, Falei; Chu, Julia; Patel, Shyam; Schaffer, David V.; Li, Song (2013-12). "Biophysical regulation of epigenetic state and cell reprogramming". Nature Materials. 12 (12): 1154–1162. doi:10.1038/nmat3777. ISSN 1476-1122.
{{cite journal}}: Check date values in:|date=(help) - ^ a b c d Pires, Cristiana F.; Rosa, Fábio F.; Kurochkin, Ilia; Pereira, Carlos-Filipe (2019). "Understanding and Modulating Immunity With Cell Reprogramming". Frontiers in Immunology. 10. doi:10.3389/fimmu.2019.02809. ISSN 1664-3224. PMC 6917620. PMID 31921109.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Hochedlinger K, Jaenisch R (June 2006). "Nuclear reprogramming and pluripotency". Nature. 441 (7097): 1061–7. Bibcode:2006Natur.441.1061H. doi:10.1038/nature04955. PMID 16810240. S2CID 4304218.
- ^ Lahiri DK, Maloney B (2006). "Genes are not our destiny: the somatic epitype bridges between the genotype and the phenotype". Nature Reviews Neuroscience. 7 (12): 976. doi:10.1038/nrn2022-c1.
- ^ Mathers JC (June 2006). "Nutritional modulation of ageing: genomic and epigenetic approaches". Mechanisms of Ageing and Development. 127 (6): 584–9. doi:10.1016/j.mad.2006.01.018. PMID 16513160. S2CID 9187848.
- ^ Wilmut, I.; Schnieke, A. E.; McWhir, J.; Kind, A. J.; Campbell, K. H. S. (1997-02). "Viable offspring derived from fetal and adult mammalian cells". Nature. 385 (6619): 810–813. doi:10.1038/385810a0. ISSN 0028-0836.
{{cite journal}}: Check date values in:|date=(help) - ^ Heurtier, Victor; Owens, Nick; Gonzalez, Inma; Mueller, Florian; Proux, Caroline; Mornico, Damien; Clerc, Philippe; Dubois, Agnes; Navarro, Pablo (2019-03-07). "The molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells". Nature Communications. 10 (1): 1109. doi:10.1038/s41467-019-09041-z. ISSN 2041-1723. PMC 6406003. PMID 30846691.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Bueno, C; Sardina, J L; Di Stefano, B; Romero-Moya, D; Muñoz-López, A; Ariza, L; Chillón, M C; Balanzategui, A; Castaño, J; Herreros, A; Fraga, M F; Fernández, A; Granada, I; Quintana-Bustamante, O; Segovia, J C (2016-03). "Reprogramming human B cells into induced pluripotent stem cells and its enhancement by C/EBPα". Leukemia. 30 (3): 674–682. doi:10.1038/leu.2015.294. ISSN 0887-6924.
{{cite journal}}: Check date values in:|date=(help) - ^ Srivastava, Deepak; DeWitt, Natalie (2016-09). "In Vivo Cellular Reprogramming: The Next Generation". Cell. 166 (6): 1386–1396. doi:10.1016/j.cell.2016.08.055. PMC 6234007. PMID 27610565.
{{cite journal}}: Check date values in:|date=(help)CS1 maint: PMC format (link) - ^ a b Paull D, Sevilla A, Zhou H, Hahn AK, Kim H, Napolitano C, Tsankov A, Shang L, Krumholz K, Jagadeesan P, Woodard CM, Sun B, Vilboux T, Zimmer M, Forero E, Moroziewicz DN, Martinez H, Malicdan MC, Weiss KA, Vensand LB, Dusenberry CR, Polus H, Sy KT, Kahler DJ, Gahl WA, Solomon SL, Chang S, Meissner A, Eggan K, Noggle SA (September 2015). "Automated, high-throughput derivation, characterization and differentiation of induced pluripotent stem cells". Nature Methods. 12 (9): 885–92. doi:10.1038/nmeth.3507. PMID 26237226. S2CID 9889991.