Differentiation of Somatic Cells in Multicellular Organisms

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Published: 2025-01-31
DOI: https://doi.org/10.5281/zenodo.14778927
Keywords:
asymmetric cell division, tf, grn, replicative aging, fibroblast cultures, telomeres

Main Article Content

Jaba Tkemaladze
Longevity Clinic
https://orcid.org/0000-0001-8651-7243

Abstract

Multicellular organisms employ intricate gene regulatory networks (GRNs) to orchestrate cell fate decisions, yet the precise regulatory mechanisms that govern transcription factors (TFs) within these networks remain exceptionally complex. A long-standing question in this field pertains to how these intricate interactions synergistically contribute to decision-making processes. To gain a comprehensive understanding of the role of regulatory logic in cell fate determinations, we developed a logical model of GRNs and examined its behavior under two distinct driving forces—one governed by stochastic noise and the other by deterministic signaling. Under noise-driven conditions, we identified a correlation between fate biasing, regulatory logic, and noise profile dynamics. In the signal-driven mode, we established a connection between regulatory logic and the trade-off between accuracy and progression speed, revealing distinct reprogramming trajectories influenced by specific logical motifs. Through differentiation studies, we characterized a unique priming stage that is dependent on regulatory logic, employing decision landscapes for analysis. Finally, we applied our findings to elucidate three biological cases: hematopoiesis, embryogenesis, and transdifferentiation. Orthogonally to classical expression profile analysis, we leveraged noise pattern recognition to construct GRNs corresponding to fate transitions. Our research presents a generalizable framework for downstream investigations of fate determination and offers a practical approach for the taxonomy of cell fate decisions.

Article Details

Issue

Vol. 1 No. 2 (2025)

Section

Reviews and Perspectives
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Articles published in "Longevity Horizons" fall under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). This means authors retain their copyright while granting the journal the right to be the first publisher. Readers are permitted to share and distribute the work as long as proper credit is given. However, the content may not be altered, modified, or used for commercial purposes.

Author Biography

Jaba Tkemaladze, Longevity Clinic

Dr Jaba Tkemaladze is a Professor, a Scientist, and a President of Longevity Alliance Georgia.

Research Director at Longevity Clinic.

Replacing old adult stem cells with induced and safe young adult stem cells.

World-renowned scientist. Developed the Centriolar theory of differentiation and the Centriolar theory of organism ageing. With acquired experience in both academia and industry.

Training in medicine at Tbilisi State Medical University and then at the Psychiatry Research Institute further deepened my knowledge in the laboratory of the Institute of Morphology. Namely, combined experimental and computational methods to study the ageing process and the various ways of manipulating age-related diseases and improvement of human health.

Also served as a Scientific Advisory Board Member in Georgia's Ministry of Defense and Longevity Alliance. Published over 50 scientific articles, given over 100 invited talks and received several awards.

His Rejuvenation Formula: Rejuvenation = Replacement of old adult stem cells with Young, safe Adult Stem Cells induced from one's own cells.

How to Cite

Tkemaladze, J. (2025). Differentiation of Somatic Cells in Multicellular Organisms. Longevity Horizons, 1(2). DOI:https://doi.org/10.5281/zenodo.14778927
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References

Abeysundara, N., Simmonds, A. J., & Hughes, S. C. (2018). Moesin is involved in polarity maintenance and cortical remodeling during asymmetric cell division. Molecular Biology of the Cell, 29(4), 419-434.

Adams, W. C., Chen, Y. H., Kratchmarov, R., Yen, B., Nish, S. A., Lin, W. H. W., ... & Reiner, S. L. (2016). Anabolism-associated mitochondrial stasis driving lymphocyte differentiation over self-renewal. Cell reports, 17(12), 3142-3152.

Akera, T., Chmátal, L., Trimm, E., Yang, K., Aonbangkhen, C., Chenoweth, D. M., ... & Lampson, M. A. (2017). Spindle asymmetry drives non-Mendelian chromosome segregation. Science, 358(6363), 668-672.

Akera, T., Trimm, E., & Lampson, M. A. (2019). Molecular strategies of meiotic cheating by selfish centromeres. Cell, 178(5), 1132-1144.

Alliegro, M. C., Alliegro, M. A., & Palazzo, R. E. (2006). Centrosome-associated RNA in surf clam oocytes. Proceedings of the National Academy of Sciences, 103(24), 9034-9038.

Allshire, R. C., & Karpen, G. H. (2008). Epigenetic regulation of centromeric chromatin: old dogs, new tricks?. Nature Reviews Genetics, 9(12), 923-937.

Atwood, S. X., & Prehoda, K. E. (2009). aPKC phosphorylates Miranda to polarize fate determinants during neuroblast asymmetric cell division. Current Biology, 19(9), 723-729.

Babour, A., Bicknell, A. A., Tourtellotte, J., & Niwa, M. (2010). A surveillance pathway monitors the fitness of the endoplasmic reticulum to control its inheritance. Cell, 142(2), 256-269.

Bärenz, F., Kschonsak, Y. T., Meyer, A., Jafarpour, A., Lorenz, H., & Hoffmann, I. (2018). Ccdc61 controls centrosomal localization of Cep170 and is required for spindle assembly and symmetry. Molecular biology of the cell, 29(26), 3105-3118.

Barros, C. S., Phelps, C. B., & Brand, A. H. (2003). Drosophila nonmuscle myosin II promotes the asymmetric segregation of cell fate determinants by cortical exclusion rather than active transport. Developmental cell, 5(6), 829-840.

Beaudouin, J., Gerlich, D., Daigle, N., Eils, R., & Ellenberg, J. (2002). Nuclear envelope breakdown proceeds by microtubule-induced tearing of the lamina. Cell, 108(1), 83-96.

Böckler, S., Chelius, X., Hock, N., Klecker, T., Wolter, M., Weiss, M., ... & Westermann, B. (2017). Fusion, fission, and transport control asymmetric inheritance of mitochondria and protein aggregates. Journal of Cell Biology, 216(8), 2481-2498.

Bouvrette, L. P. B., Cody, N. A., Bergalet, J., Lefebvre, F. A., Diot, C., Wang, X., ... & Lécuyer, E. (2018). CeFra-seq reveals broad asymmetric mRNA and noncoding RNA distribution profiles in Drosophila and human cells. Rna, 24(1), 98-113.

Boxem, M., & van den Heuvel, S. (2019). Cell polarity: getting the PARty started. Current Biology, 29(13), R637-R639.

Cabernard, C., Prehoda, K. E., & Doe, C. Q. (2010). A spindle-independent cleavage furrow positioning pathway. Nature, 467(7311), 91-94.

Cai, Y., Yu, F., Lin, S., Chia, W., & Yang, X. (2003). Apical complex genes control mitotic spindle geometry and relative size of daughter cells in Drosophila neuroblast and pI asymmetric divisions. Cell, 112(1), 51-62.

Cashikar, A. G., Duennwald, M., & Lindquist, S. L. (2005). A chaperone pathway in protein disaggregation: Hsp26 alters the nature of protein aggregates to facilitate reactivation by Hsp104. Journal of Biological Chemistry, 280(25), 23869-23875.

Chang, H. H., Hemberg, M., Barahona, M., Ingber, D. E., & Huang, S. (2008). Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature, 453(7194), 544–547. https://doi.org/10.1038/nature06965

Chen, C., Inaba, M., Venkei, Z. G., & Yamashita, Y. M. (2016). Klp10A, a stem cell centrosome-enriched kinesin, balances asymmetries in Drosophila male germline stem cell division. Elife, 5, e20977.

Chen, J. Y., Bottjer, D. J., Davidson, E. H., Dornbos, S. Q., Gao, X., Yang, Y. H., ... & Tafforeau, P. (2006). Phosphatized polar lobe-forming embryos from the Precambrian of southwest China. Science, 312(5780), 1644-1646.

Chen, X., Widmer, L. A., Stangier, M. M., Steinmetz, M. O., Stelling, J., & Barral, Y. (2019). Remote control of microtubule plus-end dynamics and function from the minus-end. Elife, 8, e48627.

Chernyakov, I., Santiago-Tirado, F., & Bretscher, A. (2013). Active segregation of yeast mitochondria by Myo2 is essential and mediated by Mmr1 and Ypt11. Current Biology, 23(18), 1818-1824.

Chichinadze, K. N., & Tkemaladze, D. V. (2008). Centrosomal hypothesis of cellular aging and differentiation. Advances in Gerontology= Uspekhi Gerontologii, 21(3), 367-371.

Chichinadze, K., Lazarashvili, A., & Tkemaladze, J. (2013). RNA in centrosomes: structure and possible functions. Protoplasma, 250(1), 397-405.

Chichinadze, K., Tkemaladze, D., & Lazarashvili, A. (2012). New class of RNA and centrosomal hypothesis of cell aging. Advances in Gerontology= Uspekhi Gerontologii, 25(1), 23-28.

Chichinadze, K., Tkemaladze, J., & Lazarashvili, A. (2012). A new class of RNAs and the centrosomal hypothesis of cell aging. Advances in Gerontology, 2(4), 287-291.

Chichinadze, K., Tkemaladze, J., & Lazarashvili, A. (2012). Discovery of centrosomal RNA and centrosomal hypothesis of cellular ageing and differentiation. Nucleosides, Nucleotides and Nucleic Acids, 31(3), 172-183.

Choksi, S. P., Southall, T. D., Bossing, T., Edoff, K., de Wit, E., Fischer, B. E., ... & Brand, A. H. (2006). Prospero acts as a binary switch between self-renewal and differentiation in Drosophila neural stem cells. Developmental cell, 11(6), 775-789.

Clay, L., Caudron, F., Denoth-Lippuner, A., Boettcher, B., Buvelot Frei, S., Snapp, E. L., & Barral, Y. (2014). A sphingolipid-dependent diffusion barrier confines ER stress to the yeast mother cell. Elife, 3, e01883.

Conduit, P. T., & Raff, J. W. (2010). Cnn dynamics drive centrosome size asymmetry to ensure daughter centriole retention in Drosophila neuroblasts. Current Biology, 20(24), 2187-2192.

Conduit, P. T., Wainman, A., & Raff, J. W. (2015). Centrosome function and assembly in animal cells. Nature reviews Molecular cell biology, 16(10), 611-624.

Conklin, E. G. (1905). Mosaic development in ascidian eggs. Journal of Experimental Zoology, 2(2), 145-223.

Connell, M., Cabernard, C., Ricketson, D., Doe, C. Q., & Prehoda, K. E. (2011). Asymmetric cortical extension shifts cleavage furrow position in Drosophila neuroblasts. Molecular biology of the cell, 22(22), 4220-4226.

Coumailleau, F., Fürthauer, M., Knoblich, J. A., & Gonzalez-Gaitan, M. (2009). Directional Delta and Notch trafficking in Sara endosomes during asymmetric cell division. Nature, 458(7241), 1051-1055.

Dalton, C. M., & Carroll, J. (2013). Biased inheritance of mitochondria during asymmetric cell division in the mouse oocyte. Journal of cell science, 126(13), 2955-2964.

Del Arco, A. G., Edgar, B. A., & Erhardt, S. (2018). In vivo analysis of centromeric proteins reveals a stem cell-specific asymmetry and an essential role in differentiated, non-proliferating cells. Cell reports, 22(8), 1982-1993.

Del Vecchio, D., Abdallah, H., Qian, Y., & Collins, J. J. (2017). A Blueprint for a Synthetic Genetic Feedback Controller to Reprogram Cell Fate. Cell systems, 4(1), 109–120.e11. https://doi.org/10.1016/j.cels.2016.12.001

Derivery, E., Seum, C., Daeden, A., Loubéry, S., Holtzer, L., Jülicher, F., & Gonzalez-Gaitan, M. (2015). Polarized endosome dynamics by spindle asymmetry during asymmetric cell division. Nature, 528(7581), 280-285.

Desai, R. V., Chen, X., Martin, B., Chaturvedi, S., Hwang, D. W., Li, W., Yu, C., Ding, S., Thomson, M., Singer, R. H., Coleman, R. A., Hansen, M. M. K., & Weinberger, L. S. (2021). A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions. Science (New York, N.Y.), 373(6557), eabc6506. https://doi.org/10.1126/science.abc6506

Dumollard, R., Duchen, M., & Carroll, J. (2007). Current topics in developmental biology. Curr. Top. Dev. Biol., 77, 21-49.

Feng, Z., Caballe, A., Wainman, A., Johnson, S., Haensele, A. F., Cottee, M. A., ... & Raff, J. W. (2017). Structural basis for mitotic centrosome assembly in flies. Cell, 169(6), 1078-1089.

Franzmann, T. M., Menhorn, P., Walter, S., & Buchner, J. (2008). Activation of the chaperone Hsp26 is controlled by the rearrangement of its thermosensor domain. Molecular cell, 29(2), 207-216.

Fusco, D., Accornero, N., Lavoie, B., Shenoy, S. M., Blanchard, J. M., Singer, R. H., & Bertrand, E. (2003). Single mRNA molecules demonstrate probabilistic movement in living mammalian cells. Current Biology, 13(2), 161-167.

Gallaud, E., Pham, T., & Cabernard, C. (2017). Drosophila melanogaster neuroblasts: a model for asymmetric stem cell divisions. Asymmetric Cell Division in Development, Differentiation and Cancer, 183-210.

Gambarotto, D., Pennetier, C., Ryniawec, J. M., Buster, D. W., Gogendeau, D., Goupil, A., ... & Basto, R. (2019). Plk4 regulates centriole asymmetry and spindle orientation in neural stem cells. Developmental cell, 50(1), 11-24.

Guillemin, A., & Stumpf, M. P. H. (2021). Noise and the molecular processes underlying cell fate decision-making. Physical biology, 18(1), 011002. https://doi.org/10.1088/1478-3975/abc9d1

Hannaford, M. R., Ramat, A., Loyer, N., & Januschke, J. (2018). aPKC-mediated displacement and actomyosin-mediated retention polarize Miranda in Drosophila neuroblasts. Elife, 7, e29939.

Hejnol, A., & Pfannenstiel, H. D. (1998). Myosin and actin are necessary for polar lobe formation and resorption in Ilyanassa obsoleta embryos. Development genes and evolution, 208, 229-233.

Hibbel, A., Bogdanova, A., Mahamdeh, M., Jannasch, A., Storch, M., Schäffer, E., ... & Howard, J. (2015). Kinesin Kip2 enhances microtubule growth in vitro through length-dependent feedback on polymerization and catastrophe. Elife, 4, e10542.

Hill, S. M., Hao, X., Grönvall, J., Spikings-Nordby, S., Widlund, P. O., Amen, T., ... & Nyström, T. (2016). Asymmetric inheritance of aggregated proteins and age reset in yeast are regulated by Vac17-dependent vacuolar functions. Cell reports, 16(3), 826-838.

Holly, R. W., Jones, K., & Prehoda, K. E. (2020). A conserved PDZ-binding motif in aPKC interacts with Par-3 and mediates cortical polarity. Current Biology, 30(5), 893-898.

Hota, S. K., Rao, K. S., Blair, A. P., Khalilimeybodi, A., Hu, K. M., Thomas, R., So, K., Kameswaran, V., Xu, J., Polacco, B. J., Desai, R. V., Chatterjee, N., Hsu, A., Muncie, J. M., Blotnick, A. M., Winchester, S. A. B., Weinberger, L. S., Hüttenhain, R., Kathiriya, I. S., Krogan, N. J., … Bruneau, B. G. (2022). Brahma safeguards canalization of cardiac mesoderm differentiation. Nature, 602(7895), 129–134. https://doi.org/10.1038/s41586-021-04336-y

Jaba, T. (2022). Dasatinib and quercetin: short-term simultaneous administration yields senolytic effect in humans. Issues and Developments in Medicine and Medical Research Vol. 2, 22-31.

Jakobsen, L., Vanselow, K., Skogs, M., Toyoda, Y., Lundberg, E., Poser, I., ... & Andersen, J. S. (2011). Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods. The EMBO journal, 30(8), 1520-1535.

Januschke, J., Llamazares, S., Reina, J., & Gonzalez, C. (2011). Drosophila neuroblasts retain the daughter centrosome. Nature communications, 2(1), 243.

Jeffery, W. R., Tomlinson, C. R., & Brodeur, R. D. (1983). Localization of actin messenger RNA during early ascidian development. Developmental biology, 99(2), 408-417.

Jonas, F. R., Royle, K. E., Aw, R., Stan, G. B. V., & Polizzi, K. M. (2018). Investigating the consequences of asymmetric endoplasmic reticulum inheritance in Saccharomyces cerevisiae under stress using a combination of single cell measurements and mathematical modelling. Synthetic and Systems Biotechnology, 3(1), 64-75.

Juliano, C. E., Voronina, E., Stack, C., Aldrich, M., Cameron, A. R., & Wessel, G. M. (2006). Germ line determinants are not localized early in sea urchin development, but do accumulate in the small micromere lineage. Developmental biology, 300(1), 406-415.

Katajisto, P., Döhla, J., Chaffer, C. L., Pentinmikko, N., Marjanovic, N., Iqbal, S., ... & Sabatini, D. M. (2015). Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science, 348(6232), 340-343.

Kemphues, K. J., Priess, J. R., Morton, D. G., & Cheng, N. (1988). Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell, 52(3), 311-320.

Kingsley, E. P., Chan, X. Y., Duan, Y., & Lambert, J. D. (2007). Widespread RNA segregation in a spiralian embryo. Evolution & development, 9(6), 527-539.

Kipshidze, M., & Tkemaladze, J. (2023). Comparative Analysis of drugs that improve the Quality of Life and Life Expectancy. Junior Researchers, 1(1), 184–193. doi: https://doi.org/10.52340/2023.01.01.19

Kipshidze, M., & Tkemaladze, J. (2023). The planaria Schmidtea mediterranea as a model system for the study of stem cell biology. Junior Researchers, 1(1), 194–218. doi: https://doi.org/10.52340/2023.01.01.20

Kipshidze, M., & Tkemaladze, J. (2024). Abastumani Resort: Balneological Heritage and Modern Potential. Junior Researchers, 2(2), 126–134. doi: https://doi.org/10.52340/jr.2024.02.02.12

Kipshidze, M., & Tkemaladze, J. (2024). Balneology in Georgia: traditions and modern situation. Junior Researchers, 2(2), 78–97. doi: https://doi.org/10.52340/jr.2024.02.02.09

Kipshidze, M., & Tkemaladze, J. (2024). Microelementoses - history and current status. Junior Researchers, 2(2), 108–125. doi: https://doi.org/10.52340/jr.2024.02.02.11

Kiyomitsu, T. (2019). The cortical force-generating machinery: how cortical spindle-pulling forces are generated. Current opinion in cell biology, 60, 1-8.’

Klinkert, K., Levernier, N., Gross, P., Gentili, C., von Tobel, L., Pierron, M., ... & Gönczy, P. (2019). Aurora A depletion reveals centrosome-independent polarization mechanism in Caenorhabditis elegans. Elife, 8, e44552.

Kovall, R. A., Gebelein, B., Sprinzak, D., & Kopan, R. (2017). The canonical Notch signaling pathway: structural and biochemical insights into shape, sugar, and force. Developmental cell, 41(3), 228-241.

Kursel, L. E., & Malik, H. S. (2018). The cellular mechanisms and consequences of centromere drive. Current Opinion in Cell Biology, 52, 58-65.

Kusek, G., Campbell, M., Doyle, F., Tenenbaum, S. A., Kiebler, M., & Temple, S. (2012). Asymmetric segregation of the double-stranded RNA binding protein Staufen2 during mammalian neural stem cell divisions promotes lineage progression. Cell stem cell, 11(4), 505-516.

Lambert, J. D., & Nagy, L. M. (2002). Asymmetric inheritance of centrosomally localized mRNAs during embryonic cleavages. Nature, 420(6916), 682-686.

Landskron, L., Steinmann, V., Bonnay, F., Burkard, T. R., Steinmann, J., Reichardt, I., ... & Knoblich, J. A. (2018). The asymmetrically segregating lncRNA cherub is required for transforming stem cells into malignant cells. Elife, 7, e31347.

Lécuyer, E., Yoshida, H., Parthasarathy, N., Alm, C., Babak, T., Cerovina, T., ... & Krause, H. M. (2007). Global analysis of mRNA localization reveals a prominent role in organizing cellular architecture and function. Cell, 131(1), 174-187.

Ledan, E., Polanski, Z., Terret, M. E., & Maro, B. (2001). Meiotic maturation of the mouse oocyte requires an equilibrium between cyclin B synthesis and degradation. Developmental biology, 232(2), 400-413.

Lengefeld, J., Yen, E., Chen, X., Leary, A., Vogel, J., & Barral, Y. (2018). Spatial cues and not spindle pole maturation drive the asymmetry of astral microtubules between new and preexisting spindle poles. Molecular biology of the cell, 29(1), 10-28.

Lerit, D. A., & Rusan, N. M. (2013). PLP inhibits the activity of interphase centrosomes to ensure their proper segregation in stem cells. Journal of Cell Biology, 202(7), 1013-1022.

Lezhava, T., Monaselidze, J., Jokhadze, T., Kakauridze, N., Khodeli, N., Rogava, M., Tkemaladze, J., ... & Gaiozishvili, M. (2011). Gerontology research in Georgia. Biogerontology, 12, 87-91. doi: 10.1007/s10522-010-9283-6. Epub 2010 May 18. PMID: 20480236; PMCID: PMC3063552

Li, P., Yang, X., Wasser, M., Cai, Y., & Chia, W. (1997). Inscuteable and Staufen Mediate Asymmetric Localization and Segregation of prosperoRNA during Drosophila Neuroblast Cell Divisions. Cell, 90(3), 437-447.

Liberek, K., Lewandowska, A., & Ziętkiewicz, S. (2008). Chaperones in control of protein disaggregation. The EMBO journal, 27(2), 328-335.

Loeffler, D., Wehling, A., Schneiter, F., Zhang, Y., Müller-Bötticher, N., Hoppe, P. S., ... & Schroeder, T. (2019). Asymmetric lysosome inheritance predicts activation of haematopoietic stem cells. Nature, 573(7774), 426-429.

Long, R. M., Singer, R. H., Meng, X., Gonzalez, I., Nasmyth, K., & Jansen, R. P. (1997). Mating type switching in yeast controlled by asymmetric localization of ASH1 mRNA. Science, 277(5324), 383-387.

Loyer, N., & Januschke, J. (2020). Where does asymmetry come from? Illustrating principles of polarity and asymmetry establishment in Drosophila neuroblasts. Current Opinion in Cell Biology, 62, 70-77.

MacArthur B. D. (2023). Stem cell biology needs a theory. Stem cell reports, 18(1), 3–5. https://doi.org/10.1016/j.stemcr.2022.11.005

Manzano-López, J., Matellán, L., Álvarez-Llamas, A., Blanco-Mira, J. C., & Monje-Casas, F. (2019). Asymmetric inheritance of spindle microtubule-organizing centres preserves replicative lifespan. Nature Cell Biology, 21(8), 952-965.

Mao, K., Wang, K., Liu, X., & Klionsky, D. J. (2013). The scaffold protein Atg11 recruits fission machinery to drive selective mitochondria degradation by autophagy. Developmental cell, 26(1), 9-18.

Matsaberidze, M., Prangishvili, A., Gasitashvili, Z., Chichinadze, K., & Tkemaladze, J. (2017). TO TOPOLOGY OF ANTI-TERRORIST AND ANTI-CRIMINAL TECHNOLOGY FOR EDUCATIONAL PROGRAMS. International Journal of Terrorism & Political Hot Spots, 12.

Matsuzaki, F., Ohshiro, T., Ikeshima-Kataoka, H., & Izumi, H. (1998). Miranda localizes staufen and prospero asymmetrically in mitotic neuroblasts and epithelial cells in early Drosophila embryogenesis. Development, 125(20), 4089-4098.

Mishra, P., & Chan, D. C. (2014). Mitochondrial dynamics and inheritance during cell division, development and disease. Nature reviews Molecular cell biology, 15(10), 634-646.

Mogessie, B., Scheffler, K., & Schuh, M. (2018). Assembly and positioning of the oocyte meiotic spindle. Annual review of cell and developmental biology, 34(1), 381-403.

Mogessie, B., Scheffler, K., & Schuh, M. (2018). Assembly and positioning of the oocyte meiotic spindle. Annual review of cell and developmental biology, 34(1), 381-403.

Mollinari, C., Lange, B., & González, C. (2002). Miranda, a protein involved in neuroblast asymmetric division, is associated with embryonic centrosomes of Drosophila melanogaster. Biology of the Cell, 94(1), 1-13.

Moore, D. L., & Jessberger, S. (2017). Creating age asymmetry: consequences of inheriting damaged goods in mammalian cells. Trends in cell biology, 27(1), 82-92.

Moore, D. L., Pilz, G. A., Araúzo-Bravo, M. J., Barral, Y., & Jessberger, S. (2015). A mechanism for the segregation of age in mammalian neural stem cells. Science, 349(6254), 1334-1338.

Morgan, T. H. (1933). The formation of the antipolar lobe in Ilyanassa. Journal of Experimental Zoology, 64(3), 433-467.

Munro, E., Nance, J., & Priess, J. R. (2004). Cortical flows powered by asymmetrical contraction transport PAR proteins to establish and maintain anterior-posterior polarity in the early C. elegans embryo. Developmental cell, 7(3), 413-424.

Nair, A. R., Singh, P., Garcia, D. S., Rodriguez-Crespo, D., Egger, B., & Cabernard, C. (2016). The microcephaly-associated protein Wdr62/CG7337 is required to maintain centrosome asymmetry in Drosophila neuroblasts. Cell reports, 14(5), 1100-1113.

Nanba, D., Toki, F., Tate, S., Imai, M., Matsushita, N., Toki, H., ... & Barrandon, Y. (2016). Cell motion predicts human epidermal stemness. Journal of Dermatological Science, 84(1), e51.

Ng, A. H. M., Khoshakhlagh, P., Rojo Arias, J. E., Pasquini, G., Wang, K., Swiersy, A., Shipman, S. L., Appleton, E., Kiaee, K., Kohman, R. E., Vernet, A., Dysart, M., Leeper, K., Saylor, W., Huang, J. Y., Graveline, A., Taipale, J., Hill, D. E., Vidal, M., Melero-Martin, J. M., … Church, G. M. (2021). A comprehensive library of human transcription factors for cell fate engineering. Nature biotechnology, 39(4), 510–519. https://doi.org/10.1038/s41587-020-0742-6

Oon, C. H., & Prehoda, K. E. (2019). Asymmetric recruitment and actin-dependent cortical flows drive the neuroblast polarity cycle. Elife, 8, e45815.

Ou, G., Stuurman, N., D’Ambrosio, M., & Vale, R. D. (2010). Polarized myosin produces unequal-size daughters during asymmetric cell division. Science, 330(6004), 677-680.

Pereira, G., Tanaka, T. U., Nasmyth, K., & Schiebel, E. (2001). Modes of spindle pole body inheritance and segregation of the Bfa1p–Bub2p checkpoint protein complex. The EMBO journal, 20(22), 6359-6370.

Pernice, W. M., Vevea, J. D., & Pon, L. A. (2016). A role for Mfb1p in region-specific anchorage of high-functioning mitochondria and lifespan in Saccharomyces cerevisiae. Nature communications, 7(1), 10595.

Pham, T. T., Monnard, A., Helenius, J., Lund, E., Lee, N., Müller, D. J., & Cabernard, C. (2019). Spatiotemporally controlled myosin relocalization and internal pressure generate sibling cell size asymmetry. Iscience, 13, 9-19.

Piña, F. J., & Niwa, M. (2015). The ER Stress Surveillance (ERSU) pathway regulates daughter cell ER protein aggregate inheritance. Elife, 4, e06970.

Poon, J., Fries, A., Wessel, G. M., & Yajima, M. (2019). Evolutionary modification of AGS protein contributes to formation of micromeres in sea urchins. Nature Communications, 10(1), 3779.

Prangishvili, A., Gasitashvili, Z., Matsaberidze, M., Chkhartishvili, L., Chichinadze, K., Tkemaladze, J., ... & Azmaiparashvili, Z. (2019). SYSTEM COMPONENTS OF HEALTH AND INNOVATION FOR THE ORGANIZATION OF NANO-BIOMEDIC ECOSYSTEM TECHNOLOGICAL PLATFORM. Current Politics and Economics of Russia, Eastern and Central Europe, 34(2/3), 299-305.

Radford, S. J., Go, A. M. M., & McKim, K. S. (2017). Cooperation between kinesin motors promotes spindle symmetry and chromosome organization in oocytes. Genetics, 205(2), 517-527.

Rafelski, S. M., Viana, M. P., Zhang, Y., Chan, Y. H. M., Thorn, K. S., Yam, P., ... & Marshall, W. F. (2012). Mitochondrial network size scaling in budding yeast. Science, 338(6108), 822-824.

Ramat, A., Hannaford, M., & Januschke, J. (2017). Maintenance of miranda localization in Drosophila neuroblasts involves interaction with the cognate mRNA. Current Biology, 27(14), 2101-2111.

Ranjan, R., Snedeker, J., & Chen, X. (2019). Asymmetric centromeres differentially coordinate with mitotic machinery to ensure biased sister chromatid segregation in germline stem cells. Cell stem cell, 25(5), 666-681.

Rebollo, E., Sampaio, P., Januschke, J., Llamazares, S., Varmark, H., & González, C. (2007). Functionally unequal centrosomes drive spindle orientation in asymmetrically dividing Drosophila neural stem cells. Developmental cell, 12(3), 467-474.

Render, J. (1989). Development of Ilyanassa obsoleta embryos after equal distribution of polar lobe material at first cleavage. Developmental biology, 132(1), 241-250.

Roubinet, C., & Cabernard, C. (2014). Control of asymmetric cell division. Current opinion in cell biology, 31, 84-91.

Roubinet, C., Tsankova, A., Pham, T. T., Monnard, A., Caussinus, E., Affolter, M., & Cabernard, C. (2017). Spatio-temporally separated cortical flows and spindle geometry establish physical asymmetry in fly neural stem cells. Nature communications, 8(1), 1383.

Saarikangas, J., Caudron, F., Prasad, R., Moreno, D. F., Bolognesi, A., Aldea, M., & Barral, Y. (2017). Compartmentalization of ER-bound chaperone confines protein deposit formation to the aging yeast cell. Current Biology, 27(6), 773-783.

Salina, D., Bodoor, K., Eckley, D. M., Schroer, T. A., Rattner, J. B., & Burke, B. (2002). Cytoplasmic dynein as a facilitator of nuclear envelope breakdown. Cell, 108(1), 97-107.

Sallé, J., Xie, J., Ershov, D., Lacassin, M., Dmitrieff, S., & Minc, N. (2019). Asymmetric division through a reduction of microtubule centering forces. Journal of Cell Biology, 218(3), 771-782.

Salzmann, V., Chen, C., Chiang, C. Y. A., Tiyaboonchai, A., Mayer, M., & Yamashita, Y. M. (2014). Centrosome-dependent asymmetric inheritance of the midbody ring in Drosophila germline stem cell division. Molecular biology of the cell, 25(2), 267-275.

Schuldt, A. J., Adams, J. H., Davidson, C. M., Micklem, D. R., Haseloff, J., St Johnston, D., & Brand, A. H. (1998). Miranda mediates asymmetric protein and RNA localization in the developing nervous system. Genes & development, 12(12), 1847-1857.

Shakiba, N., Li, C., Garcia-Ojalvo, J., Cho, K. H., Patil, K., Walczak, A., Liu, Y. Y., Kuehn, S., Nie, Q., Klein, A., Deco, G., Kringelbach, M., & Iyer-Biswas, S. (2022). How can Waddington-like landscapes facilitate insights beyond developmental biology?. Cell systems, 13(1), 4–9. https://doi.org/10.1016/j.cels.2021.12.003

Simon, C. S., Hadjantonakis, A. K., & Schröter, C. (2018). Making lineage decisions with biological noise: Lessons from the early mouse embryo. Wiley interdisciplinary reviews. Developmental biology, 7(4), e319. https://doi.org/10.1002/wdev.319

Skamagki, M., Wicher, K. B., Jedrusik, A., Ganguly, S., & Zernicka-Goetz, M. (2013). Asymmetric localization of Cdx2 mRNA during the first cell-fate decision in early mouse development. Cell reports, 3(2), 442-457.

Sousa-Nunes, R., Chia, W., & Somers, W. G. (2009). Protein phosphatase 4 mediates localization of the Miranda complex during Drosophila neuroblast asymmetric divisions. Genes & development, 23(3), 359-372.

Stanoev, A., & Koseska, A. (2022). Robust cell identity specifications through transitions in the collective state of growing developmental systems. Current Opinion in Systems Biology, 31, 100437.

Thayer, N. H., Leverich, C. K., Fitzgibbon, M. P., Nelson, Z. W., Henderson, K. A., Gafken, P. R., ... & Gottschling, D. E. (2014). Identification of long-lived proteins retained in cells undergoing repeated asymmetric divisions. Proceedings of the National Academy of Sciences, 111(39), 14019-14026.

Tkemaladze J. Editorial: Molecular mechanism of ageing and therapeutic advances through targeting glycative and oxidative stress. Front Pharmacol. 2024 Mar 6;14:1324446. doi: 10.3389/fphar.2023.1324446. PMID: 38510429; PMCID: PMC10953819.

Tkemaladze, J. (2023). Cross-senolytic effects of dasatinib and quercetin in humans. Georgian Scientists, 5(3), 138–152. doi: https://doi.org/10.52340/2023.05.03.15

Tkemaladze, J. (2023). Is the selective accumulation of oldest centrioles in stem cells the main cause of organism ageing?. Georgian Scientists, 5(3), 216–235. doi: https://doi.org/10.52340/2023.05.03.22

Tkemaladze, J. (2023). Long-Term Differences between Regenerations of Head and Tail Fragments in Schmidtea Mediterranea Ciw4. Available at SSRN 4257823.

Tkemaladze, J. (2023). Reduction, proliferation, and differentiation defects of stem cells over time: a consequence of selective accumulation of old centrioles in the stem cells?. Molecular Biology Reports, 50(3), 2751-2761.

Tkemaladze, J. (2023). Structure and possible functions of centriolar RNA with reference to the centriolar hypothesis of differentiation and replicative senescence. Junior Researchers, 1(1), 156–170. doi: https://doi.org/10.52340/2023.01.01.17

Tkemaladze, J. (2023). The centriolar hypothesis of differentiation and replicative senescence. Junior Researchers, 1(1), 123–141. doi: https://doi.org/10.52340/2023.01.01.15

Tkemaladze, J. (2024). Absence of centrioles and regenerative potential of planaria. Georgian Scientists, 6(4), 59–75. doi: https://doi.org/10.52340/gs.2024.06.04.08

Tkemaladze, J. (2024). Cell center and the problem of accumulation of oldest centrioles in stem cells. Georgian Scientists, 6(2), 304–322. doi: https://doi.org/10.52340/gs.2024.06.02.32

Tkemaladze, J. (2024). Elimination of centrioles. Georgian Scientists, 6(4), 291–307. doi: https://doi.org/10.52340/gs.2024.06.04.25

Tkemaladze, J. (2024). Main causes of intelligence decrease and prospects for treatment. Georgian Scientists, 6(2), 425–432. doi: https://doi.org/10.52340/gs.2024.06.02.44

Tkemaladze, J. (2024). The rate of stem cell division decreases with age. Georgian Scientists, 6(4), 228–242. doi: https://doi.org/10.52340/gs.2024.06.04.21

Tkemaladze, J. (2025). A Universal Approach to Curing All Diseases: From Theoretical Foundations to the Prospects of Applying Modern Biotechnologies in Future Medicine. doi: 10.13140/RG.2.2.24481.11366

Tkemaladze, J. (2025). Strategic Importance of the Caucasian Bridge and Global Power Rivalries. doi: 10.13140/RG.2.2.19153.03680

Tkemaladze, J. (2025). The Epistemological Reconfiguration and Transubstantial Reinterpretation of Eucharistic Practices Established by the Divine Figure of Jesus Christ in Relation to Theological Paradigms. doi: 10.13140/RG.2.2.28347.73769

Tkemaladze, J. (2025). Transforming the psyche with phoneme frequencies "Habere aliam linguam est possidere secundam animam" Charlemagne. doi: 10.13140/RG.2.2.16105.61286

Tkemaladze, J. (2025). Anatomy, Biogenesis, and Role in Cell Biology of Centrioles. Longevity Horizons, 108(2). https://doi.org/10.5281/zenodo.14742232

Tkemaladze, J. (2025). Concept to The Alive Language. Longevity Horizons, 108(1). doi: https://doi.org/10.5281/zenodo.14688792

Tkemaladze, J. (2025). Concept to The Caucasian Bridge. Longevity Horizons, 108(1). doi: https://doi.org/10.5281/zenodo.14689276

Tkemaladze, J. (2025). Concept to The Curing All Diseases. Longevity Horizons, 108(1). https://doi.org/10.5281/zenodo.14676208

Tkemaladze, J. (2025). Concept to The Eternal Youth. Longevity Horizons, 108(1). doi: https://doi.org/10.5281/zenodo.14681902

Tkemaladze, J. (2025). Concept to The Food Security. Longevity Horizons, 108(1). doi: https://doi.org/10.5281/zenodo.14642407

Tkemaladze, J. (2025). Concept to the Living Space. Longevity Horizons, 108(1). doi: https://doi.org/10.5281/zenodo.14635991

Tkemaladze, J. (2025). Concept to The Restoring Dogmas. Longevity Horizons, 108(1). https://doi.org/10.5281/zenodo.14708980

Tkemaladze, J. (2025). Replicative Hayflick Limit. Longevity Horizons, 108(2). https://doi.org/10.5281/zenodo.14752664

Tkemaladze, J. (2025). Solutions to the Living Space Problem to Overcome the Fear of Resurrection from the Dead. doi: 10.13140/RG.2.2.34655.57768

Tkemaladze, J. (2025). The Concept of Data-Driven Automated Governance. Georgian Scientists, 6(4), 399–410. doi: https://doi.org/10.52340/gs.2024.06.04.38

Tkemaladze, J. (2025).Achieving Perpetual Vitality Through Innovation. doi: 10.13140/RG.2.2.31113.35685

Tkemaladze, J. (2025).Systemic Resilience and Sustainable Nutritional Paradigms in Anthropogenic Ecosystems. doi: 10.13140/RG.2.2.18943.32169/1

Tkemaladze, J. V., & Chichinadze, K. N. (2005). Centriolar mechanisms of differentiation and replicative aging of higher animal cells. Biochemistry (Moscow), 70, 1288-1303.

Tkemaladze, J., & Apkhazava, D. (2019). Dasatinib and quercetin: short-term simultaneous administration improves physical capacity in human. J Biomedical Sci, 8(3), 3.

Tkemaladze, J., & Chichinadze, K. (2005). Potential role of centrioles in determining the morphogenetic status of animal somatic cells. Cell biology international, 29(5), 370-374.

Tkemaladze, J., & Chichinadze, K. (2010). Centriole, differentiation, and senescence. Rejuvenation research, 13(2-3), 339-342.

Tkemaladze, J., & Samanishvili, T. (2024). Mineral ice cream improves recovery of muscle functions after exercise. Georgian Scientists, 6(2), 36–50. doi: https://doi.org/10.52340/gs.2024.06.02.04

Tkemaladze, J., Tavartkiladze, A., & Chichinadze, K. (2012). Programming and Implementation of Age-Related Changes. In Senescence. IntechOpen.

Tkemaladze, Jaba and Kipshidze, Mariam, Regeneration Potential of the Schmidtea Mediterranea CIW4 Planarian. Available at SSRN: https://ssrn.com/abstract=4633202 or http://dx.doi.org/10.2139/ssrn.4633202

Toledo-Jacobo, L., Henson, J. H., & Shuster, C. B. (2019). Cytoskeletal polarization and cytokinetic signaling drives polar lobe formation in spiralian embryos. Developmental biology, 456(2), 201-211.

Tozer, S., Baek, C., Fischer, E., Goiame, R., & Morin, X. (2017). Differential routing of Mindbomb1 via centriolar satellites regulates asymmetric divisions of neural progenitors. Neuron, 93(3), 542-551.

Tsankova, A., Pham, T. T., Garcia, D. S., Otte, F., & Cabernard, C. (2017). Cell polarity regulates biased myosin activity and dynamics during asymmetric cell division via Drosophila Rho kinase and protein kinase N. Developmental Cell, 42(2), 143-155.

Van De Rijn, M., Heimfeld, S., Spangrude, G. J., & Weissman, I. L. (1989). Mouse hematopoietic stem-cell antigen Sca-1 is a member of the Ly-6 antigen family. Proceedings of the National Academy of Sciences, 86(12), 4634-4638.

van Leen, E. V., Di Pietro, F., & Bellaïche, Y. (2020). Oriented cell divisions in epithelia: from force generation to force anisotropy by tension, shape and vertices. Current Opinion in Cell Biology, 62, 9-16.

Waddington CH (1957) The Strategy of the Genes: A Discussion of Some Aspects of Theoretical Biology

Walter, P., & Ron, D. (2011). The unfolded protein response: from stress pathway to homeostatic regulation. science, 334(6059), 1081-1086.

Wang, J., Wang, L., Feng, G., Wang, Y., Li, Y., Li, X., ... & Zhou, Q. (2018). Asymmetric expression of LincGET biases cell fate in two-cell mouse embryos. Cell, 175(7), 1887-1901.

Wang, X., Tsai, J. W., Imai, J. H., Lian, W. N., Vallee, R. B., & Shi, S. H. (2009). Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature, 461(7266), 947-955.

Weinmaster, G., & Fischer, J. A. (2011). Notch ligand ubiquitylation: what is it good for?. Developmental cell, 21(1), 134-144.

Wheat, J. C., Sella, Y., Willcockson, M., Skoultchi, A. I., Bergman, A., Singer, R. H., & Steidl, U. (2020). Single-molecule imaging of transcription dynamics in somatic stem cells. Nature, 583(7816), 431–436. https://doi.org/10.1038/s41586-020-2432-4

Winkley, K., Ward, S., Reeves, W., & Veeman, M. (2019). Iterative and complex asymmetric divisions control cell volume differences in Ciona notochord tapering. Current Biology, 29(20), 3466-3477.

Wooten, M., Ranjan, R., & Chen, X. (2020). Asymmetric histone inheritance in asymmetrically dividing stem cells. Trends in Genetics, 36(1), 30-43.

Wooten, M., Snedeker, J., Nizami, Z. F., Yang, X., Ranjan, R., Urban, E., ... & Chen, X. (2019). Asymmetric histone inheritance via strand-specific incorporation and biased replication fork movement. Nature structural & molecular biology, 26(8), 732-743.

Xie, J., Wooten, M., Tran, V., Chen, B. C., Pozmanter, C., Simbolon, C., ... & Chen, X. (2015). Histone H3 threonine phosphorylation regulates asymmetric histone inheritance in the Drosophila male germline. Cell, 163(4), 920-933.

Yamashita, Y. M., Mahowald, A. P., Perlin, J. R., & Fuller, M. T. (2007). Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science, 315(5811), 518-521.

Yu, F., Morin, X., Cai, Y., Yang, X., & Chia, W. (2000). Analysis of partner of inscuteable, a novel player of Drosophila asymmetric divisions, reveals two distinct steps in inscuteable apical localization. Cell, 100(4), 399-409.

Zhang, F., Huang, Z. X., Bao, H., Cong, F., Wang, H., Chai, P. C., ... & Yang, X. (2016). Phosphotyrosyl phosphatase activator facilitates localization of Miranda through dephosphorylation in dividing neuroblasts. Development, 143(1), 35-44.

Zhou, C., Slaughter, B. D., Unruh, J. R., Guo, F., Yu, Z., Mickey, K., ... & Li, R. (2014). Organelle-based aggregation and retention of damaged proteins in asymmetrically dividing cells. Cell, 159(3), 530-542.

Прангишвили, А. И., Гаситашвили, З. А., Мацаберидзе, М. И., Чичинадзе, К. Н., Ткемаладзе, Д. В., & Азмайпарашвили, З. А. (2017). К топологии антитеррористических и антикриминальных технологии для образовательных программ. В научном издании представлены материалы Десятой международной научно-технической конфе-ренции «Управление развитием крупномасштабных систем (MLSD’2016)» по следующим направле-ниям:• Проблемы управления развитием крупномасштабных систем, включая ТНК, Госхолдин-ги и Гос-корпорации., 284.

Прангишвили, А. И., Гаситашвили, З. А., Мацаберидзе, М. И., Чхартишвили, Л. С., Чичинадзе, К. Н., & Ткемаладзе, Д. В. (2017). & Азмайпарашвили, ЗА (2017). Системные составляющие здравоохранения и инноваций для организации европейской нано-биомедицинской екосистемной технологической платформы. Управление развитием крупномасштабных систем MLSD, 365-368.

Ткемаладзе, Д. (2025). Анатомия, биогенез и роль в клеточной биологии центриолей. doi: 10.13140/RG.2.2.27441.70245

Ткемаладзе, Д. (2025). Репликативный Лимит Хейфлика. doi: 10.13140/RG.2.2.25803.30249

Ткемаладзе, Д. В., & Чичинадзе, К. Н. (2005). Центриолярные механизмы дифференцировки и репликативного старения клеток высших животных. Биохимия, 70(11), 1566-1584.

Ткемаладзе, Д., Цомаиа, Г., & Жоржолиани, И. (2001). Создание искусственных самоадаптирующихся систем на основе Теории Прогноза. Искусственный интеллект. УДК 004.89. Искусственный интеллект. УДК 004.89.

Чичинадзе, К. Н., & Ткемаладзе, Д. В. (2008). Центросомная гипотеза клеточного старения и дифференциации. Успехи геронтологии, 21(3), 367-371.

Чичинадзе, К., Ткемаладзе, Д., & Лазарашвили, А. (2012). НОВЫЙ КЛАСС РНК И ЦЕНТРОСОМНАЯ ГИПОТЕЗА СТАРЕНИЯ КЛЕТОК. Успехи геронтологии, 25(1), 23-28.