{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:51:06Z","timestamp":1785372666964,"version":"3.55.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>Direct cellular reprogramming exhibits distinct advantages over reprogramming from an induced pluripotent stem cell intermediate. These include a reduced risk of tumorigenesis and the likely preservation of epigenetic data. <jats:italic>In vitro<\/jats:italic> direct reprogramming approaches primarily aim to model the pathophysiological development of neurological disease and identify therapeutic targets, while <jats:italic>in vivo<\/jats:italic> direct reprogramming aims to develop treatments for various neurological disorders, including cerebral injury and cancer. In both approaches, there is progress toward developing increased control of subtype-specific production of induced neurons. A majority of research primarily utilizes fibroblasts as the donor cells. However, there are a variety of other somatic cell types that have demonstrated the potential for reprogramming into induced neurons. This review highlights studies that utilize non-fibroblastic cell sources for reprogramming, such as astrocytes, olfactory ensheathing cells, peripheral blood cells, M\u00fcller glia, and more. We will examine benefits and obstructions for translation into therapeutics or disease modeling, as well as efficiency of the conversion. A summary of donor cells, induced neuron types, and methods of induction is also provided.<\/jats:p>","DOI":"10.3389\/fbioe.2021.658498","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T09:44:00Z","timestamp":1615542240000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Induced Neurons for Disease Modeling and Repair: A Focus on Non-fibroblastic Cell Sources in Direct Reprogramming"],"prefix":"10.3389","volume":"9","author":[{"given":"Kathryn M.","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mentor","family":"Thaqi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Marr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-019-1255-4","article-title":"Examining the fundamental biology of a novel population of directly reprogrammed human neural precursor cells.","volume":"10","author":"Ahlfors","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/978-1-0716-0655-1_4","article-title":"In vitro direct reprogramming of mouse and human astrocytes to induced neurons","author":"Aravantinou-Fatorou","year":"2020","journal-title":"Stem Cells and Tissue Repair: Methods and Protocols"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1506","DOI":"10.1016\/j.stemcr.2017.04.013","article-title":"NEUROD1 instructs neuronal conversion in non-reactive astrocytes.","volume":"8","author":"Brulet","year":"2017","journal-title":"Stem Cell Rep."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1016\/j.stemcr.2014.10.008","article-title":"Fast and efficient neural conversion of human hematopoietic cells.","volume":"3","author":"Casta\u00f1o","year":"2014","journal-title":"Stem Cell Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.stem.2020.08.015","article-title":"Deconstructing stepwise fate conversion of human fibroblasts to neurons by microRNAs.","volume":"28","author":"Cates","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.ymthe.2019.09.003","article-title":"A NeuroD1 AAV-based gene therapy for functional brain repair after ischemic injury through in vivo astrocyte-to-neuron conversion.","volume":"28","author":"Chen","year":"2019","journal-title":"Mol. Ther."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/cells8060571","article-title":"Inhibition of glioma development by ASCL1-mediated direct neuronal reprogramming.","volume":"8","author":"Cheng","year":"2019","journal-title":"Cells"},{"key":"B8","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.stemcr.2017.05.009","article-title":"Lineage reprogramming of astroglial cells from different origins into distinct neuronal subtypes.","volume":"9","author":"Chouchane","year":"2017","journal-title":"Stem Cell Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1038\/nbt.3835","article-title":"Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson\u2019s disease model.","volume":"35","author":"di Val Cervo","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00460","article-title":"Potentials of cellular reprogramming as a novel strategy for neuroregeneration.","volume":"12","author":"Fang","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.stem.2017.06.011","article-title":"Identification and successful negotiation of a metabolic checkpoint in direct neuronal reprogramming.","volume":"18","author":"Gasc\u00f3n","year":"2016","journal-title":"Cell Stem Cell"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3373","article-title":"Environmental impact on direct neuronal reprogramming in vivo in the adult brain.","volume":"4","author":"Grande","year":"2013","journal-title":"Nat. Commun."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2019.00334","article-title":"Very low efficiency of direct reprogramming of astrocytes into neurons in the brains of young and aged mice after cerebral ischemia.","volume":"11","author":"Gresita","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1002\/sctm.20-0134","article-title":"Grafted human pluripotent stem cell-derived cortical neurons integrate into adult human cortical neural circuitry.","volume":"9","author":"Gr\u00f8nning Hansen","year":"2020","journal-title":"Stem Cells Transl. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"124","DOI":"10.4103\/1673-5374.243717","article-title":"Olfactory ensheathing cells promote nerve regeneration and functional recovery after facial nerve defects.","volume":"14","author":"Gu","year":"2019","journal-title":"Neural. Regen. Res."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00410","article-title":"Evidence of M\u00fcller glia conversion into retina ganglion cells using neurogenin2.","volume":"12","author":"Guimar\u00e3es","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.stem.2013.12.001","article-title":"In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer\u2019s disease model.","volume":"14","author":"Guo","year":"2014","journal-title":"Cell Stem Cell"},{"key":"B18","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/978-1-4939-9007-8_6","article-title":"In vitro functional characterization of human neurons and astrocytes using calcium imaging and electrophysiology","author":"Hansen","year":"2019","journal-title":"Neural Stem Cells: Methods and Protocols"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1016\/j.stemcr.2014.10.007","article-title":"Sox2-mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortex.","volume":"3","author":"Heinrich","year":"2014","journal-title":"Stem Cell Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.stem.2020.12.007","article-title":"One big step to a neuron, two small steps for miRNAs.","volume":"28","author":"Herdy","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.stemcr.2018.12.017","article-title":"Region-restrict astrocytes exhibit heterogeneous susceptibility to neuronal reprogramming.","volume":"12","author":"Hu","year":"2019","journal-title":"Stem Cell Rep."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.18648","article-title":"Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts.","volume":"5","author":"Huh","year":"2016","journal-title":"eLife"},{"key":"B23","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/nature23283","article-title":"Stimulation of functional neuronal regeneration from M\u00fcller glia in adult mice.","volume":"548","author":"Jorstad","year":"2017","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1016\/j.celrep.2020.01.075","article-title":"STAT signaling modifies Ascl1 chromatin binding and limits neural regeneration from Muller glia in adult mouse retina.","volume":"30","author":"Jorstad","year":"2020","journal-title":"Cell Rep."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3390\/cells8091043","article-title":"mRNA-driven generation of transgene-free neural stem cells from human urine-derived cells.","volume":"8","author":"Kang","year":"2019","journal-title":"Cells"},{"key":"B26","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1038\/s41593-018-0168-3","article-title":"Direct pericyte-to-neuron reprogramming via unfolding of a neural stem cell-like program.","volume":"21","author":"Karow","year":"2018","journal-title":"Nat. Neurosci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.stem.2012.07.007","article-title":"Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells.","volume":"11","author":"Karow","year":"2012","journal-title":"Cell Stem Cell"},{"key":"B28","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1016\/j.celrep.2019.06.042","article-title":"Conversion of astrocytes and fibroblasts into functional noradrenergic neurons.","volume":"28","author":"Li","year":"2019","journal-title":"Cell Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1002\/glia.20241","article-title":"Olfactory ensheathing cells and olfactory nerve fibroblasts maintain continuous open channels for regrowth of olfactory nerve fibres.","volume":"52","author":"Li","year":"2005","journal-title":"Glia"},{"key":"B30","doi-asserted-by":"publisher","first-page":"7783","DOI":"10.1523\/JNEUROSCI.23-21-07783.2003","article-title":"Transplanted olfactory ensheathing cells promote regeneration of cut adult rat optic nerve axons.","volume":"23","author":"Li","year":"2003","journal-title":"J. Neurosci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1111\/cns.12821","article-title":"Myt1l induced direct reprogramming of pericytes into cholinergic neurons.","volume":"24","author":"Liang","year":"2018","journal-title":"CNS Neurosci. Ther."},{"key":"B32","doi-asserted-by":"publisher","first-page":"342","DOI":"10.4103\/1673-5374.265185","article-title":"Differential neuronal reprogramming induced by NeuroD1 from astrocytes in grey matter versus white matter.","volume":"15","author":"Liu","year":"2020","journal-title":"Neural. Regen. Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"9336","DOI":"10.1523\/JNEUROSCI.3975-14.2015","article-title":"Ascl1 converts dorsal midbrain astrocytes into functional neurons in vivo.","volume":"35","author":"Liu","year":"2015","journal-title":"J. Neurosci."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1101\/2020.02.02.929091","article-title":"Direct reprogramming of astrocytes to neurons leads to functional recovery after stroke.","author":"Livingston","year":"2020","journal-title":"bioRxiv"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-018-0132-x","article-title":"Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons.","volume":"7","author":"Ma","year":"2018","journal-title":"Transl. Neurodegener."},{"key":"B36","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1016\/j.stem.2015.09.001","article-title":"Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects.","volume":"17","author":"Mertens","year":"2015","journal-title":"Cell Stem Cell"},{"key":"B37","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1016\/j.stemcr.2020.08.013","article-title":"Direct reprogramming of human fetal- and stem cell-derived glial progenitor cells into midbrain dopaminergic neurons.","volume":"15","author":"Nolbrant","year":"2020","journal-title":"Stem Cell Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.neuroscience.2018.03.033","article-title":"Transcription factors in regulatory and protein subnetworks during generation of neural stem cells and neurons from direct reprogramming of non-fibroblastic cell sources.","volume":"380","author":"Omrani","year":"2018","journal-title":"Neuroscience"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3791\/59465","article-title":"In vivo direct reprogramming of resident glial cells into interneurons by intracerebral injection of viral vectors.","author":"Pereira","year":"2019","journal-title":"J. Vis. Exp."},{"key":"B40","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1016\/j.stemcr.2017.07.023","article-title":"Direct reprogramming of resident NG2 glia into neurons with properties of fast-spiking parvalbumin-containing interneurons.","volume":"9","author":"Pereira","year":"2017","journal-title":"Stem Cell Rep."},{"key":"B41","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1038\/s41586-020-2388-4","article-title":"Reversing a model of Parkinson\u2019s disease with in situ converted nigral neurons.","volume":"582","author":"Qian","year":"2020","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2018.00173","article-title":"Transdifferentiating astrocytes into neurons using ASCL1 functionalized with a novel intracellular protein delivery technology.","volume":"6","author":"Robinson","year":"2018","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.10.015","article-title":"CRISPR-mediated induction of neuron-enriched mitochondrial proteins boosts direct glia-to-neuron conversion.","author":"Russo","year":"2020","journal-title":"Cell Stem Cell"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1016\/j.cell.2016.08.055","article-title":"In vivo cellular reprogramming: the next generation.","volume":"166","author":"Srivastava","year":"2016","journal-title":"Cell"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4338","article-title":"In vivo conversion of astrocytes to neurons in the injured adult spinal cord.","volume":"5","author":"Su","year":"2014","journal-title":"Nat. Commun."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-020-00960-3","article-title":"Transplantation of induced neural stem cells (iNSCs) into chronically demyelinated corpus callosum ameliorates motor deficits.","volume":"8","author":"Sullivan","year":"2020","journal-title":"Acta Neuropathol. Commun."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1887-4","article-title":"Direct neuronal reprogramming of olfactory ensheathing cells for CNS repair.","volume":"10","author":"Sun","year":"2019","journal-title":"Cell Death Dis."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3390\/antiox8080323","article-title":"Antioxidant regulation of cell reprogramming.","volume":"8","author":"Suzuki","year":"2019","journal-title":"Antioxidants (Basel)"},{"key":"B49","doi-asserted-by":"publisher","first-page":"6470","DOI":"10.1073\/pnas.1720273115","article-title":"Transdifferentiation of human adult peripheral blood T cells into neurons.","volume":"115","author":"Tanabe","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B50","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.stem.2018.11.015","article-title":"Identification of embryonic neural plate border stem cells and their generation by direct reprogramming from adult human blood cells.","volume":"24","author":"Thier","year":"2019","journal-title":"Cell Stem Cell"},{"key":"B51","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1016\/j.celrep.2015.06.040","article-title":"In vivo reprogramming of striatal NG2 glia into functional neurons that integrate into local host circuitry.","volume":"12","author":"Torper","year":"2015","journal-title":"Cell Rep."},{"key":"B52","doi-asserted-by":"publisher","first-page":"7038","DOI":"10.1073\/pnas.1303829110","article-title":"Generation of induced neurons via direct conversion in vivo.","volume":"110","author":"Torper","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B53","doi-asserted-by":"publisher","first-page":"3316","DOI":"10.1002\/1873-3468.13678","article-title":"Next\u2212generation disease modeling with direct conversion: a new path to old neurons.","volume":"593","author":"Traxler","year":"2019","journal-title":"FEBS Lett."},{"key":"B54","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.molmed.2018.12.005","article-title":"Novel direct conversion of microglia to neurons.","volume":"25","author":"Trudler","year":"2019","journal-title":"Trends Mol. Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"13717","DOI":"10.1073\/pnas.1510595112","article-title":"Transgenic expression of the proneural transcription factor Ascl1 in M\u00fcller glia stimulates retinal regeneration in young mice.","volume":"112","author":"Ueki","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1002\/sctm.19-0054","article-title":"Chemotherapy\u2212induced neuropathy and drug discovery platform using human sensory neurons converted directly from adult peripheral blood.","volume":"8","author":"Vojnits","year":"2019","journal-title":"Stem Cells Transl. Med."},{"key":"B57","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s12975-019-0691-x","article-title":"Transplantation of directly reprogrammed human neural precursor cells following stroke promotes synaptogenesis and functional recovery.","volume":"11","author":"Vonderwalde","year":"2020","journal-title":"Transl. Stroke Res."},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-020-0184-6","article-title":"Reprogrammed astrocytes display higher neurogenic competence, migration ability and cell death resistance than reprogrammed fibroblasts.","volume":"9","author":"Xia","year":"2020","journal-title":"Transl. Neurodegener."},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-53007-6","article-title":"Direct conversion of human urine cells to neurons by small molecules.","volume":"9","author":"Xu","year":"2019","journal-title":"Sci. Rep."},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2020.594170","article-title":"Development of neuroregenerative gene therapy to reverse glial scar tissue back to neuron-enriched tissue.","volume":"14","author":"Zhang","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"B61","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1016\/j.cell.2020.03.024","article-title":"Glia-to-neuron conversion by CRISPR-CasRx alleviates symptoms of neurological disease in mice.","volume":"181","author":"Zhou","year":"2020","journal-title":"Cell"}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2021.658498\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T09:44:02Z","timestamp":1615542242000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2021.658498\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":61,"alternative-id":["10.3389\/fbioe.2021.658498"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2021.658498","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,12]]},"article-number":"658498"}}