Kirouac, D. C. & Zandstra, P. W. The systematic production of cells for cell therapies. Cell Stem Cell 3, 369–381 (2008).
Google Scholar
Jenkins, M. J. & Farid, S. S. Human pluripotent stem cell-derived products: advances towards robust, scalable and cost-effective manufacturing strategies. Biotechnol. J. 10, 83–95 (2014).
Google Scholar
Adil, M. M. & Schaffer, D. V. Expansion of human pluripotent stem cells. Curr. Opin. Chem. Eng. 15, 24–35 (2017).
Google Scholar
Kempf, H., Andree, B. & Zweigerdt, R. Large-scale production of human pluripotent stem cell derived cardiomyocytes. Adv. Drug Deliv. Rev. 96, 18–30 (2016).
Google Scholar
Kropp, C., Massai, D. & Zweigerdt, R. Progress and challenges in large-scale expansion of human pluripotent stem cells. Process Biochem. 59, 244–254 (2017).
Google Scholar
Pellegrini, G. et al. From discovery to approval of an advanced therapy medicinal product-containing stem cells, in the EU. Regen. Med. 11, 407–420 (2016).
Google Scholar
Yin, X. et al. Stem cell organoid engineering. Cell Stem Cell 18, 25–38 (2016).
Google Scholar
Chen, K. G. et al. Pluripotent stem cell platforms for drug discovery. Trends Mol. Med. 24, 805–820 (2018).
Google Scholar
Romito, A. & Cobellis, G. Pluripotent stem cells: current understanding and future directions. Stem Cells Int. 2016, 1–20 (2016).
Google Scholar
Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
Google Scholar
Caulfield, T. et al. International stem cell environments: a world of difference. Nat. Rep. Stem Cells 1, 1–5 (2009).
Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010).
Google Scholar
Robinton, D. A. & Daley, G. Q. The promise of induced pluripotent stem cells in research and therapy. Nature 481, 295–305 (2012).
Google Scholar
Flavahan, W. A., Gaskell, E. & Bernstein, B. E. Epigenetic plasticity and the hallmarks of cancer. Science 357, 1–9 (2017).
Google Scholar
Volarevic, V. et al. Ethical and safety issues of stem cell-based therapy. Int. J. Med. Sci. 15, 36–45 (2018).
Google Scholar
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).
Google Scholar
Bai, L. et al. Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Nat. Neurosci. 15, 862–870 (2012).
Google Scholar
Trounson, A. & McDonald, C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17, 11–22 (2015).
Google Scholar
Garbern, J. C. & Lee, R. T. Cardiac stem cell therapy and the promise of heart regeneration. Cell Stem Cell 12, 689–698 (2013).
Google Scholar
Trounson, A. & DeWitt, N. D. Pluripotent stem cells progressing to the clinic. Nat. Rev. Mol. Cell Biol. 17, 194–200 (2016).
Google Scholar
Braganca, J., Lopes, J. A., Mendes-Silva, L. & Santos, J. M. A. Induced pluripotent stem cells, a giant leap for mankind therapeutic applications. World J. Stem Cells 11, 421–430 (2019).
Google Scholar
Kim, M. & Kino-oka, M. Bioengineering considerations for a nurturing way to enhance scalable expansion of human pluripotent stem cells. Biotechnol. J. 15, 1–16 (2020).
Wu, S. M. & Hochedlinger, K. Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nat. Cell Biol. 13, 497–505 (2011).
Google Scholar
Lund, R. J., Narva, E. & Lahesmaa, R. Understanding the genetics behind complex human disease with large-scale iPSC collections. Nat. Rev. Genet. 13, 732–744 (2012).
Google Scholar
Popp, B. et al. Need for high-resolution Genetic Analysis in iPSC: results and lessons from the ForIPS consortium. Sci. Rep. 8, 1–14 (2018).
Google Scholar
Liang, G. & Zhang, Y. Genetic and epigenetic variations in iPSCs: potential causes and implications for application. Cell Stem Cell 13, 149–159 (2013).
Google Scholar
Merkle, F. T. et al. Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations. Nature 545, 229–233 (2017).
Google Scholar
Cao, J. et al. Cells derived from iPSC can be immunogenic—yes or no? Protein Cell 5, 1–3 (2014).
Google Scholar
Liu, X., Li, W., Fu, X. & Xu, Y. The immunogenicity and immune tolerance of pluripotent stem cell derivatives. Front. Immunol. 8, 1–6 (2017).
Chhabra, A. Inherent immunogenicity or lack thereof of pluripotent stem cells: implications for cell replacement therapy. Front. Immunol. 8, 1–11 (2017).
Google Scholar
Pera, M. F. Stem cells: the dark side of induced pluripotency. Nature 471, 46–47 (2011).
Google Scholar
Nishino, K. et al. DNA methylation dynamics in human induced pluripotent stem cells over time. PLoS Genet. 7, 1–14 (2011).
Google Scholar
Youssef, A. A. et al. The promise and challenge of induced pluripotent stem cells for cardiovascular applications. JACC Basic Transl. Sci. 1, 510–523 (2016).
Google Scholar
D’Urso, A. & Brickner, J. H. Mechanisms of epigenetic memory. Trends Genet. 30, 230–236 (2014).
Google Scholar
Khoo, T. S. et al. Retention of somatic memory associated with cell identity, age and metabolism in induced pluripotent stem (iPS) cells reprogramming. Stem Cell Rev. Rep. 16, 251–261 (2020).
Google Scholar
Lee, J. E. & Lee, D. R. Human embryonic stem cells: derivation, maintenance and cryopreservation. Int. J. Stem Cells 4, 1–8 (2011).
Google Scholar
Yamanaka, S. Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 10, 678–684 (2012).
Google Scholar
Kyttala, A. et al. Genetic variability overrides the impact of parental cell type and determines iPSC differentiation potential. Stem Cell Rep. 6, 200–212 (2016).
Google Scholar
Kim, M. & Costello, J. DNA methylation: an epigenetic mark of cellular memory. Exp. Mol. Med. 49, 1–8 (2017).
Google Scholar
Nishizawa, M. et al. Epigenetic variation between human induced pluripotent stem cell lines is an indicator of differentiation capacity. Cell Stem Cell 19, 341–354 (2016).
Google Scholar
Schwartzentruber, J. et al. Molecular and functional variation in iPSC-derived sensory neurons. Nat. Genet. 50, 54–61 (2018).
Google Scholar
Anguera, M. C. et al. Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes. Cell Stem Cell 11, 75–90 (2012).
Google Scholar
Ronen, D. & Benvenisty, N. Sex-dependent gene expression in human pluripotent stem cells. Cell Stem Cell 8, 923–932 (2014).
Google Scholar
Rubin, J. B. et al. Sex differences in cancer mechanisms. Biol. Sex. Differences 11, 1–29 (2020).
Google Scholar
Kass, S. U., Pruss, D. & Wolffe, A. P. How does DNA methylation repress transcription? Trends Genet. 13, 444–449 (1997).
Google Scholar
Perrera, V. & Martello, G. How does reprogramming to pluripotency affect genomic imprinting? Front. Cell Dev. Biol. 7, 1–16 (2019).
Google Scholar
Pick, M. et al. Clone‐ and gene‐specific aberrations of parental imprinting in human induced pluripotent stem cells. Stem Cells 27, 2686–2690 (2009).
Google Scholar
Panoupoulos, A. D. et al. Aberrant DNA methylation in human iPSCs associates with MYC-binding motifs in a clone-specific manner independent of genetics. Cell Stem Cell 20, 505–517 (2017).
Google Scholar
Assou, S. et al. Recurrent genetic abnormalities in human pluripotent stem cells: definition and routine detection in culture supernatant by targeted droplet digital PCR. Stem Cell Rep. 14, 1–8 (2020).
Google Scholar
Lessard, J. A. & Crabtree, G. R. Chromatin regulatory mechanisms in pluripotency. Annu. Rev. Cell Dev. Biol. 26, 503–532 (2010).
Google Scholar
Collier, A. J. & Rugg-Gunn, P. J. Identifying human naïve pluripotent stem cells−evaluating state‐specific reporter lines and cell‐surface markers. Bioessays 40, 1–12 (2018).
Google Scholar
Efroni, S. et al. Global transcription in pluripotent embryonic stem cells. Cell Stem Cell 2, 437–447 (2008).
Google Scholar
Harvey, A. et al. Interplay between metabolites and the epigenome in regulating embryonic and adult stem cell potency and maintenance. Stem Cell Rep. 13, 573–589 (2019).
Google Scholar
Kapinas, K. et al. The abbreviated pluripotent cell cycle. J. Cell Physiol. 1, 9–20 (2013).
Google Scholar
Mathieu, J. & Ruohola-Baker, H. Metabolic remodeling during the loss and acquisition of pluripotency. Development 144, 541–555 (2017).
Google Scholar
Hassani, S. et al. Inhibition of TGFβ signaling promotes ground state pluripotency. Stem Cell Rev. Rep. 10, 16–30 (2014).
Google Scholar
Burgess, R. J., Agathocleous, M. & Morrison, S. J. Metabolic regulation of stem cell function. J. Intern. Med. 276, 12–24 (2014).
Google Scholar
Carey, B. W. et al. Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. Cell Stem Cell 6, 588–598 (2011).
Google Scholar
Baker, D. et al. Detecting genetic mosaicism in cultures of human pluripotent stem cells. Stem Cell Rep. 7, 998–1012 (2016).
Google Scholar
Wu, J., Yamauchi, T. & Belmonte, J. C. I. An overview of mammalian pluripotency. Development 143, 1644–1648 (2016).
Google Scholar
Pennings, S., Liu, K. J. & Qian, H. The stem cell niche: interactions between stem cells and their environment. Stem Cells Int. 2018, 1–3 (2018).
Google Scholar
Efthymiou, A. G., Chen, G., Rao, M., Chen, G. & Boehm, M. Self-renewal and cell lineage differentiation strategies in human embryonic stem cells and induced pluripotent stem cells. Expert Opin. Biol. Ther. 14, 1333–1344 (2014).
Google Scholar
Liu, X. et al. Reprogramming roadmap reveals route to human induced trophoblast stem cells. Nature 586, 101–107 (2020).
Google Scholar
Liu, M., Liu, N., Zang, R., Li, Y. & Yang, S. Engineering stem cell niches in bioreactors. World J. Stem Cells 5, 124–135 (2013).
Google Scholar
Kilens, S. et al. Parallel derivation of isogenic human primed and naive induced pluripotent stem cells. Nat. Commun. 9, 1–13 (2018).
Google Scholar
Saito, S. et al. Emerging roles of hypoxia-inducible factors and reactive oxygen species in cancer and pluripotent stem cells. Kaohsiung J. Med. Sci. 31, 279–286 (2015).
Google Scholar
Borys, B. S. et al. Optimized serial expansion of human induced pluripotent stem cells using low‐density inoculation to generate clinically relevant quantities in vertical‐wheel bioreactors. Stem Cells Transl. Med. 9, 1036–1052 (2020).
Google Scholar
Assou, S., Bouckenheimer, J. & De Vos, J. Concise Review: assessing the genome integrity of human induced pluripotent stem cells: what quality control metrics? Stem Cells Transl. Med. 36, 814–821 (2018).
Google Scholar
Buta, C. et al. Reconsidering pluripotency tests: do we still need teratoma assays? Stem Cell Res. 11, 552–562 (2013).
Google Scholar
Mao, A. S. & Mooney, D. J. Regenerative medicine: current therapies and future directions. Proc. Natl Acad. Sci. USA 112, 14452–14459 (2015).
Google Scholar
Li, K., Zhang, M., Xie, F., Liu, P. & Xu, S. Differentiation of pluripotent stem cells for regenerative medicine. Biochem. Biophys. Res. Commun. 471, 1–4 (2016).
Google Scholar
Joddar, B. & Ito, Y. Artificial niche substrates for embryonic and induced pluripotent stem cell cultures. J. Biotechnol. 168, 218–228 (2013).
Google Scholar
Baghbaderani, B. A. et al. Detailed characterization of human induced pluripotent stem cells manufactured for therapeutic applications. Stem Cell Rev. Rep. 12, 394–420 (2016).
Google Scholar
Sart, S., Bejoy, J. & Li, Y. Characterization of 3D pluripotent stem cell aggregates and the impact of their properties on bioprocessing. Process Biochem. 59, 276–288 (2017).
Google Scholar
Galvanauskas, V. et al. Current state and perspectives in modeling and control of human pluripotent stem cell expansion processes in stirred-tank bioreactors. Biotechnol. Prog. 33, 355–364 (2017).
Google Scholar
Polanco, A., Kuang, B. & Yoon, S. Bioprocess technologies that preserve the quality of iPSCs. Trends Biotechnol. 38, 1128–1140 (2020).
Google Scholar
Tohyama, S. et al. Efficient large-scale 2D culture system for human induced pluripotent stem cells and differentiated cardiomyocytes. Stem Cell Rep. 9, 1406–1414 (2017).
Google Scholar
Lavon, N., Zimerman, M. & Itskovitz-Eldor, J. In Advances in Biochemical Engineering/Biotechnology Book Series, ABE 163, 22–37 (2017). Edited by Scheper, T., Zhong, J. Published by Springer-Verlag Berlin Heidelberg NewYork.
Oyetunde, T., Bao, F. S., Chen, J. W., Martin, H. C. & Tang, Y. J. Leveraging knowledge engineering and machine learning for microbial manufacturing. Biotechnol. Adv. 36, 1308–1315 (2018).
Google Scholar
Zitnik, M. et al. Machine learning for integrating data in biology and medicine: principles, practice, and opportunities. Inf. Fusion 50, 71–91 (2019).
Google Scholar
Doulgkeroglou, M. et al. Automation, monitoring, and standardization of cell product manufacturing. Front. Bioeng. Biotechnol. 8, 1–12 (2020).
Google Scholar
Malta, T. M. et al. Machine learning identifies stemness features associated with oncogenic dedifferentiation. Cell 173, 338–354 (2018).
Google Scholar
Sugimoto, K. Machine learning-driven label-free cell sorting for CAR-T cell manufacturing. Cytotherapy 21, S39 (2019).
Google Scholar
Williams, B. et al. Prediction of human induced pluripotent stem cell cardiac differentiation outcome by multifactorial process modeling. Front. Bioeng. Biotechnol. 8, 1–15 (2020).
Google Scholar
Kobold, S. et al. A manually curated database on clinical studies involving cell products derived from human pluripotent stem cells. Stem Cell Rep. 15, 546–555 (2020).
Google Scholar
Deinsberger, J., Reisinger, D. & Weber, B. Global trends in clinical trials involving pluripotent stem cells: a systematic multi-database analysis. npj Regen. Med. 5, 1–13 (2020).
Google Scholar
Sung, Y. et al. Long-term safety and tolerability of subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium in Asian Stargardt disease patients. Br. J. Opthalmol. 105, 829–837 (2021).
Google Scholar
Mandai, M. et al. Autologous induced stem cell-derived retinal cells for macular degeneration. N. Engl. J. Med. 376, 1038–1046 (2017).
Google Scholar
Bloor, A. J. C. et al. Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study. Nat. Med. 26, 1720–1725 (2020).
Google Scholar
Doss, M. X. & Sachinidis, A. Current challenges of iPSC-based modeling and therapeutic implications. Cells 8, 1–16 (2019).
Google Scholar
Dashtban, M., Panchalingam, K. M., Shafa, M. & Baghbaderani, B. A. Addressing manufacturing challenges for commercialization of iPSC-based therapies. Methods Mol. Biol. 2286, 179–198 (2021).
Google Scholar
Yamanaka, S. Pluripotent stem cell-based cell therapy – promise and challenges. Cell Stem Cell 27, 523–531 (2020).
Google Scholar
Ozay, E. I. et al. Cymerus iPSC-MSCs significantly prolong survival in a pre-clinical, humanized mouse model of Graft-vs-host disease. Stem Cell Res. 35, 1–13 (2019).
Google Scholar
Menasche, P. et al. Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. J. Am. Coll. Cardiol. 71, 429–438 (2018).
Google Scholar
Kamao, H. et al. Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application. Stem Cell Rep. 2, 205–218 (2014).
Google Scholar
Wang, Y. et al. Human clinical-grade parthenogenetic ESC-derived dopaminergic neurons recover locomotive defects of nonhuman primate models of Parkinson’s disease. Stem Cell Rep. 11, 171–182 (2018).
Google Scholar

