Acquisition of functional neurons by direct conversion: Switching the developmental clock directly.

Identifying approaches for treating neurodegeneration is a thorny task but is important for a growing number of patients. Researchers have focused on discovering the underlying molecular mechanisms of reprogramming and optimizing the technologies for acquiring neurons. Direct conversion is one of the most important processes for treating neurological disorders. Induced neurons derived from direct conversion, which bypass the pluripotency stage, are more effective, more quickly obtained, and are safer than those produced via induced pluripotent stem cells (iPSCs). Based on iPSC strategies, scientists have derived methods to obtain functional neurons by direct conversion, such as neuron-related transcriptional factors, small molecules, microRNAs, and epigenetic modifiers. In this review, we discuss the present strategies for direct conversion of somatic cells into functional neurons and the potentials of direct conversion for producing functional neurons and treating neurodegeneration.

[1]  J. Boockvar,et al.  Direct conversion of human fibroblasts to functional neurons in one step. , 2011, Neurosurgery.

[2]  Kechun Zhou,et al.  Induction of fibroblasts to neurons through adenoviral gene delivery , 2011, Cell Research.

[3]  Sheng Ding,et al.  Chemical approaches to stem cell biology and therapeutics. , 2013, Cell stem cell.

[4]  Kevin Eggan,et al.  Conversion of mouse and human fibroblasts into functional spinal motor neurons. , 2011, Cell stem cell.

[5]  Z. Deng,et al.  The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes , 2011, Nature.

[6]  B. Ebrahimi Engineering cell fate: Spotlight on cell-activation and signaling-directed lineage conversion. , 2016, Tissue & cell.

[7]  Peter Wernet,et al.  Small molecules enable highly efficient neuronal conversion of human fibroblasts , 2012, Nature Methods.

[8]  Fang Li,et al.  Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells , 2011, Cell Research.

[9]  Chun-li Zhang,et al.  Small Molecules Modulate Chromatin Accessibility to Promote NEUROG2-Mediated Fibroblast-to-Neuron Reprogramming , 2016, Stem cell reports.

[10]  I. Velasco,et al.  Concise Review: Generation of Neurons From Somatic Cells of Healthy Individuals and Neurological Patients Through Induced Pluripotency or Direct Conversion , 2014, Stem cells.

[11]  N. Heintz,et al.  The Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in Purkinje Neurons and the Brain , 2009, Science.

[12]  P. Jin,et al.  Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons. , 2015, Cell stem cell.

[13]  Ryan Thompson,et al.  Forskolin and IBMX Induce Neural Transdifferentiation of MSCs Through Downregulation of the NRSF , 2019, Scientific Reports.

[14]  Xu Zhang,et al.  Direct Reprogramming of Fibroblasts via a Chemically Induced XEN-like State. , 2017, Cell stem cell.

[15]  Hi-Joon Park,et al.  Electromagnetized gold nanoparticles mediate direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson's disease therapy. , 2017, Nature nanotechnology.

[16]  Marius Wernig,et al.  Direct somatic lineage conversion , 2015, Philosophical Transactions of the Royal Society B: Biological Sciences.

[17]  S. Linnarsson,et al.  Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model , 2017, Nature Biotechnology.

[18]  Yunlong Huang,et al.  Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion , 2015, Scientific Reports.

[19]  E. Finch,et al.  MicroRNA-Mediated In Vitro and In Vivo Direct Reprogramming of Cardiac Fibroblasts to Cardiomyocytes , 2012, Circulation research.

[20]  Li Li,et al.  MicroRNA-mediated conversion of human fibroblasts to neurons , 2011, Nature.

[21]  Yi Hu,et al.  A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion , 2019, Molecular therapy : the journal of the American Society of Gene Therapy.

[22]  Yi Zhang,et al.  Direct Conversion of Fibroblasts to Neurons by Reprogramming PTB-Regulated MicroRNA Circuits , 2013, Cell.

[23]  Xin Xie,et al.  Chemical reprogramming and transdifferentiation. , 2017, Current opinion in genetics & development.

[24]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[25]  Liu Wang,et al.  Generation of dopaminergic neurons directly from mouse fibroblasts and fibroblast-derived neural progenitors , 2012, Cell Research.

[26]  Xinzhong Dong,et al.  Generation of multipotent induced neural crest by direct reprogramming of human postnatal fibroblasts with a single transcription factor. , 2014, Cell stem cell.

[27]  R. Yasuda,et al.  The effect of substrate topography on direct reprogramming of fibroblasts to induced neurons. , 2014, Biomaterials.

[28]  R. Bachoo,et al.  In vivo reprogramming of astrocytes to neuroblasts in the adult brain , 2013, Nature Cell Biology.

[29]  Maria Teresa Dell'Anno,et al.  Direct generation of functional dopaminergic neurons from mouse and human fibroblasts , 2011, Nature.

[30]  Thomas Vierbuchen,et al.  Induction of human neuronal cells by defined transcription factors , 2011, Nature.

[31]  Masaki Ieda,et al.  Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. , 2010, Cell.

[32]  O. Lindvall,et al.  Direct conversion of human fibroblasts to functional excitatory cortical neurons integrating into human neural networks , 2017, Stem Cell Research & Therapy.

[33]  J. Mesirov,et al.  Role of Tet1/3 Genes and Chromatin Remodeling Genes in Cerebellar Circuit Formation , 2016, Neuron.

[34]  N. Neff,et al.  Dissecting direct reprogramming from fibroblast to neuron using single-cell RNA-seq , 2016, Nature.

[35]  Chen Yu,et al.  Chemical approaches to cell reprogramming. , 2014, Current opinion in genetics & development.

[36]  C. Lengner,et al.  Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. , 2011, Cell stem cell.

[37]  Wardiya Afshar Saber,et al.  Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts , 2014, Nature Neuroscience.

[38]  Mary Anne Wheeler,et al.  Stem , 1985 .

[39]  I. Bezprozvanny,et al.  Small-molecule activation of neuronal cell fate. , 2008, Nature chemical biology.

[40]  K. Baldwin,et al.  Selective conversion of fibroblasts into peripheral sensory neurons , 2014, Nature Neuroscience.

[41]  T. Graf,et al.  Historical origins of transdifferentiation and reprogramming. , 2011, Cell stem cell.

[42]  T. Südhof,et al.  Induced neuronal cells: how to make and define a neuron. , 2011, Cell stem cell.

[43]  S. Lang,et al.  Small molecules increase direct neural conversion of human fibroblasts , 2016, Scientific Reports.

[44]  Zhen Yan,et al.  Direct conversion of human fibroblasts to induced serotonergic neurons , 2015, Molecular Psychiatry.

[45]  K. Shirahige,et al.  Pioneer Factor NeuroD1 Rearranges Transcriptional and Epigenetic Profiles to Execute Microglia-Neuron Conversion , 2019, Neuron.

[46]  Seung Woo Jung,et al.  Generation of Induced Neuronal Cells by the Single Reprogramming Factor ASCL1 , 2014, Stem cell reports.

[47]  Lewis Eb The 1991 Albert Lasker Medical Awards. Clusters of master control genes regulate the development of higher organisms. , 1992 .

[48]  L. Aravind,et al.  Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 , 2010, Nature.

[49]  Thomas Vierbuchen,et al.  Direct conversion of fibroblasts to functional neurons by defined factors , 2010, Nature.

[50]  Paul Flicek,et al.  Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during Neurogenesis , 2015, Cell reports.

[51]  M. Götz,et al.  Directing Astroglia from the Cerebral Cortex into Subtype Specific Functional Neurons , 2010, PLoS biology.

[52]  Joshua C. Chang,et al.  Small Molecules Enable Neurogenin 2 to Efficiently Convert Human Fibroblasts to Cholinergic Neurons , 2013, Nature Communications.

[53]  K. Hochedlinger,et al.  Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells , 2010, Nature Biotechnology.

[54]  S. Lipton,et al.  Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. , 2011, Cell stem cell.

[55]  H. Weintraub,et al.  Expression of a single transfected cDNA converts fibroblasts to myoblasts , 1987, Cell.

[56]  Qinqin Deng,et al.  Direct reprogramming of fibroblasts into neural stem cells by single non-neural progenitor transcription factor Ptf1a , 2018, Nature Communications.

[57]  Xiang Li,et al.  Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons. , 2015, Cell stem cell.

[58]  J. Kim,et al.  Direct Reprogramming of Human Dermal Fibroblasts Into Endothelial Cells Using ER71/ETV2 , 2017, Circulation research.

[59]  Howard Y. Chang,et al.  Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons , 2018, bioRxiv.

[60]  T. Cai,et al.  Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. , 2013, Cell stem cell.

[61]  Qinying Wang,et al.  Direct Conversion of Normal and Alzheimer's Disease Human Fibroblasts into Neuronal Cells by Small Molecules. , 2015, Cell stem cell.

[62]  Phuc Van Pham,et al.  Production of endothelial progenitor cells from skin fibroblasts by direct reprogramming for clinical usages , 2017, In Vitro Cellular & Developmental Biology - Animal.

[63]  Qi Zhou,et al.  Tet3-Mediated DNA Demethylation Contributes to the Direct Conversion of Fibroblast to Functional Neuron. , 2016, Cell reports.

[64]  F. Dong,et al.  Chemical Conversion of Human Fetal Astrocytes into Neurons through Modulation of Multiple Signaling Pathways , 2019, Stem cell reports.

[65]  G. Turcatti,et al.  Targeting STING with covalent small-molecule inhibitors , 2018, Nature.

[66]  M. Sur,et al.  Direct Lineage Conversion of Adult Mouse Liver Cells and B Lymphocytes to Neural Stem Cells , 2014, Stem cell reports.

[67]  N. Murthy,et al.  Peptide-enhanced mRNA transfection in cultured mouse cardiac fibroblasts and direct reprogramming towards cardiomyocyte-like cells , 2015, International journal of nanomedicine.

[68]  Ziyuan Guo,et al.  Reversing Glial Scar Back To Neural Tissue Through NeuroD1-Mediated Astrocyte-To-Neuron Conversion , 2018, bioRxiv.

[69]  R. Schugar,et al.  Small molecules in stem cell self-renewal and differentiation , 2008, Gene Therapy.

[70]  Xiaocheng Lu,et al.  Neurogenin 2 enhances the generation of patient-specific induced neuronal cells , 2015, Brain Research.

[71]  Giovanni Coppola,et al.  Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair , 2015, Nature Neuroscience.

[72]  Gong Chen,et al.  Transcriptome Analysis of Small Molecule–Mediated Astrocyte-to-Neuron Reprogramming , 2019, Front. Cell Dev. Biol..

[73]  A. Björklund,et al.  Generation of induced neurons via direct conversion in vivo , 2013, Proceedings of the National Academy of Sciences.

[74]  F. Gage,et al.  Chemical modulation of transcriptionally enriched signaling pathways to optimize the conversion of fibroblasts into neurons , 2019, eLife.

[75]  E. Lewis,et al.  The 1991 Albert Lasker Medical Awards. Clusters of master control genes regulate the development of higher organisms. , 1992, JAMA.

[76]  Zachary D. Smith,et al.  DNA methylation: roles in mammalian development , 2013, Nature Reviews Genetics.

[77]  Weiguang Li,et al.  Generation of patient-specific induced neuronal cells using a direct reprogramming strategy. , 2014, Stem cells and development.

[78]  T. Elsdale,et al.  Sexually Mature Individuals of Xenopus laevis from the Transplantation of Single Somatic Nuclei , 1958, Nature.

[79]  Lei Zhang,et al.  In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model. , 2014, Cell stem cell.

[80]  B. Grothe,et al.  Functional Properties of Neurons Derived from In Vitro Reprogrammed Postnatal Astroglia , 2007, The Journal of Neuroscience.

[81]  S. Lipton,et al.  Direct reprogramming of mouse fibroblasts to neural progenitors , 2011, Proceedings of the National Academy of Sciences.

[82]  N. Bresolin,et al.  Direct Reprogramming of Adult Somatic Cells into other Lineages: Past Evidence and Future Perspectives , 2013, Cell transplantation.

[83]  Ulrich Pfisterer,et al.  Direct conversion of human fibroblasts to dopaminergic neurons , 2011, Proceedings of the National Academy of Sciences.

[84]  Howard Y. Chang,et al.  Hierarchical Mechanisms for Direct Reprogramming of Fibroblasts to Neurons , 2013, Cell.

[85]  Matheus B. Victor,et al.  Generation of Human Striatal Neurons by MicroRNA-Dependent Direct Conversion of Fibroblasts , 2014, Neuron.

[86]  Skirmantas Kriaucionis,et al.  MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. , 2012, Cell.

[87]  Hongkui Deng,et al.  Direct lineage reprogramming: strategies, mechanisms, and applications. , 2015, Cell stem cell.

[88]  Yoshinori Harada,et al.  Highly efficient direct conversion of human fibroblasts to neuronal cells by chemical compounds , 2015, Journal of clinical biochemistry and nutrition.

[89]  Peng Jin,et al.  5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging , 2011, Nature Neuroscience.

[90]  R. Young,et al.  Stem Cells, the Molecular Circuitry of Pluripotency and Nuclear Reprogramming , 2008, Cell.

[91]  D. Jeon,et al.  Direct lineage reprogramming of mouse fibroblasts to functional midbrain dopaminergic neuronal progenitors. , 2014, Stem cell research.

[92]  O. Kretz,et al.  Direct reprogramming of fibroblasts into renal tubular epithelial cells by defined transcription factors , 2016, Nature Cell Biology.