Production of Functional Gametes from Somatic Cells of the Planarian Schmidtea Mediterranea Via in Vitro Gametogenesis

Article Sidebar

PDF
Published: 2025-09-16
DOI: https://doi.org/10.5281/zenodo.17131291
Keywords:
In Vitro Gametogenesis, IVG, Planarian, Schmidtea Mediterranea, Direct Reprogramming, Germ Cell, Transdifferentiation, Somatic Cell, Reprogramming

Main Article Content

Jaba Tkemaladze
Longevity Clinic
https://orcid.org/0000-0001-8651-7243
Gabro Gakely
Longevity Clinic
Laura Gegelia
Longevity Clinic
Iason Papadopulo
Longevity Clinic
Alexander Taktakidze
Longevity Clinic
Nino Metreveli
Longevity Clinic
Natia Berozashvili
Longevity Clinic
Natalia Bondarenko
Longevity Clinic
Ucha Maglakelidze
Longevity Clinic

Abstract

This study establishes a novel and robust protocol for the direct reprogramming of differentiated somatic cells into functional gamete precursors in the planarian Schmidtea mediterranea, bypassing the need for a pluripotent intermediate state. Through an optimized two-phase in vitro gametogenesis (IVG) protocol involving transient low-dose Yamanaka factor exposure followed by a defined germline-commitment cocktail, we successfully redirected cell fate. Molecular analyses confirmed a stepwise transcriptional and epigenetic reprogramming towards a germline identity, marked by the activation of conserved markers (vasa, nanos, sycp1/3) and global DNA demethylation. While in vitro-derived cells (gametocytes) displayed characteristic oocyte-like and spermatid-like morphologies and ultrastructures, full terminal maturation required in vivo transplantation. Crucially, these IVG-derived gametocytes demonstrated full functionality: upon injection into sterilized recipients, they migrated to gonads, completed maturation, and produced viable, genetically donor-derived offspring. This work provides a powerful platform for studying germ cell development and represents a significant proof-of-concept for somatic cell-to-gamete conversion.

Article Details

Issue

Vol. 1 No. 3 (2025)

Section

Research Article
Creative Commons License

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

Articles published in Longevity Horizon 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 Biographies

Jaba Tkemaladze, Longevity Clinic

A physician-scientist specializing in the biology of ageing and longevity. His research focuses on the potential of stem cell therapies for age-related diseases and healthspan extension.

Current Roles:

  • President, Longevity Alliance Georgia.
  • Head of Department, Longevity Clinic, Inc., Georgia.

Research Focus:
His primary research involves exploring methodologies for cellular rejuvenation, specifically the potential application of induced pluripotent stem (iPS) cell technology to regenerate aged tissues. His theoretical work includes the development of the Centriolar Theory of Differentiation and the Centriolar Theory of Organismal Ageing, which propose a role for the centriole in cellular ageing and development.

Background:
Dr. Tkemaladze trained in medicine at Tbilisi State Medical University and pursued further research in the laboratory of the Institute of Morphology at the Psychiatry Research Institute. His work employs a combined approach of experimental and computational methods to study the ageing process and develop interventions for age-related diseases.

Service and Recognition:
He has served on scientific advisory boards, including for the Georgian Ministry of Defense and the Longevity Alliance. He is the author of over 100 scientific publications and has been an invited speaker at numerous national and international conferences.

Gabro Gakely, Longevity Clinic

Research and Development Division, Longevity Clinic, Inc, Georgia

Laura Gegelia, Longevity Clinic

Research and Development Division, Longevity Clinic, Inc, Georgia

Iason Papadopulo, Longevity Clinic

Research and Development Division, Longevity Clinic, Inc, Georgia

Alexander Taktakidze, Longevity Clinic

Research and Development Division, Longevity Clinic, Inc, Georgia

Nino Metreveli, Longevity Clinic

Research and Development Division, Longevity Clinic, Inc, Georgia

Natia Berozashvili, Longevity Clinic

Research and Development Division, Longevity Clinic, Inc, Georgia

Natalia Bondarenko, Longevity Clinic

Research and Development Division, Longevity Clinic, Inc, Georgia

Ucha Maglakelidze, Longevity Clinic

Research and Development Division, Longevity Clinic, Inc, Georgia

How to Cite

Tkemaladze, J., Gakely, G., Gegelia, L., Papadopulo, I., Taktakidze, A., Metreveli, N., Berozashvili, N., Bondarenko, N., & Maglakelidze, U. (2025). Production of Functional Gametes from Somatic Cells of the Planarian Schmidtea Mediterranea Via in Vitro Gametogenesis. Longevity Horizon, 1(3). DOI:https://doi.org/10.5281/zenodo.17131291
Crossref
Scopus
Google Scholar
Europe PMC

References

Abbott, A. L., & Ducibella, T. (2001). Calcium and the control of mammalian cortical granule exocytosis. Frontiers in Bioscience, 6, D792–D806. https://doi.org/10.2741/abbott

Aphkhazava, D., Sulashvili, N., & Tkemaladze, J. (2025). Stem Cell Systems and Regeneration. Georgian Scientists, 7(1), 271–319. doi: https://doi.org/10.52340/gs.2025.07.01.26

Aphkhazava, D., Sulashvili, N., Maglakelidze, G., & Tkemaladze, J. (2025). Ageless Creatures: Molecular Insights into Organisms That Defy Aging. Georgian Scientists, 7(3), 346–396. doi: https://doi.org/10.52340/gs.2025.07.03.24

Bolcun-Filas, E., & Schimenti, J. C. (2012). Genetics of meiosis and recombination in mice. International Review of Cell and Molecular Biology, 298, 179–227. https://doi.org/10.1016/B978-0-12-394309-8.00005-5

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.

Chong, T., Stary, J. M., & Newmark, P. A. (2013). Molecular markers to characterize the hermaphroditic reproductive system of the planarian Schmidtea mediterranea. BMC Developmental Biology, 13, 2. https://doi.org/10.1186/1471-213X-13-2

Chong, T., Stary, J. M., & Newmark, P. A. (2013). Molecular markers to characterize the hermaphroditic reproductive system of the planarian Schmidtea mediterranea. BMC Developmental Biology, 13, 2. https://doi.org/10.1186/1471-213X-13-2

Chong, T., Stary, J. M., & Newmark, P. A. (2013). Molecular markers to characterize the hermaphroditic reproductive system of the planarian Schmidtea mediterranea. BMC Developmental Biology, 13, 2. https://doi.org/10.1186/1471-213X-13-2

Clark, J. M., & Eddy, E. M. (1975). Fine structural observations on the origin and associations of primordial germ cells of the mouse. Developmental Biology, 47(1), 136–155. https://doi.org/10.1016/0012-1606(75)90263-8

Clevers, H. (2016). Modeling Development and Disease with Organoids. Cell, 165(7), 1586–1597. https://doi.org/10.1016/j.cell.2016.05.082

Comizzoli, P., & Holt, W. V. (2019). Breakthroughs and new horizons in reproductive biology of rare and endangered animal species. Biology of Reproduction, 101(3), 514–525. https://doi.org/10.1093/biolre/ioz031

Comizzoli, P., & Holt, W. V. (2019). Breakthroughs and new horizons in reproductive biology of rare and endangered animal species. Biology of Reproduction, 101(3), 514–525. https://doi.org/10.1093/biolre/ioz031

Comizzoli, P., & Holt, W. V. (2019). Breakthroughs and new horizons in reproductive biology of rare and endangered animal species. Biology of Reproduction, 101(3), 514–525. https://doi.org/10.1093/biolre/ioz031

Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013). STAR: ultrafast universal RNA-seq aligner. Bioinformatics, 29(1), 15–21. https://doi.org/10.1093/bioinformatics/bts635

Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013). STAR: ultrafast universal RNA-seq aligner. Bioinformatics, 29(1), 15–21. https://doi.org/10.1093/bioinformatics/bts635

El Elfettahi, A., & Tkemaladze, J. (2025). The Neuro-Hepatic-Affective Model (NHAM): A Systems Framework for Liver–Brain Modulation of Emotion in Precision Psychiatry. doi: https://doi.org/10.20944/preprints202508.1312.v1

Elkouby, Y. M., & Mullins, M. C. (2017). Coordination of cellular differentiation, polarity, mitosis and meiosis - New findings from early vertebrate oogenesis. Developmental Biology, 430(2), 275–287. https://doi.org/10.1016/j.ydbio.2017.06.029

Elkouby, Y. M., & Mullins, M. C. (2017). Coordination of cellular differentiation, polarity, mitosis and meiosis - New findings from early vertebrate oogenesis. Developmental Biology, 430(2), 275–287. https://doi.org/10.1016/j.ydbio.2017.06.029

Extavour, C. G. (2020). The Evolution of the Germline. In Current Topics in Developmental Biology (Vol. 140, pp. 1-35). Academic Press. https://doi.org/10.1016/bs.ctdb.2020.04.002

Fincher, C. T., Wurtzel, O., de Hoog, T., Kravarik, K. M., & Reddien, P. W. (2018). Cell type transcriptome atlas for the planarian Schmidtea mediterranea. Science, 360(6391), eaaq1736. https://doi.org/10.1126/science.aaq1736

Forsthoefel, D. J., Park, A. E., & Newmark, P. A. (2011). Stem cell-based growth, regeneration, and remodeling of the planarian intestine. Developmental Biology, 356(2), 445–459. https://doi.org/10.1016/j.ydbio.2011.05.669

Forsthoefel, D. J., Park, A. E., & Newmark, P. A. (2011). Stem cell-based growth, regeneration, and remodeling of the planarian intestine. Developmental Biology, 356(2), 445–459. https://doi.org/10.1016/j.ydbio.2011.05.669

Forsthoefel, D. J., Park, A. E., & Newmark, P. A. (2011). Stem cell-based growth, regeneration, and remodeling of the planarian intestine. Developmental Biology, 356(2), 445–459. https://doi.org/10.1016/j.ydbio.2011.05.669

Greenberg, M. V. C., & Bourc'his, D. (2019). The diverse roles of DNA methylation in mammalian development and disease. Nature Reviews Molecular Cell Biology, 20(10), 590–607. https://doi.org/10.1038/s41580-019-0159-6

Griswold, M. D. (2016). Spermatogenesis: The Commitment to Meiosis. Physiological Reviews, 96(1), 1–17. https://doi.org/10.1152/physrev.00013.2015

Gurdon, J. B., & Melton, D. A. (2008). Nuclear reprogramming in cells. Science, 322(5909), 1811–1815. https://doi.org/10.1126/science.1160810

Hayashi, T., Asami, M., Higuchi, S., Shibata, N., & Agata, K. (2006). Isolation of planarian X-ray-sensitive stem cells by fluorescence-activated cell sorting. Development, Growth & Differentiation, 48(6), 371–380. https://doi.org/10.1111/j.1440-169X.2006.00876.x

Hayashi, T., Asami, M., Higuchi, S., Shibata, N., & Agata, K. (2006). Isolation of planarian X-ray-sensitive stem cells by fluorescence-activated cell sorting. Development, Growth & Differentiation, 48(6), 371–380. https://doi.org/10.1111/j.1440-169X.2006.00876.x

Hikabe, O., Hamazaki, N., Nagamatsu, G., Obata, Y., Hirao, Y., Hamada, N., ... & Saitou, M. (2016). Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature, 539(7628), 299–303. https://doi.org/10.1038/nature20104

Hikabe, O., Hamazaki, N., Nagamatsu, G., Obata, Y., Hirao, Y., Hamada, N., ... & Saitou, M. (2016). Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature, 539(7628), 299–303. https://doi.org/10.1038/nature20104

Hikabe, O., Hamazaki, N., Nagamatsu, G., Obata, Y., Hirao, Y., Hamada, N., ... & Saitou, M. (2016). Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature, 539(7628), 299–303. https://doi.org/10.1038/nature20104

Inaba, K. (2011). Sperm flagella: comparative and phylogenetic perspectives of protein components. Molecular Human Reproduction, 17(8), 524–538. https://doi.org/10.1093/molehr/gar034

Ishii, T. (2018). Reproductive medicine and in vitro gametogenesis: A paradigm shift in the context of ethical issues. Reproductive Medicine and Biology, 17(2), 124–128. https://doi.org/10.1002/rmb2.12083

Issigonis, M., Qin, P., Garzia, A., Sharma, P. P., Mehta, B., Khan, U., ... & Newmark, P. A. (2022). A kinase of the germinal center kinase (GCK) family is essential for gametogenesis in the planarian Schmidtea mediterranea. Proceedings of the National Academy of Sciences, 119(10), e2115005119. https://doi.org/10.1073/pnas.2115005119

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.

Juliano, C. E., Swartz, S. Z., & Wessel, G. M. (2010). A conserved germline multipotency program. Development, 137(24), 4113–4126. https://doi.org/10.1242/dev.047969

Juliano, C. E., Swartz, S. Z., & Wessel, G. M. (2010). A conserved germline multipotency program. Development, 137(24), 4113–4126. https://doi.org/10.1242/dev.047969

Kim, Y., Jeong, J., & Choi, D. (2021). Small-molecule-mediated reprogramming: a silver lining for regenerative medicine. Experimental & Molecular Medicine, 52(2), 213-226. https://doi.org/10.1038/s12276-020-00538-y

Kim, Y., Jeong, J., & Choi, D. (2021). Small-molecule-mediated reprogramming: a silver lining for regenerative medicine. Experimental & Molecular Medicine, 52(2), 213-226. https://doi.org/10.1038/s12276-020-00538-y

Kim, Y., Jeong, J., & Choi, D. (2021). Small-molecule-mediated reprogramming: a silver lining for regenerative medicine. Experimental & Molecular Medicine, 52(2), 213-226. https://doi.org/10.1038/s12276-020-00538-y

Kim, Y., Jeong, J., & Choi, D. (2021). Small-molecule-mediated reprogramming: a silver lining for regenerative medicine. Experimental & Molecular Medicine, 52(2), 213-226. https://doi.org/10.1038/s12276-020-00538-y

Kim, Y., Jeong, J., & Choi, D. (2021). Small-molecule-mediated reprogramming: a silver lining for regenerative medicine. Experimental & Molecular Medicine, 52(2), 213-226. https://doi.org/10.1038/s12276-020-00538-y

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

Lawson, K. A., Dunn, N. R., Roelen, B. A., Zeinstra, L. M., Davis, A. M., Wright, C. V., ... & Hogan, B. L. (1999). Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes & Development, 13(4), 424–436. https://doi.org/10.1101/gad.13.4.424

Lei, L., & Spradling, A. C. (2016). Mouse oocytes differentiate through organelle enrichment from sister cyst germ cells. Science, 352(6281), 95–99. https://doi.org/10.1126/science.aad2156

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

Love, M. I., Huber, W., & Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biology, 15(12), 550. https://doi.org/10.1186/s13059-014-0550-8

Love, M. I., Huber, W., & Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biology, 15(12), 550. https://doi.org/10.1186/s13059-014-0550-8

Ma, H., Li, Y., & Yi, P. (2019). In vitro gametogenesis: A new route to reproductive medicine. Reproductive and Developmental Medicine, 3(3), 129-135. https://doi.org/10.4103/2096-2924.268153

Ma, H., Li, Y., & Yi, P. (2019). In vitro gametogenesis: A new route to reproductive medicine. Reproductive and Developmental Medicine, 3(3), 129-135. https://doi.org/10.4103/2096-2924.268153

Ma, H., Li, Y., & Yi, P. (2019). In vitro gametogenesis: A new route to reproductive medicine. Reproductive and Developmental Medicine, 3(3), 129-135. https://doi.org/10.4103/2096-2924.268153

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.

Miller, C. M., & Newmark, P. A. (2005). An insulin-like peptide regulates size and adult stem cells in planarians. The International Journal of Developmental Biology, 56(5), 375-382. https://doi.org/10.1387/ijdb.113443cm

Miller, C. M., & Newmark, P. A. (2005). An insulin-like peptide regulates size and adult stem cells in planarians. The International Journal of Developmental Biology, 56(5), 375-382. https://doi.org/10.1387/ijdb.113443cm

Molyneaux, K. A., & Wylie, C. (2004). Primordial germ cell migration. The International Journal of Developmental Biology, 48(5-6), 537–544. https://doi.org/10.1387/ijdb.041833km

Newmark, P. A., Wang, Y., & Chong, T. (2008). Germ cell development and regeneration in planarians. Cold Spring Harbor Symposia on Quantitative Biology, 73, 573–581. https://doi.org/10.1101/sqb.2008.73.022

Ohnishi, K., Semi, K., Yamamoto, T., Shimizu, M., Tanaka, A., Mitsunaga, K., ... & Yamada, Y. (2014). Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell, 156(4), 663–677. https://doi.org/10.1016/j.cell.2014.01.005

Piprek, R. P., Kloc, M., & Kubiak, J. Z. (2018). The Role of Cell Adhesion and Cell Compaction in the Formation of the Mouse Blastocyst. In Cell Adhesion and Migration in the Regulation of Embryogenesis (pp. 1-18). Springer, Cham. https://doi.org/10.1007/978-3-319-92486-1_1

Plass, M., Solana, J., Wolf, F. A., Ayoub, S., Misios, A., Glažar, P., ... & Rajewsky, N. (2018). Cell type atlas and lineage tree of a whole complex animal by single-cell transcriptomics. Science, 360(6391), eaaq1723. https://doi.org/10.1126/science.aaq1723

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.

Reddien, P. W. (2018). The cellular and molecular basis for planarian regeneration. Cell, 175(2), 327–345. https://doi.org/10.1016/j.cell.2018.09.021

Richardson, B. E., & Lehmann, R. (2010). Mechanisms guiding primordial germ cell migration: strategies from different organisms. Nature Reviews Molecular Cell Biology, 11(1), 37–49. https://doi.org/10.1038/nrm2815

Richardson, B. E., & Lehmann, R. (2010). Mechanisms guiding primordial germ cell migration: strategies from different organisms. Nature Reviews Molecular Cell Biology, 11(1), 37–49. https://doi.org/10.1038/nrm2815

Roberts-Galbraith, R. H., & Newmark, P. A. (2013). Follistatin antagonizes activin signaling and acts with notum to direct planarian head regeneration. Proceedings of the National Academy of Sciences of the United States of America, 110(4), 1363–1368. https://doi.org/10.1073/pnas.1214053110

Roberts-Galbraith, R. H., & Newmark, P. A. (2013). Follistatin antagonizes activin signaling and acts with notum to direct planarian head regeneration. Proceedings of the National Academy of Sciences of the United States of America, 110(4), 1363–1368. https://doi.org/10.1073/pnas.1214053110

Roberts-Galbraith, R. H., & Newmark, P. A. (2013). Follistatin antagonizes activin signaling and acts with notum to direct planarian head regeneration. Proceedings of the National Academy of Sciences of the United States of America, 110(4), 1363–1368. https://doi.org/10.1073/pnas.1214053110

Rouhana, L. (2020). Planarians as a model to study the molecular mechanisms of stem cell evolution. Molecular Reproduction and Development, 87(3), 323–335. https://doi.org/10.1002/mrd.23331

Rouhana, L., & Weiss, J. A. (2021). Germ cell development and sexual reprogramming in planarians. Current Topics in Developmental Biology, 144, 139–172. https://doi.org/10.1016/bs.ctdb.2020.12.009

Rouhana, L., Vieira, A. P., Roberts-Galbraith, R. H., & Newmark, P. A. (2013). PRMT5 and the role of symmetrical dimethylarginine in chromatoid bodies of planarian stem cells. Development, 139(6), 1083–1094. https://doi.org/10.1242/dev.083162

Rouhana, L., Vieira, A. P., Roberts-Galbraith, R. H., & Newmark, P. A. (2013). PRMT5 and the role of symmetrical dimethylarginine in chromatoid bodies of planarian stem cells. Development, 139(6), 1083–1094. https://doi.org/10.1242/dev.083162

Saitou, M., & Miyauchi, H. (2016). Gametogenesis from pluripotent stem cells. Cell Stem Cell, 18(6), 721–735. https://doi.org/10.1016/j.stem.2016.05.001

Saitou, M., & Miyauchi, H. (2016). Gametogenesis from pluripotent stem cells. Cell Stem Cell, 18(6), 721–735. https://doi.org/10.1016/j.stem.2016.05.001

Saitou, M., & Yamaji, M. (2012). Primordial germ cells in mice. Cold Spring Harbor Perspectives in Biology, 4(11), a008375. https://doi.org/10.1101/cshperspect.a008375

Scimone, M. L., Kravarik, K. M., Lapan, S. W., & Reddien, P. W. (2014). Neoblast specialization in regeneration of the planarian Schmidtea mediterranea. Stem Cell Reports, 3(2), 339–352. https://doi.org/10.1016/j.stemcr.2014.06.001

Seisenberger, S., Andrews, S., Krueger, F., Arand, J., Walter, J., Santos, F., ... & Reik, W. (2012). The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Molecular Cell, 48(6), 849–862. https://doi.org/10.1016/j.molcel.2012.11.001

Seisenberger, S., Andrews, S., Krueger, F., Arand, J., Walter, J., Santos, F., ... & Reik, W. (2012). The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Molecular Cell, 48(6), 849–862. https://doi.org/10.1016/j.molcel.2012.11.001

Shim, Y. H. (2013). Metabolism in embryonic and cancer stemness. Archives of Pharmacal Research, 36(1), 123-135. https://doi.org/10.1007/s12272-013-0006-9

Shioda, T. (2019). In vitro gametogenesis from embryonic stem cells in mammals. Reproductive Medicine and Biology, 18(3), 225–233. https://doi.org/10.1002/rmb2.12271

Soyal, S. M., Amleh, A., & Dean, J. (2000). FIGalpha, a germ cell-specific transcription factor required for ovarian follicle formation. Development, 127(21), 4645–4654. https://doi.org/10.1242/dev.127.21.4645

Spradling, A., Drummond-Barbosa, D., & Kai, T. (2001). Stem cells find their niche. Nature, 414(6859), 98–104. https://doi.org/10.1038/35102160

Sutovsky, P. (2009). Sperm-egg adhesion and fusion in mammals. Expert Reviews in Molecular Medicine, 11, e11. https://doi.org/10.1017/S1462399409001035

Takahashi, K., & Yamanaka, S. (2016). A decade of transcription factor-mediated reprogramming to pluripotency. Nature Reviews Molecular Cell Biology, 17(3), 183–193. https://doi.org/10.1038/nrm.2016.8

Tasaki, J., Shibata, N., & Agata, K. (2011). Role of c-Jun N-terminal kinase activation in blastema formation during planarian regeneration. Development, Growth & Differentiation, 53(3), 389–400. https://doi.org/10.1111/j.1440-169X.2011.01255.x

Tasaki, J., Shibata, N., & Agata, K. (2011). Role of c-Jun N-terminal kinase activation in blastema formation during planarian regeneration. Development, Growth & Differentiation, 53(3), 389–400. https://doi.org/10.1111/j.1440-169X.2011.01255.x

Tasaki, J., Shibata, N., & Agata, K. (2011). Role of c-Jun N-terminal kinase activation in blastema formation during planarian regeneration. Development, Growth & Differentiation, 53(3), 389–400. https://doi.org/10.1111/j.1440-169X.2011.01255.x

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). 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. (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: http://dx.doi.org/10.13140/RG.2.2.24481.11366

Tkemaladze, J. (2025). Adaptive Systems and World Models. doi: http://dx.doi.org/10.13140/RG.2.2.13617.90720

Tkemaladze, J. (2025). Aging Model - Drosophila Melanogaster. doi: http://dx.doi.org/10.13140/RG.2.2.16706.49607

Tkemaladze, J. (2025). Allotransplantation Between Adult Drosophila of Different Ages and Sexes. doi: http://dx.doi.org/10.13140/RG.2.2.27711.62884

Tkemaladze, J. (2025). Anti-Blastomic Substances in the Blood Plasma of Schizophrenia Patients. doi: http://dx.doi.org/10.13140/RG.2.2.12721.08807

Tkemaladze, J. (2025). Centriole Elimination as a Mechanism for Restoring Cellular Order. doi: http://dx.doi.org/10.13140/RG.2.2.12890.66248/1

Tkemaladze, J. (2025). Hypotheses on the Role of Centrioles in Aging Processes. doi: http://dx.doi.org/10.13140/RG.2.2.15014.02887/1

Tkemaladze, J. (2025). Limits of Cellular Division: The Hayflick Phenomenon. doi: http://dx.doi.org/10.13140/RG.2.2.25803.30249

Tkemaladze, J. (2025). Molecular Mechanisms of Aging and Modern Life Extension Strategies: From Antiquity to Mars Colonization. doi: http://dx.doi.org/10.13140/RG.2.2.13208.51204

Tkemaladze, J. (2025). Pathways of Somatic Cell Specialization in Multicellular Organisms. doi: http://dx.doi.org/10.13140/RG.2.2.23348.97929/1

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

Tkemaladze, J. (2025). Structure, Formation, and Functional Significance of Centrioles in Cellular Biology. doi: http://dx.doi.org/10.13140/RG.2.2.27441.70245/1

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: http://dx.doi.org/10.13140/RG.2.2.28347.73769/1

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

Tkemaladze, J. (2025). Uneven Centrosome Inheritance and Its Impact on Cell Fate. doi: http://dx.doi.org/10.13140/RG.2.2.34917.31206

Tkemaladze, J. (2025). Ze World Model with Predicate Actualization and Filtering. doi: http://dx.doi.org/10.13140/RG.2.2.15218.62407

Tkemaladze, J. (2025). Ze метод создания пластичного счетчика хронотропных частот чисел бесконечного потока информации. doi: http://dx.doi.org/10.13140/RG.2.2.29162.43207

Tkemaladze, J. (2025). A Novel Integrated Bioprocessing Strategy for the Manufacturing of Shelf-Stable, Nutritionally Upgraded Activated Wheat: Development of a Comprehensive Protocol, In-Depth Nutritional Characterization, and Evaluation of Biofunctional Properties. Longevity Horizon, 1(3). DOI:https://doi.org/10.5281/zenodo.16950787

Tkemaladze, J. (2025). Activated Wheat: The Power of Super Grains. Preprints. doi: https://doi.org/10.20944/preprints202508.1724.v1

Tkemaladze, J. (2025). Adaptive Cognitive System Ze. Longevity Horizon, 1(3). doi: https://doi.org/10.5281/zenodo.15309162

Tkemaladze, J. (2025). Aging Model Based on Drosophila melanogaster: Mechanisms and Perspectives. Longevity Horizon, 1(3). doi: https://doi.org/10.5281/zenodo.14955643

Tkemaladze, J. (2025). Anatomy, Biogenesis, and Role in Cell Biology of Centrioles. Longevity Horizon, 1(2). doi: https://doi.org/10.5281/zenodo.14742232

Tkemaladze, J. (2025). Anti-Blastomic Substances in the Plasma of Schizophrenia Patients: A Dual Role of Complement C4 in Synaptic Pruning and Tumor Suppression. Longevity Horizon, 1(3). doi : https://doi.org/10.5281/zenodo.15042448

Tkemaladze, J. (2025). Asymmetry in the Inheritance of Centrosomes / Centrioles and Its Consequences. Longevity Horizon, 1(2). doi: https://doi.org/10.5281/zenodo.14837352

Tkemaladze, J. (2025). Centriole Elimination: A Mechanism for Resetting Entropy in the Cell. Longevity Horizon, 1(2). doi: https://doi.org/10.5281/zenodo.14876013

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

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

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

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

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

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

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

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

Tkemaladze, J. (2025). Direct Reprogramming of Somatic Cells to Functional Gametes in Planarians via a Novel In Vitro Gametogenesis Protocol. Preprints. doi:https://doi.org/10.20944/preprints202509.1071.v1

Tkemaladze, J. (2025). Induction of germline-like cells (PGCLCs). Longevity Horizon, 1(3). doi: https://doi.org/10.5281/zenodo.16414775

Tkemaladze, J. (2025). Long-Lived Non-Renewable Structures in the Human Body. doi: http://dx.doi.org/10.13140/RG.2.2.14826.43206

Tkemaladze, J. (2025). Mechanisms of Learning Through the Actualization of Discrepancies. Longevity Horizon, 1(3). doi : https://doi.org/10.5281/zenodo.15200612

Tkemaladze, J. (2025). Memorizing an Infinite Stream of Information in a Limited Memory Space: The Ze Method of a Plastic Counter of Chronotropic Number Frequencies. Longevity Horizon, 1(3). doi : https://doi.org/10.5281/zenodo.15170931

Tkemaladze, J. (2025). Memorizing an Infinite Stream of Information in a Limited.

Tkemaladze, J. (2025). Molecular Insights and Radical Longevity from Ancient Elixirs to Mars Colonies. Longevity Horizon, 1(2). doi: https://doi.org/10.5281/zenodo.14895222

Tkemaladze, J. (2025). Ontogenetic Permanence of Non-Renewable Biomechanical Configurations in Homo Sapiens Anatomy. Longevity Horizon, 1(3). doi : https://doi.org/10.5281/zenodo.15086387

Tkemaladze, J. (2025). Protocol for Transplantation of Healthy Cells Between Adult Drosophila of Different Ages and Sexes. Longevity Horizon, 1(2). doi: https://doi.org/10.5281/zenodo.14889948

Tkemaladze, J. (2025). Replicative Hayflick Limit. Longevity Horizon, 1(2). doi: 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: http://dx.doi.org/10.13140/RG.2.2.34655.57768

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

Tkemaladze, J. (2025). The Centriolar Theory of Differentiation Explains the Biological Meaning of the.

Tkemaladze, J. (2025). The Centriole Paradox in Planarian Biology: Why Acentriolar Stem Cells Divide and Centriolar Somatic Cells Do Not. doi: https://doi.org/10.20944/preprints202509.0382.v1

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). The Stage of Differentiation Into Mature Gametes During Gametogenesis in Vitro. Longevity Horizon, 1(3). doi: https://doi.org/10.5281/zenodo.16808827

Tkemaladze, J. (2025). The Tkemaladze Method: A Modernized Caucasian Technology for the Production of Shelf-Stable Activated Wheat with Enhanced Nutritional Properties. Longevity Horizon, 1(3). doi: https://doi.org/10.5281/zenodo.16905079

Tkemaladze, J. (2025). Through In Vitro Gametogenesis — Young Stem Cells. Longevity Horizon, 1(3). doi:https://doi.org/10.5281/zenodo.15847116

Tkemaladze, J. (2025). Unlocking the Voynich Cipher via the New Algorithmic Coding Hypothesis. Longevity Horizon, 1(3). doi: https://doi.org/10.5281/zenodo.17054312

Tkemaladze, J. (2025). Voynich Manuscript Decryption: A Novel Compression-Based Hypothesis and Computational Framework. doi: https://doi.org/10.20944/preprints202509.0403.v1

Tkemaladze, J. (2025). Why do planarian cells without centrioles divide and cells with centrioles do not divide?. Longevity Horizon, 1(3). doi: https://doi.org/10.5281/zenodo.17054142

Tkemaladze, J. (2025). Гаметогенез In Vitro: современное состояние, технологии и перспективы применения. Research Gate. http://dx.doi.org/10.13140/RG.2.2.28647.36000

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

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., & Gakely, G. (2025). A Novel Biotechnological Approach for the Production of Shelf-Stable, Nutritionally Enhanced Activated Wheat: Protocol Development, Nutritional Profiling, and Bioactivity Assessment. doi: https://doi.org/10.20944/preprints202508.1997.v1

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

Vogt, E. J. (2018). Tudor domain proteins in development. Development, 145(15), dev158865. https://doi.org/10.1242/dev.158865

Voog, J., & Jones, D. L. (2010). Stem cells and the niche: a dynamic duo. Cell Stem Cell, 6(2), 103–115. https://doi.org/10.1016/j.stem.2010.01.011

Voronina, E., López, M., Juliano, C. E., & King, N. (2011). The conserved RNA-binding protein NANOS is required for germ cell development. Developmental Biology, 355(2), 432–433. https://doi.org/10.1016/j.ydbio.2011.04.036

Voronina, E., López, M., Juliano, C. E., & King, N. (2011). The conserved RNA-binding protein NANOS is required for germ cell development. Developmental Biology, 355(2), 432–433. https://doi.org/10.1016/j.ydbio.2011.04.036

Voronina, E., López, M., Juliano, C. E., & King, N. (2011). The conserved RNA-binding protein NANOS is required for germ cell development. Developmental Biology, 355(2), 432–433. https://doi.org/10.1016/j.ydbio.2011.04.036

Wagner, D. E., Wang, I. E., & Reddien, P. W. (2011). Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration. Science, 332(6031), 811–816. https://doi.org/10.1126/science.1203983

Wang, Y., Stary, J. M., & Newmark, P. A. (2010). A functional genomic screen in planarians identifies novel regulators of germ cell development. Genes & Development, 24(18), 2081–2092. https://doi.org/10.1101/gad.1951010

Wang, Y., Stary, J. M., & Newmark, P. A. (2010). A functional genomic screen in planarians identifies novel regulators of germ cell development. Genes & Development, 24(18), 2081–2092. https://doi.org/10.1101/gad.1951010

Wang, Y., Stary, J. M., & Newmark, P. A. (2010). A functional genomic screen in planarians identifies novel regulators of germ cell development. Genes & Development, 24(18), 2081–2092. https://doi.org/10.1101/gad.1951010

Wang, Y., Stary, J. M., & Newmark, P. A. (2010). A functional genomic screen in planarians identifies novel regulators of germ cell development. Genes & Development, 24(18), 2081–2092. https://doi.org/10.1101/gad.1951010

Wang, Y., Stary, J. M., & Newmark, P. A. (2010). A functional genomic screen in planarians identifies novel regulators of germ cell development. Genes & Development, 24(18), 2081–2092. https://doi.org/10.1101/gad.1951010

Wang, Y., Zayas, R. M., Guo, T., & Newmark, P. A. (2007). nanos function is essential for development and regeneration of planarian germ cells. Proceedings of the National Academy of Sciences of the United States of America, 104(14), 5901–5906. https://doi.org/10.1073/pnas.0609708104

Yu, G., Wang, L. G., Han, Y., & He, Q. Y. (2012). clusterProfiler: an R package for comparing biological themes among gene clusters. Omics : a journal of integrative biology, 16(5), 284–287. https://doi.org/10.1089/omi.2011.0118

Yu, G., Wang, L. G., Han, Y., & He, Q. Y. (2012). clusterProfiler: an R package for comparing biological themes among gene clusters. Omics : a journal of integrative biology, 16(5), 284–287. https://doi.org/10.1089/omi.2011.0118

Zhu, S. J., & Pearson, B. J. (2016). The planarian neoblast: The state of the art and future perspectives. In Results and Problems in Cell Differentiation (Vol. 58, pp. 327-343). Springer, Cham. https://doi.org/10.1007/978-3-319-31973-5_12

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: http://dx. doi. org/10.13140. RG, 2(27441.70245), 1

Ткемаладзе, Д. (2025). Асимметрия в наследовании центросом/центриолей и ее последствия. doi: http://dx. doi. org/10.13140. RG, 2(34917.312), 06.

Ткемаладзе, Д. (2025). Гаметогенез in vitro (IVG) -Этап дифференцировки в зрелые гаметы. http://dx.doi.org/10.13140/RG.2.2.20429.96482

Ткемаладзе, Д. (2025). Дифференциация соматических клеток многоклеточных животных. doi: http://dx. doi. org/10.13140. RG, 2(23348.97929), 1.

Ткемаладзе, Д. (2025). Индукция примордиальных клеток, подобных зародышевым клеткам (PGCLCs) современные достижения, механизмы и перспективы применения. http://dx.doi.org/10.13140/RG.2.2.27152.32004

Ткемаладзе, Д. (2025). Репликативный Лимит Хейфлика. doi: http://dx. doi. org/10.13140. RG, 2(25803.302), 49.

Ткемаладзе, Д. (2025). Элиминация Центриолей: Механизм Обнуления Энтропии в Клетке. doi: http://dx. doi. org/10.13140. RG, 2(12890.66248), 1.

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.