Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Next-generation stem cells — ushering in a new era of cell-based therapies

Nature Reviews Drug Discovery volume 19, pages 463–479 (2020)Cite this article

Subjects

Abstract

Naturally occurring stem cells isolated from humans have been used therapeutically for decades. This has primarily involved the transplantation of primary cells such as haematopoietic and mesenchymal stem cells and, more recently, derivatives of pluripotent stem cells. However, the advent of cell-engineering approaches is ushering in a new generation of stem cell-based therapies, greatly expanding their therapeutic utility. These next-generation stem cells are being used as ‘Trojan horses’ to improve the delivery of drugs and oncolytic viruses to intractable tumours and are also being engineered with angiogenic, neurotrophic and anti-inflammatory molecules to accelerate the repair of injured or diseased tissues. Moreover, gene therapy and gene editing technologies are being used to create stem cell derivatives with improved functionality, specificity and responsiveness compared with their natural counterparts. Here, we review these engineering approaches and areas in which they will help broaden the utility and clinical applicability of stem cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The stem cell toolkit and its application in developing next-generation stem cells.
Fig. 2: Tumour-tropism of stem cells can be leveraged to enhance targeted drug delivery to hard-to-reach tumours and sites of metastases.
Fig. 3: Gene editing to create universally immunocompatible PSC-based therapies.
Fig. 4: Timeline for stem cell-based therapies.

Similar content being viewed by others

References

  1. Atala, A., Lanza, R., Mikos, T., Nerem, R. Principles of Regenerative Medicine 3rd edn, (Academic, 2019).

  2. Thomas, E. D., Lochte, H. L. Jr., Cannon, J. H., Sahler, O. D. & Ferrebee, J. W. Supralethal whole body irradiation and isologous marrow transplantation in man. J. Clin. Invest. 38, 1709–1716 (1959).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Hass, R., Kasper, C., Böhm, S. & Jacobs, R. Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun. Signal. 9, 12–12 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Lazarus, H. M., Haynesworth, S. E., Gerson, S. L., Rosenthal, N. S. & Caplan, A. I. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 16, 557–564 (1995).

    CAS  PubMed  Google Scholar 

  5. Squillaro, T., Peluso, G. & Galderisi, U. Clinical trials with mesenchymal stem cells: an update. Cell Transplant. 25, 829–848 (2016).

    PubMed  Google Scholar 

  6. Galipeau, J. & Sensébé, L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 22, 824–833 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Mendicino, M., Bailey, A. M., Wonnacott, K., Puri, R. K. & Bauer, S. R. MSC-based product characterization for clinical trials: an FDA perspective. Cell Stem Cell 14, 141–145 (2014).

    CAS  PubMed  Google Scholar 

  8. Madrazo, I. et al. Transplantation of fetal substantia nigra and adrenal medulla to the caudate nucleus in two patients with Parkinson’s disease. N. Engl. J. Med. 318, 51 (1988).

    CAS  PubMed  Google Scholar 

  9. Ishii, T. & Eto, K. Fetal stem cell transplantation: past, present, and future. World J. Stem Cell 6, 404–420 (2014).

    Google Scholar 

  10. Kefalopoulou, Z. et al. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 71, 83–87 (2014).

    PubMed  PubMed Central  Google Scholar 

  11. Olanow, C. W. et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann. Neurol. 54, 403–414 (2003).

    PubMed  Google Scholar 

  12. Hasan, S. M. et al. Immortalized human fetal retinal cells retain progenitor characteristics and represent a potential source for the treatment of retinal degenerative disease. Cell Transplant. 19, 1291–1306 (2010).

    PubMed  Google Scholar 

  13. Liu, Y. et al. Long-term safety of human retinal progenitor cell transplantation in retinitis pigmentosa patients. Stem Cell Res. Ther. 8, 209–209 (2017).

    PubMed  PubMed Central  Google Scholar 

  14. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  PubMed  Google Scholar 

  15. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    CAS  PubMed  Google Scholar 

  16. Williams, L. A., Davis-Dusenbery, B. N. & Eggan, K. C. SnapShot: directed differentiation of pluripotent stem cells. Cell 149, 1174–1174.e1 (2012).

    CAS  PubMed  Google Scholar 

  17. Kimbrel, E. A. & Lanza, R. Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat. Rev. Drug Discov. 14, 681–692 (2015).

    CAS  PubMed  Google Scholar 

  18. Frantz, S. Embryonic stem cell pioneer Geron exits field, cuts losses. Nat. Biotechnol. 30, 12–13 (2012).

    CAS  PubMed  Google Scholar 

  19. Schwartz, S. D. et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379, 713–720 (2012).

    CAS  PubMed  Google Scholar 

  20. Schwartz, S. D. et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet 385, 509–516 (2015).

    PubMed  Google Scholar 

  21. Kashani, A. H. et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration. Sci. Transl. Med. 10, eaao4097 (2018).

    PubMed  Google Scholar 

  22. Mandai, M. et al. Autologous induced stem-cell–derived retinal cells for macular degeneration. N. Engl. J. Med. 376, 1038–1046 (2017).

    CAS  PubMed  Google Scholar 

  23. Mehat, M. S. et al. Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells in macular degeneration. Ophthalmology 125, 1765–1775 (2018).

    PubMed  Google Scholar 

  24. Menasché, 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).

    PubMed  Google Scholar 

  25. Cyranoski, D. ‘Reprogrammed’ stem cells implanted into patient with Parkinson’s disease. Nature https://doi.org/10.1038/d41586-018-07407-9 (2018).

    Article  PubMed  Google Scholar 

  26. Cyranoski, D. Japan poised to allow ‘reprogrammed’ stem-cell therapy for damaged corneas. Nature https://doi.org/10.1038/d41586-019-00860-0 (2019).

    Article  PubMed  Google Scholar 

  27. Cyranoski, D. ‘Reprogrammed’ stem cells to treat spinal-cord injuries for the first time. Nature https://doi.org/10.1038/d41586-019-00656-2 (2019).

    Article  PubMed  Google Scholar 

  28. Izrael, M. et al. Safety and efficacy of human embryonic stem cell-derived astrocytes following intrathecal transplantation in SOD1(G93A) and NSG animal models. Stem Cell Res. Ther. 9, 152–152 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang, Y.-K. 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).

    CAS  Google Scholar 

  30. Merkle, F. T. et al. Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations. Nature 545, 229–233 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Milone, M. C. & O’Doherty, U. Clinical use of lentiviral vectors. Leukemia 32, 1529–1541 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Hacein-Bey-Abina, S. et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Invest. 118, 3132–3142 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lewinski, M. K. et al. Retroviral DNA integration: viral and cellular determinants of target-site selection. PLoS Pathog. 2, e60 (2006).

    PubMed  PubMed Central  Google Scholar 

  34. Aiuti, A. et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott–Aldrich syndrome. Science 341, 1233151 (2013).

    PubMed  PubMed Central  Google Scholar 

  35. Scala, S. et al. Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans. Nat. Med. 24, 1683–1690 (2018).

    CAS  PubMed  Google Scholar 

  36. Naldini, L. Genetic engineering of hematopoiesis: current stage of clinical translation and future perspectives. EMBO Mol. Med. 11, e9958 (2019).

    PubMed  PubMed Central  Google Scholar 

  37. Dull, T. et al. A third-generation lentivirus vector with a conditional packaging system. J. Virol. 72, 8463–8471 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Zufferey, R. et al. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J. Virol. 72, 9873–9880 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Maeder, M. L. & Gersbach, C. A. Genome-editing technologies for gene and cell therapy. Mol. Ther. 24, 430–446 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kim, Y. G., Cha, J. & Chandrasegaran, S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc. Natl Acad. Sci. USA 93, 1156–1160 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Urnov, F. D., Rebar, E. J., Holmes, M. C., Zhang, H. S. & Gregory, P. D. Genome editing with engineered zinc finger nucleases. Nat. Rev. Genet. 11, 636–646 (2010).

    CAS  PubMed  Google Scholar 

  42. Boch, J. et al. Breaking the code of DNA binding specificity of TAL-type III effectors. Science 326, 1509–1512 (2009).

    CAS  PubMed  Google Scholar 

  43. Jiang, F. & Doudna, J. A. CRISPR–Cas9 structures and mechanisms. Annu. Rev. Biophys. 46, 505–529 (2017).

    CAS  PubMed  Google Scholar 

  44. Wiedenheft, B., Sternberg, S. H. & Doudna, J. A. RNA-guided genetic silencing systems in bacteria and archaea. Nature 482, 331–338 (2012).

    CAS  PubMed  Google Scholar 

  45. Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Dai, W.-J. et al. CRISPR–Cas9 for in vivo gene therapy: promise and hurdles. Mol. Ther. Nucleic Acids 5, e349–e349 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhang, X.-H., Tee, L. Y., Wang, X.-G., Huang, Q.-S. & Yang, S.-H. Off-target effects in CRISPR/Cas9-mediated genome engineering. Mol. Ther. Nucleic Acids 4, e264 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Fu, Y. et al. High-frequency off-target mutagenesis induced by CRISPR–Cas nucleases in human cells. Nat. Biotechnol. 31, 822 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Gaj, T., Epstein, B. E. & Schaffer, D. V. Genome engineering using adeno-associated virus: basic and clinical research applications. Mol. Ther. 24, 458–464 (2016).

    CAS  PubMed  Google Scholar 

  50. Adli, M. The CRISPR tool kit for genome editing and beyond. Nat. Commun. 9, 1911 (2018).

    PubMed  PubMed Central  Google Scholar 

  51. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zetsche, B. et al. Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR–Cas system. Cell 163, 759–771 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Strecker, J. et al. Engineering of CRISPR–Cas12b for human genome editing. Nat. Commun. 10, 212 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Liu, J. J. et al. CasX enzymes comprise a distinct family of RNA-guided genome editors. Nature 566, 218–223 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Guilinger, J. P., Thompson, D. B. & Liu, D. R. Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification. Nat. Biotechnol. 32, 577–582 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ran, F. A. et al. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154, 1380–1389 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Lo, A. & Qi, L. Genetic and epigenetic control of gene expression by CRISPR–Cas systems. F1000Res. 6 (2017).

  58. Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Gonzalez, F. et al. An iCRISPR platform for rapid, multiplexable, and inducible genome editing in human pluripotent stem cells. Cell Stem Cell 15, 215–226 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. [No authors listed] Keep off-target effects in focus. Nat. Med. 24, 1081–1081 (2018).

  61. Wienert, B. et al. Unbiased detection of CRISPR off-targets in vivo using DISCOVER–Seq. Science 364, 286 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Zuo, E. et al. Cytosine base editor generates substantial off-target single-nucleotide variants in mouse embryos. Science 364, 289 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Jin, S. et al. Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice. Science 364, 292 (2019).

    CAS  PubMed  Google Scholar 

  64. Anzalone, A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576, 149–157 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Ledford, H. Super-precise new CRISPR tool could tackle a plethora of genetic diseases. Nature 574, 464–465 (2019).

    CAS  PubMed  Google Scholar 

  66. Pomeroy, J. E., Nguyen, H. X., Hoffman, B. D. & Bursac, N. Genetically encoded photoactuators and photosensors for characterization and manipulation of pluripotent stem cells. Theranostics 7, 3539–3558 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Klapper, S. D. et al. On-demand optogenetic activation of human stem-cell-derived neurons. Sci. Rep. 7, 14450 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. Sokolik, C. et al. Transcription factor competition allows embryonic stem cells to distinguish authentic signals from noise. Cell Syst. 1, 117–129 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Shao, J. et al. Synthetic far-red light-mediated CRISPR–dCas9 device for inducing functional neuronal differentiation. Proc. Natl Acad. Sci. USA 115, E6722–E6730 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Motta-Mena, L. B. et al. An optogenetic gene expression system with rapid activation and deactivation kinetics. Nat. Chem. Biol. 10, 196 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Roth, B. L. DREADDs for neuroscientists. Neuron 89, 683–694 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Weston, M. et al. Olanzapine: a potent agonist at the hM4D(Gi) DREADD amenable to clinical translation of chemogenetics. Sci. Adv. 5, eaaw1567 (2019).

    PubMed  PubMed Central  Google Scholar 

  73. Bonaventura, J. et al. High-potency ligands for DREADD imaging and activation in rodents and monkeys. Nat. Commun. 10, 4627 (2019).

    PubMed  PubMed Central  Google Scholar 

  74. Aldrin-Kirk, P. et al. DREADD modulation of transplanted DA neurons reveals a novel Parkinsonian dyskinesia mechanism mediated by the serotonin 5-HT6 receptor. Neuron 90, 955–968 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Upadhya, D. et al. Human induced pluripotent stem cell-derived MGE cell grafting after status epilepticus attenuates chronic epilepsy and comorbidities via synaptic integration. Proc. Natl Acad. Sci. USA 116, 287 (2019).

    CAS  PubMed  Google Scholar 

  76. Ji, B. et al. Multimodal imaging for DREADD-expressing neurons in living brain and their application to implantation of iPSC-derived neural progenitors. J. Neurosci. 36, 11544–11558 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Chen, Y. et al. Chemical control of grafted human PSC-derived neurons in a mouse model of Parkinson’s disease. Cell Stem Cell 18, 817–826 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Takayama, Y., Kusamori, K. & Nishikawa, M. Click chemistry as a tool for cell engineering and drug delivery. Molecules 24, 172 (2019).

    PubMed Central  Google Scholar 

  79. Layek, B., Sadhukha, T. & Prabha, S. Glycoengineered mesenchymal stem cells as an enabling platform for two-step targeting of solid tumors. Biomaterials 88, 97–109 (2016).

    CAS  PubMed  Google Scholar 

  80. Hargadon, K. M., Johnson, C. E. & Williams, C. J. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int. Immunopharmacol. 62, 29–39 (2018).

    CAS  PubMed  Google Scholar 

  81. Darvin, P., Toor, S. M., Sasidharan Nair, V. & Elkord, E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp. Mol. Med. 50, 165 (2018).

    CAS  PubMed Central  Google Scholar 

  82. Hu, Q. et al. Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy. Nat. Biomed. Eng. 2, 831–840 (2018). This study demonstrates the feasibility and therapeutic potential of a novel tripartite engineered stem cell-based anti-leukaemia therapy; HSCs provide effective homing to the bone marrow, and conjugated platelets enable the delivery and subsequent offloading of a checkpoint inhibitor to kill bone marrow-resident leukaemia cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Aboody, K. S., Najbauer, J. & Danks, M. K. Stem and progenitor cell-mediated tumor selective gene therapy. Gene Ther. 15, 739–752 (2008).

    CAS  PubMed  Google Scholar 

  84. Spaeth, E., Klopp, A., Dembinski, J., Andreeff, M. & Marini, F. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther. 15, 730–738 (2008).

    CAS  PubMed  Google Scholar 

  85. López-Lázaro, M. The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis. Oncoscience 2, 467–475 (2015).

    PubMed  PubMed Central  Google Scholar 

  86. Landskron, G., De la Fuente, M., Thuwajit, P., Thuwajit, C. & Hermoso, M. A. Chronic inflammation and cytokines in the tumor microenvironment. J. Immunol. Res. 2014, 149185 (2014).

    PubMed  PubMed Central  Google Scholar 

  87. Aboody, K. S. et al. Neural stem cell–mediated enzyme/prodrug therapy for glioma: preclinical studies. Sci. Transl. Med. 5, 184ra159 (2013).

    Google Scholar 

  88. Kim, S. U. Human neural stem cells genetically modified for brain repair in neurological disorders. Neuropathology 24, 159–171 (2004).

    PubMed  Google Scholar 

  89. Davis, M. E. Glioblastoma: overview of disease and treatment. Clin. J. Oncol. Nurs. 20, S2–S8 (2016).

    PubMed  PubMed Central  Google Scholar 

  90. Hottinger, A. F., Stupp, R. & Homicsko, K. Standards of care and novel approaches in the management of glioblastoma multiforme. Chin. J. Cancer 33, 32–39 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Portnow, J. et al. Neural stem cell-based anticancer gene therapy: a first-in-human study in recurrent high-grade glioma patients. Clin. Cancer Res. 23, 2951–2960 (2017). This first-in-human study provides evidence for the safe use of an NSC-based approach to penetrate the blood–brain barrier and enhance the delivery of a chemotherapeutic agent to high-grade glioma. It represents the first clinical step in developing this modality further.

    CAS  PubMed  Google Scholar 

  92. Heo, J.-R., Hwang, K.-A., Kim, S. U. & Choi, K.-C. A potential therapy using engineered stem cells prevented malignant melanoma in cellular and xenograft mouse models. Cancer Res. Treat. 51, 797–811 (2019).

    CAS  PubMed  Google Scholar 

  93. Metz, M. Z. et al. Neural stem cell-mediated delivery of irinotecan-activating carboxylesterases to glioma: implications for clinical use. Stem Cell Transl. Med. 2, 983–992 (2013).

    CAS  Google Scholar 

  94. Gutova, M. et al. Quantitative evaluation of intraventricular delivery of therapeutic neural stem cells to orthotopic glioma. Front. Oncol. 9, 68 (2019).

    PubMed  PubMed Central  Google Scholar 

  95. von Einem, J. C. et al. Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: results from the phase 1/2 TREAT-ME-1 trial. Int. J. Cancer 145, 1538–1546 (2019).

    Google Scholar 

  96. Springer, C. J. & Niculescu-Duvaz, I. Prodrug-activating systems in suicide gene therapy. J. Clin. Invest. 105, 1161–1167 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Soria, J. C. et al. Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer. J. Clin. Oncol. 29, 4442–4451 (2011).

    CAS  PubMed  Google Scholar 

  98. Ganten, T. M. et al. Preclinical differentiation between apparently safe and potentially hepatotoxic applications of TRAIL either alone or in combination with chemotherapeutic drugs. Clin. Cancer Res. 12, 2640–2646 (2006).

    CAS  PubMed  Google Scholar 

  99. Davies, A. et al. TACTICAL: a phase I/II trial to assess the safety and efficacy of MSCTRAIL in the treatment of metastatic lung adenocarcinoma. J. Clin. Oncol. 37, TPS9116–TPS9116 (2019).

    Google Scholar 

  100. Bago, J. R. et al. Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma. Nat. Commun. 7, 10593 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Rossignoli, F. et al. Inducible Caspase9-mediated suicide gene for MSC-based cancer gene therapy. Cancer Gene Ther. 26, 11–16 (2019).

    CAS  PubMed  Google Scholar 

  102. Klopp, A. H., Gupta, A., Spaeth, E., Andreeff, M. & Marini, F. III. Concise review: Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cell 29, 11–19 (2011).

    CAS  Google Scholar 

  103. Yuan, Z., Kolluri, K. K., Gowers, K. H. C. & Janes, S. M. TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy. J. Extracell. Vesicles 6, 1265291–1265291 (2017).

    PubMed  PubMed Central  Google Scholar 

  104. Lou, G. et al. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J. Hematol. Oncol. 8, 122–122 (2015).

    PubMed  PubMed Central  Google Scholar 

  105. Mendt, M. et al. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight https://doi.org/10.1172/jci.insight.99263 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Kamerkar, S. et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546, 498 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Zheng, M., Huang, J., Tong, A. & Yang, H. Oncolytic viruses for cancer therapy: barriers and recent advances. Mol. Ther. Oncolytics 15, 234–247 (2019).

    PubMed  PubMed Central  Google Scholar 

  108. Ilkow, C. S., Swift, S. L., Bell, J. C. & Diallo, J.-S. From scourge to cure: tumour-selective viral pathogenesis as a new strategy against cancer. PLoS Pathog. 10, e1003836–e1003836 (2014).

    PubMed  PubMed Central  Google Scholar 

  109. Gujar, S., Bell, J. & Diallo, J. S. SnapShot: cancer immunotherapy with oncolytic viruses. Cell 176, 1240–1240.e1 (2019).

    CAS  PubMed  Google Scholar 

  110. Pol, J., Kroemer, G. & Galluzzi, L. First oncolytic virus approved for melanoma immunotherapy. Oncoimmunology 5, e1115641 (2016).

    PubMed  Google Scholar 

  111. Conry, R. M., Westbrook, B., McKee, S. & Norwood, T. G. Talimogene laherparepvec: first in class oncolytic virotherapy. Hum. Vaccin. Immunother. 14, 839–846 (2018).

    PubMed  PubMed Central  Google Scholar 

  112. Du, W. et al. Stem cell-released oncolytic herpes simplex virus has therapeutic efficacy in brain metastatic melanomas. Proc. Natl Acad. Sci. USA 114, E6157 (2017). This study demonstrates the benefit of using stem cells to increase the biodistribution of an oncolytic virus and reach metastatic sites that otherwise would not have been reached as a stand-alone therapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Leoni, V. et al. Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases. Oncotarget 6, 34774–34787 (2015).

    PubMed  PubMed Central  Google Scholar 

  114. Draganov, D. D. et al. Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers. J. Transl. Med. 17, 100 (2019).

    PubMed  PubMed Central  Google Scholar 

  115. Tobias, A. L. et al. The timing of neural stem cell-based virotherapy is critical for optimal therapeutic efficacy when applied with radiation and chemotherapy for the treatment of glioblastoma. Stem Cell Transl. Med. 2, 655–666 (2013).

    CAS  Google Scholar 

  116. Mader, E. K. et al. Optimizing patient derived mesenchymal stem cells as virus carriers for a phase I clinical trial in ovarian cancer. J. Transl. Med. 11, 20 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566–581 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Zhao, L. & Cao, Y. J. Engineered T cell therapy for cancer in the clinic. Front. Immunol. 10, 2250 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Herzig, E. et al. Attacking latent HIV with convertibleCAR-T cells, a highly adaptable killing platform. Cell 179, 880–894.e10 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Joglekar, A. et al. Hematopoietic stem/progenitor cells engineered with T cell receptors for immunotherapy for HIV infection. J. Immunol. 200, 180.185 (2018).

    Google Scholar 

  121. Puig-Saus, C. et al. IND-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-18-0963 (2018). This paper details IND-enabling studies for an antigen-specific, T cell receptor-based HSC/T cell therapy being used in phase I clinical trials to treat relapsed/refractory ovarian, fallopian or primary peritoneal cancer with the added feature of a sr39TK suicide gene to control persistence of the cells, if needed.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Zhen, A. et al. Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS. PLoS Pathog. 13, e1006753 (2017).

    PubMed  PubMed Central  Google Scholar 

  123. Golinelli, G. et al. Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors. Cancer Gene Ther. https://doi.org/10.1038/s41417-018-0062-x (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Themeli, M. et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31, 928–933 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Li, Y., Hermanson, D. L., Moriarity, B. S. & Kaufman, D. S. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23, 181–192.e5 (2018). This paper illustrates the potential power of combining iPSC and CAR technologies, and also details how improved design of a CAR based upon the cell type in which it is expressed can improve its efficacy.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Senju, S. et al. Generation of dendritic cells and macrophages from human induced pluripotent stem cells aiming at cell therapy. Gene Ther. 18, 874–883 (2011).

    CAS  PubMed  Google Scholar 

  127. Vatakis, D. N. et al. Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells. Proc. Natl Acad. Sci. USA 108, E1408–E1416 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. van Lent, A. U. et al. Functional human antigen-specific T cells produced in vitro using retroviral T cell receptor transfer into hematopoietic progenitors. J. Immunol. 179, 4959 (2007).

    PubMed  Google Scholar 

  129. Guedan, S., Calderon, H., Posey, A. D. Jr. & Maus, M. V. Engineering and design of chimeric antigen receptors. Mol. Ther. Methods Clin. Dev. 12, 145–156 (2018).

    PubMed  PubMed Central  Google Scholar 

  130. Yu, S., Yi, M., Qin, S. & Wu, K. Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Mol. Cancer 18, 125 (2019).

    PubMed  PubMed Central  Google Scholar 

  131. De Oliveira, S. N. et al. Modification of hematopoietic stem/progenitor cells with CD19-specific chimeric antigen receptors as a novel approach for cancer immunotherapy. Hum. Gene Ther. 24, 824–839 (2013).

    PubMed  PubMed Central  Google Scholar 

  132. Kao, C.-Y. & Papoutsakis, E. T. Engineering human megakaryocytic microparticles for targeted delivery of nucleic acids to hematopoietic stem and progenitor cells. Sci. Adv. 4, eaau6762 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Steinberg, G. K. et al. Two-year safety and clinical outcomes in chronic ischemic stroke patients after implantation of modified bone marrow-derived mesenchymal stem cells (SB623): a phase 1/2a study. J. Neurosurg. https://doi.org/10.3171/2018.5.JNS173147 (2018).

    Article  PubMed  Google Scholar 

  135. Hess, D. C. et al. Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 16, 360–368 (2017).

    PubMed  Google Scholar 

  136. Klein, S. M. et al. GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum. Gene Ther. 16, 509–521 (2005).

    CAS  PubMed  Google Scholar 

  137. Akhtar, A. A. et al. Inducible expression of GDNF in transplanted iPSC-derived neural progenitor cells. Stem Cell Rep. 10, 1696–1704 (2018).

    CAS  Google Scholar 

  138. Liu, Y.-W. et al. Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nat. Biotechnol. 36, 597–605 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Terashvili, M. & Bosnjak, Z. J. Stem cell therapies in cardiovascular disease. J. Cardiothorac. Vasc. Anesthesia 33, 209–222 (2019).

    Google Scholar 

  140. Vagnozzi, R. J. et al. An acute immune response underlies the benefit of cardiac stem-cell therapy. Nature 577, 405–409 (2020).

    CAS  PubMed  Google Scholar 

  141. Makkar, R. R. et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379, 895–904 (2012).

    PubMed  PubMed Central  Google Scholar 

  142. Malliaras, K. et al. Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction). J. Am. Coll. Cardiol. 63, 110–122 (2014).

    PubMed  Google Scholar 

  143. Menasche, P. Cell therapy trials for heart regeneration — lessons learned and future directions. Nat. Rev. Cardiol. 15, 659–671 (2018).

    PubMed  Google Scholar 

  144. Davis, D. R. Cardiac stem cells in the post-Anversa era. Eur. Heart J. 40, 1039–1041 (2019).

    PubMed  Google Scholar 

  145. Tongers, J., Losordo, D. W. & Landmesser, U. Stem and progenitor cell-based therapy in ischaemic heart disease: promise, uncertainties, and challenges. Eur. Heart J. 32, 1197–1206 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Tang, J. et al. Targeted repair of heart injury by stem cells fused with platelet nanovesicles. Nat. Biomed. Eng. 2, 17–26 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Lemcke, H., Voronina, N., Steinhoff, G. & David, R. Recent progress in stem cell modification for cardiac regeneration. Stem Cell Int. 2018, 22 (2018).

    Google Scholar 

  148. Hwang, C. W. et al. Stem cell impregnated nanofiber stent sleeve for on-stent production and intravascular delivery of paracrine factors. Biomaterials 52, 318–326 (2015).

    CAS  PubMed  Google Scholar 

  149. Cavazzana, M., Bushman, F. D., Miccio, A., André-Schmutz, I. & Six, E. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges. Nat. Rev. Drug Discov. 18, 447–462 (2019).

    CAS  PubMed  Google Scholar 

  150. Rio, P. et al. Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia. Nat. Med. 25, 1396–1401 (2019).

    CAS  PubMed  Google Scholar 

  151. Anderson, J. S., Javien, J., Nolta, J. A. & Bauer, G. Preintegration HIV-1 inhibition by a combination lentiviral vector containing a chimeric TRIM5α protein, a CCR5 shRNA, and a TAR decoy. Mol. Ther. 17, 2103–2114 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Hirsch, T. et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature 551, 327 (2017). This case report shows how gene therapy and expansion of autologous skin stem cells/progenitors within keratinocyte biopsies can be used to generate therapeutic skin grafts for the treatment of junctional epidermolysis bullosa.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Iyer, P. S. et al. Autologous cell therapy approach for Duchenne muscular dystrophy using PiggyBac transposons and mesoangioblasts. Mol. Ther. 26, 1093–1108 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Hockemeyer, D. & Jaenisch, R. Induced pluripotent stem cells meet genome editing. Cell Stem Cell 18, 573–586 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Psatha, N. et al. Disruption of the BCL11A erythroid enhancer reactivates fetal hemoglobin in erythroid cells of patients with β-thalassemia major. Mol. Ther. Methods Clin. Dev. 10, 313–326 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Wu, Y. et al. Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nat. Med. 25, 776–783 (2019). This paper describes how gene editing at the Bcl11a enhancer region in HSCs can be used to treat β-thalassaemia and sickle cell disease, a strategy being employed in three recent autologous HSC-based clinical trials.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Xu, S. et al. Editing aberrant splice sites efficiently restores β-globin expression in β-thalassemia. Blood 133, 2255–2262 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Román-Rodríguez, F. J. et al. NHEJ-mediated repair of CRISPR-Cas9-induced DNA breaks efficiently corrects mutations in HSPCs from patients with Fanconi anemia. Cell Stem Cell 25, 607–621.e7 (2019).

    PubMed  Google Scholar 

  159. DiGiusto, D. L. et al. Preclinical development and qualification of ZFN-mediated CCR5 disruption in human hematopoietic stem/progenitor cells. Mol. Ther. Methods Clin. Dev. https://doi.org/10.1038/mtm.2016.67 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Cyranoski, D. The CRISPR-baby scandal: what’s next for human gene-editing. Nature 566, 440–442 (2019).

    CAS  PubMed  Google Scholar 

  161. Lanza, R., Russell, D. W. & Nagy, A. Engineering universal cells that evade immune detection. Nat. Rev. Immunol. 19, 723–733 (2019).

    CAS  PubMed  Google Scholar 

  162. Gornalusse, G. G. et al. HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat. Biotechnol. 35, 765–772 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Deuse, T. et al. Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat. Biotechnol. 37, 252–258 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Huaigeng, Xu, et al. Targeted disruption of HLA genes via CRISPR–Cas9 generates iPSCs with enhanced immune compatibility. Cell Stem Cell 24, 1–13 (2019).

    Google Scholar 

  165. Zhao, L., Teklemariam, T. & Hantash, B. M. Heterelogous expression of mutated HLA-G decreases immunogenicity of human embryonic stem cells and their epidermal derivatives. Stem Cell Res. 13, 342–354 (2014).

    CAS  PubMed  Google Scholar 

  166. Rong, Z. et al. An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell 14, 121–130 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Turner, L. & Knoepfler, P. Selling stem cells in the USA: assessing the direct-to-consumer industry. Cell Stem Cell 19, 154–157 (2016).

    CAS  PubMed  Google Scholar 

  168. Petricciani, J., Hayakawa, T., Stacey, G., Trouvin, J.-H. & Knezevic, I. Scientific considerations for the regulatory evaluation of cell therapy products. Biology 50, 20–26 (2017).

    Google Scholar 

  169. Yu, Z., Pestell, T. G., Lisanti, M. P. & Pestell, R. G. Cancer stem cells. Int. J. Biochem. Cell Biol. 44, 2144–2151 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Liang, Q. et al. Linking a cell-division gene and a suicide gene to define and improve cell therapy safety. Nature 563, 701–704 (2018).

    CAS  PubMed  Google Scholar 

  171. Gargett, T. & Brown, M. P. The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front. Pharmacol. 5, 235–235 (2014).

    PubMed  PubMed Central  Google Scholar 

  172. Yamaguchi, T. & Uchida, E. Oncolytic virus: regulatory aspects from quality control to clinical studies. Curr. Cancer Drug Targets 18, 202–208 (2018).

    CAS  PubMed  Google Scholar 

  173. van der Loo, J. C. & Wright, J. F. Progress and challenges in viral vector manufacturing. Hum. Mol. Genet. 25, R42–R52 (2016).

    PubMed  Google Scholar 

  174. Guru, A., Post, R. J., Ho, Y.-Y. & Warden, M. R. Making sense of optogenetics. Int. J. Neuropsychopharmacol. 18, pyv079–pyv079 (2015).

    PubMed  PubMed Central  Google Scholar 

  175. Klapper, S. D., Swiersy, A., Bamberg, E. & Busskamp, V. Biophysical properties of optogenetic tools and their application for vision restoration approaches. Front. Syst. Neurosci. 10, 74–74 (2016).

    PubMed  PubMed Central  Google Scholar 

  176. Garita-Hernandez, M. et al. Restoration of visual function by transplantation of optogenetically engineered photoreceptors. Nat. Commun. 10, 4524 (2019). This paper demonstrates a proof of concept for rescuing vision through the transplantation and light-induced stimulation of optogenetically engineered iPSC-derived cone photoreceptors in a retinal degenerative model.

    PubMed  PubMed Central  Google Scholar 

  177. Ono, K. et al. Optogenetic control of cell differentiation in channelrhodopsin-2-expressing OS3, a bipotential glial progenitor cell line. Neurochem. Int. 104, 49–63 (2017).

    CAS  PubMed  Google Scholar 

  178. Zenchak, J. R. et al. Bioluminescence-driven optogenetic activation of transplanted neural precursor cells improves motor deficits in a Parkinson’s disease mouse model. J. Neurosci. Res. 98, 458–468 (2018).

    PubMed  PubMed Central  Google Scholar 

  179. Steinbeck, J. A. et al. Optogenetics enables functional analysis of human embryonic stem cell-derived grafts in a Parkinson’s disease model. Nat. Biotechnol. 33, 204 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Jia, Z. et al. Stimulating cardiac muscle by light: cardiac optogenetics by cell delivery. Circ. Arrhythm. Electrophysiol. 4, 753–760 (2011).

    PubMed  PubMed Central  Google Scholar 

  181. Nussinovitch, U. & Gepstein, L. Optogenetics for in vivo cardiac pacing and resynchronization therapies. Nat. Biotechnol. 33, 750 (2015).

    CAS  PubMed  Google Scholar 

  182. Bingen, B. O. et al. Light-induced termination of spiral wave arrhythmias by optogenetic engineering of atrial cardiomyocytes. Cardiovasc. Res. 104, 194–205 (2014).

    CAS  PubMed  Google Scholar 

  183. Björk, S. et al. Evaluation of optogenetic electrophysiology tools in human stem cell-derived cardiomyocytes. Front. Physiol. 8, 884 (2017).

    PubMed  PubMed Central  Google Scholar 

  184. Zhang, F. & Tzanakakis, E. S. Optogenetic regulation of insulin secretion in pancreatic β-cells. Sci. Rep. 7, 9357 (2017).

    PubMed  PubMed Central  Google Scholar 

  185. Millman, J. R. & Pagliuca, F. W. Autologous pluripotent stem cell-derived β-like cells for diabetes cellular therapy. Diabetes 66, 1111–1120 (2017).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Astellas Institute for Regenerative Medicine, Westborough, MA, USA

    Erin A. Kimbrel & Robert Lanza

Authors
  1. Erin A. Kimbrel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Lanza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Erin A. Kimbrel or Robert Lanza.

Ethics declarations

Competing interests

E.A.K. and R.L. are employees of Astellas Institute for Regenerative Medicine.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Are Stem Cells Ready for Prime Time? A Look at FDA Research Advances in Regenerative Medicine: https://www.fda.gov/science-research/about-science-research-fda/are-stem-cells-ready-prime-time-look-fda-research-advances-regenerative-medicine (2018)

Asterias Provides Top Line 12 Month Data Update for its OPC1 Phase 1/2a Clinical Trial in Severe Spinal Cord Injury: https://www.globenewswire.com/news-release/2019/01/24/1704757/0/en/Asterias-Provides-Top-Line-12-Month-Data-Update-for-its-OPC1-Phase-1-2a-Clinical-Trial-in-Severe-Spinal-Cord-Injury.html

CRISPR Therapeutics and ViaCyte Announce Strategic Collaboration to Develop Gene-Edited Stem Cell-Derived Therapy for Diabetes: http://www.crisprtx.com/about-us/press-releases-and-presentations/crispr-therapeutics-and-via-cyte-announce-strategic-collaboration-to-develop-gene-edited-stemcell-derived-therapy-for-diabetes-1/ (2018)

Cynata CYP-001 Stem Cell Therapy Meets All Safety and Efficacy Endpoints in Phase 1 Trial in GvHD: https://www.globenewswire.com/news-release/2018/08/30/1563317/0/en/Cynata-CYP-001-Stem-Cell-Therapy-Meets-All-Safety-and-Efficacy-Endpoints-in-Phase-1-Trial-in-GvHD.html (2018)

Fate Therapeutics Presents its First Off-the-shelf, iPSC-derived CAR T-Cell Cancer Immunotherapy Program at ASH Annual Meeting: https://ir.fatetherapeutics.com/news-releases/news-release-details/fate-therapeutics-presents-its-first-shelf-ipsc-derived-car-t/ (2016)

FDA Warns About Stem Cell Therapies: https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stemcell-therapies/(2019).

First iPSC-Derived CAR T-Cell Therapy Created by Kyoto University CiRA and Takeda Collaboration Enters Process Development Towards Clinical Testing: https://www.takeda.com/newsroom/newsreleases/2019/first-ipsc-derived-car-t-cell-therapy-created-by-kyoto-university-cira-and–takeda-collaboration-enters-process-development-towards-clinical-testing/ (2019)

Framework for the Regulation of Regenerative Medicine Products: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/framework-regulation-regenerative-medicine-products (2019)

Gene Therapy Clinical Trials Worldwide Provided by the Journal of Gene Medicine: http://www.abedia.com/wiley/vectors.php (2018)

Japan’s Regenerative Medicine Environment — A Guide to Understand the Pathways to Get Approval in Japan: https://firm.or.jp/_rmit/wp-content/uploads/2018/10/Japans-RM-Environment-2018.pdf (2018)

Multidisciplinary: cell therapy and tissue engineering: https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciplinary/multidisciplinary-cell-therapy-tissue-engineering (2019)

SanBio: SB623, an Investigational Product, Granted Advanced Therapy Medicinal Product Classification by European Medicines Agency: https://www.businesswire.com/news/home/20190424006185/en/ (2019)

SanBio and Sumitomo Dainippon Pharma Announce Topline Results from a Phase 2b Study in the U.S. Evaluating SB623, a Regenerative Cell Medicine for the Treatment of Patients with Chronic Stroke: https://www.ds-pharma.com/ir/news/pdf/ene20190129.1.pdf/ (2019)

SanBio Announces SB623 Regenerative Cell Therapy for Traumatic Brain Injury Has Received Ministry of Health, Labour and Welfare (MHLW) Sakigake Designation: https://www.businesswire.com/news/home/20190408005341/en/ (2019)

Two-year Data from ViaCyte’s STEP ONE Clinical Trial Presented at ADA 2018: https://www.prnewswire.com/news-releases/two-year-data-from-viacytes-step-one-clinical-trial-presented-at-ada-2018-300671013.html

World Health Organization: Haematopoietic Stem Cell Transplantation HSCtx: https://www.who.int/transplantation/hsctx/en/ (2019)

Glossary

Multipotent

The ability to give rise to many different cell types.

Human leukocyte antigen (HLA) genes

Genes located on chromosome 6 that encode major histocompatibility complex proteins, a set of proteins that help immune cells to distinguish self from non-self cells. HLA mismatches are responsible for immune-mediated rejection of allogeneic cells.

Pluripotent

The ability to give rise to all cell types in the body.

Tumour tropism

The tendency (for a stem cell) to migrate towards a tumour, usually induced by chemoattraction of that cell to chemoattractants, angiogenic factors or inflammatory signals produced by a tumour.

Chimeric antigen receptor

(CAR). A class of genetically engineered, modular receptors that can be used to elicit highly potent, antigen-specific immune responses. The basic CAR structure consists of an extracellular antigen-specific binding domain, a hinge domain, a transmembrane domain and an intracellular signalling domain, although many versions of CARs also contain co-stimulatory domains and other modular features.

Optogenetic

An engineering approach to introduce genes that encode light-responsive proteins into cells in order to be able to control cellular signalling pathways upon exposure to specific wavelengths of light.

X-linked severe combined immunodeficiency

(SCID). A rare inherited immune system disorder caused by mutations in the IL2RG gene, which is typically fatal early in life unless reconstitution of the immune system is achieved through bone marrow transplantation or gene therapy.

Wiskott–Aldrich syndrome

An X-linked primary immunodeficiency disorder caused by mutations in the WAS gene, which encodes a cytoskeletal protein essential for normal immune cell function. Insertion of a normal, wild-type WAS gene into a patient’s haematopoietic stem and progenitor cells may thus be able to functionally compensate for their mutated gene upon their differentiation into the afflicted immune cells.

Chemogenetics

An engineering approach to express genes encoding designer receptors in cells in order to be able to control the cells’ activity through administration of chemicals/drugs specifically designed to bind to the designer receptors.

Click chemistry

The use of bio-orthogonal functional groups that enables linking two molecules of interest (biological and/or purely synthetic) together, such as the attachment of azide-coated cells with cyclooctyene-coated nanoparticles.

γδ T cells

A rare subset of T cells that can be found in the gut mucosa, skin and lungs, thought to help bridge the innate and adaptive immune systems. Their name originates from the unique composition of their T cell receptor, which consists of a γ-chain and a δ-chain, as opposed to the more abundant αβ T cell subset whose T cell receptor consists of an α-chain and a β-chain.

Duchenne muscular dystrophy

A neuromuscular disorder caused by mutations in the gene encoding dystrophin, which result in severe muscle wasting.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kimbrel, E.A., Lanza, R. Next-generation stem cells — ushering in a new era of cell-based therapies. Nat Rev Drug Discov 19, 463–479 (2020). https://doi.org/10.1038/s41573-020-0064-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41573-020-0064-x

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research