Within just over a decade, human reprogramming-based disease modeling has developed from a rather outlandish idea into an essential part of disease research. While iPSCs are a valuable tool for modeling developmental and monogenetic disorders, their rejuvenated identity poses limitations for modeling age-associated diseases. Direct cell-type conversion of fibroblasts into induced neurons (iNs) circumvents rejuvenation and preserves hallmarks of cellular aging. iNs are thus advantageous for modeling diseases that possess strong age-related and epigenetic contributions and can complement iPSC-based strategies for disease modeling. In this review, we provide an overview of the state of the art of direct iN conversion and describe the key epigenetic, transcriptomic, and metabolic changes that occur in converting fibroblasts. Furthermore, we summarize new insights into this fascinating process, particularly focusing on the rapidly changing criteria used to define and characterize in vitro-born human neurons. Finally, we discuss the unique features that distinguish iNs from other reprogramming-based neuronal cell models and how iNs are relevant to disease modeling.
Keywords: aging; cellular reprogramming; direct conversion; disease modeling; epigenetics; geriatric diseases; induced neurons; metabolism; neurodegenerative disorders.
© 2019 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Direct Neuronal Reprogramming for Disease Modeling Studies Using Patient-Derived Neurons: What Have We Learned?Front Neurosci. 2017 Sep 28;11:530. doi: 10.3389/fnins.2017.00530. eCollection 2017. Front Neurosci. 2017. PMID: 29033781 Free PMC article. Review.
Human neurons to model aging: A dish best served old.Drug Discov Today Dis Models. 2018 Spring;27:43-49. doi: 10.1016/j.ddmod.2019.01.001. Epub 2019 Feb 12. Drug Discov Today Dis Models. 2018. PMID: 31745399 Free PMC article.
Direct Reprogramming Rather than iPSC-Based Reprogramming Maintains Aging Hallmarks in Human Motor Neurons.Front Mol Neurosci. 2017 Nov 2;10:359. doi: 10.3389/fnmol.2017.00359. eCollection 2017. Front Mol Neurosci. 2017. PMID: 29163034 Free PMC article.
Aging in a Dish: iPSC-Derived and Directly Induced Neurons for Studying Brain Aging and Age-Related Neurodegenerative Diseases.Annu Rev Genet. 2018 Nov 23;52:271-293. doi: 10.1146/annurev-genet-120417-031534. Epub 2018 Sep 12. Annu Rev Genet. 2018. PMID: 30208291 Free PMC article. Review.
Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects.Cell Stem Cell. 2015 Dec 3;17(6):705-718. doi: 10.1016/j.stem.2015.09.001. Epub 2015 Oct 8. Cell Stem Cell. 2015. PMID: 26456686 Free PMC article.
Cited by 1 article
Take the shortcut - direct conversion of somatic cells into induced neural stem cells and their biomedical applications.FEBS Lett. 2019 Dec;593(23):3353-3369. doi: 10.1002/1873-3468.13656. Epub 2019 Dec 1. FEBS Lett. 2019. PMID: 31663609 Free PMC article. Review.