{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T07:19:26Z","timestamp":1792653566493,"version":"4.5.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000},"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. Cell Dev. Biol."],"abstract":"<jats:p>Stem cell therapy using human skin-derived neural precursors holds much promise for the treatment of stroke patients. Two main mechanisms have been proposed to give rise to the improved recovery in animal models of stroke after transplantation of these cells. First, the so called by-stander effect, which could modulate the environment during early phases after brain tissue damage, resulting in moderate improvements in the outcome of the insult. Second, the neuronal replacement and functional integration of grafted cells into the impaired brain circuitry, which will result in optimum long-term structural and functional repair. Recently developed sophisticated research tools like optogenetic control of neuronal activity and rabies virus monosynaptic tracing, among others, have made it possible to provide solid evidence about the functional integration of grafted cells and its contribution to improved recovery in animal models of brain damage. Moreover, previous clinical trials in patients with Parkinson\u2019s Disease represent a proof of principle that stem cell-based neuronal replacement could work in humans. Our studies with<jats:italic>in vivo<\/jats:italic>and<jats:italic>ex vivo<\/jats:italic>transplantation of human skin-derived cells neurons in animal model of stroke and organotypic cultures of adult human cortex, respectively, also support the hypothesis that human somatic cells reprogrammed into neurons can get integrated in the human lesioned neuronal circuitry. In the present short review, we summarized our data and recent studies from other groups supporting the above hypothesis and opening new avenues for development of the future clinical applications.<\/jats:p>","DOI":"10.3389\/fcell.2021.662636","type":"journal-article","created":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T05:35:22Z","timestamp":1617687322000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"title":["Neuronal Replacement in Stem Cell Therapy for Stroke: Filling the Gap"],"prefix":"10.3389","volume":"9","author":[{"given":"Sara","family":"Palma-Tortosa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berta","family":"Coll-San Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaal","family":"Kokaia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Tornero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00684","article-title":"Pluripotent stem cells for brain repair: protocols and preclinical applications in cortical and hippocampal pathologies.","volume":"13","author":"Alia","year":"2019","journal-title":"Front. Neurosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4708","DOI":"10.1093\/cercor\/bhaa075","article-title":"Transplanted embryonic neurons improve functional recovery by increasing activity in injured cortical circuits.","volume":"30","author":"Andreoli","year":"2020","journal-title":"Cereb. Cortex"},{"key":"B3","doi-asserted-by":"publisher","first-page":"5163","DOI":"10.1073\/pnas.0700293104","article-title":"Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.","volume":"104","author":"Armbruster","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B4","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.3727\/096368912X657314","article-title":"Therapeutic potential of human induced pluripotent stem cells in experimental stroke.","volume":"22","author":"Chang","year":"2013","journal-title":"Cell Transplant."},{"key":"B5","doi-asserted-by":"publisher","first-page":"12913","DOI":"10.1073\/pnas.1404109111","article-title":"Optogenetic neuronal stimulation promotes functional recovery after stroke.","volume":"111","author":"Cheng","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B6","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms14162","article-title":"Whole-brain 3D mapping of human neural transplant innervation.","volume":"8","author":"Doerr","year":"2017","journal-title":"Nat. Commun."},{"key":"B7","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-17165-w","article-title":"Pre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson\u2019s disease.","volume":"11","author":"Doi","year":"2020","journal-title":"Nat. Commun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"841","DOI":"10.5966\/sctm.2014-0184","article-title":"Bystander effect fuels human induced pluripotent stem cell-derived neural stem cells to quickly attenuate early stage neurological deficits after stroke.","volume":"4","author":"Eckert","year":"2015","journal-title":"Stem Cells Transl. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2732","DOI":"10.1016\/j.celrep.2018.04.094","article-title":"Human pluripotent stem-cell-derived cortical neurons integrate functionally into the lesioned adult murine visual cortex in an area-specific way.","volume":"23","author":"Espuny-Camacho","year":"2018","journal-title":"Cell Rep."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029597","article-title":"Capture of neuroepithelial-like stem cells from pluripotent stem cells provides a versatile system for in vitro production of human neurons.","volume":"7","author":"Falk","year":"2012","journal-title":"PLoS One"},{"key":"B11","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nature20113","article-title":"Transplanted embryonic neurons integrate into adult neocortical circuits.","volume":"539","author":"Falkner","year":"2016","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"crossref","DOI":"10.1038\/s41536-017-0033-0","article-title":"Neuronal replacement therapy: previous achievements and challenges ahead.","volume":"2","author":"Grade","year":"2017","journal-title":"NPJ Regen. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1016\/j.stemcr.2015.04.011","article-title":"Monosynaptic tracing using modified rabies virus reveals early and extensive circuit integration of human embryonic stem cell-derived neurons.","volume":"4","author":"Grealish","year":"2015","journal-title":"Stem Cell Reports"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1648","DOI":"10.1523\/jneurosci.2715-17.2018","article-title":"Sensorimotor functional and structural networks after intracerebral stem cell grafts in the ischemic mouse brain.","volume":"38","author":"Green","year":"2018","journal-title":"J. Neurosci."},{"key":"B15","doi-asserted-by":"crossref","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":"Gronning Hansen","year":"2020","journal-title":"Stem Cells Transl. Med."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00729","article-title":"Pluripotent stem cell therapies for parkinson disease: present challenges and future opportunities.","volume":"8","author":"Kim","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/bs.pbr.2016.11.013","article-title":"Transplantation of reprogrammed neurons for improved recovery after stroke.","volume":"231","author":"Kokaia","year":"2017","journal-title":"Prog. Brain Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1002\/mds.870130303","article-title":"Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson\u2019s disease.","volume":"13","author":"Kordower","year":"1998","journal-title":"Mov. Disord."},{"key":"B19","doi-asserted-by":"publisher","first-page":"6544","DOI":"10.1073\/pnas.1605245113","article-title":"Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain.","volume":"113","author":"Li","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B20","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1016\/j.neuron.2019.10.002","article-title":"Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits.","volume":"104","author":"Linaro","year":"2019","journal-title":"Neuron"},{"key":"B21","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1126\/science.2105529","article-title":"Grafts of fetal dopamine neurons survive and improve motor function in Parkinson\u2019s disease.","volume":"247","author":"Lindvall","year":"1990","journal-title":"Science"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1016\/j.cell.2012.08.020","article-title":"Long-distance growth and connectivity of neural stem cells after severe spinal cord injury.","volume":"150","author":"Lu","year":"2012","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1016\/j.neuron.2015.02.001","article-title":"Area-specific reestablishment of damaged circuits in the adult cerebral cortex by cortical neurons derived from mouse embryonic stem cells.","volume":"85","author":"Michelsen","year":"2015","journal-title":"Neuron"},{"key":"B24","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.nbd.2012.12.006","article-title":"Grafted human neural stem cells enhance several steps of endogenous neurogenesis and improve behavioral recovery after middle cerebral artery occlusion in rats.","volume":"52","author":"Mine","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"B25","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1002\/jnr.22547","article-title":"Small-molecule inhibitors of bone morphogenic protein and activin\/nodal signals promote highly efficient neural induction from human pluripotent stem cells.","volume":"89","author":"Morizane","year":"2011","journal-title":"J. Neurosci. Res."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/adbi.201800113","article-title":"Shear containment of BDNF within molecular hydrogels promotes human stem cell engraftment and postinfarction remodeling in stroke.","volume":"2","author":"Nisbet","year":"2018","journal-title":"Adv. Biosys."},{"key":"B27","doi-asserted-by":"publisher","first-page":"16825","DOI":"10.1073\/pnas.1108077108","article-title":"Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice.","volume":"108","author":"Nori","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B28","doi-asserted-by":"publisher","first-page":"9094","DOI":"10.1073\/pnas.2000690117","article-title":"Activity in grafted human iPS cell-derived cortical neurons integrated in stroke-injured rat brain regulates motor behavior.","volume":"117","author":"Palma-Tortosa","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2011.00030","article-title":"Pluripotent stem cells for the study of CNS development.","volume":"4","author":"Petros","year":"2011","journal-title":"Front. Mol. Neurosci."},{"key":"B30","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.stem.2021.01.004","article-title":"Preclinical efficacy and safety of a human embryonic stem cell-derived midbrain dopamine progenitor product, MSK-DA01.","volume":"28","author":"Piao","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/nbt.3777","article-title":"Combined small-molecule inhibition accelerates the derivation of functional cortical neurons from human pluripotent stem cells.","volume":"35","author":"Qi","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"B32","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1056\/NEJMoa1915872","article-title":"Personalized iPSC-derived dopamine progenitor cells for parkinson\u2019s disease.","volume":"382","author":"Schweitzer","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1964","DOI":"10.1016\/j.celrep.2017.07.069","article-title":"Peptide-based scaffolds support human cortical progenitor graft integration to reduce atrophy and promote functional repair in a model of stroke.","volume":"20","author":"Somaa","year":"2017","journal-title":"Cell Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.neuron.2015.03.002","article-title":"Moving stem cells to the clinic: potential and limitations for brain repair.","volume":"86","author":"Steinbeck","year":"2015","journal-title":"Neuron"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2020.102035","article-title":"Haplobanking induced pluripotent stem cells for clinical use.","volume":"49","author":"Sullivan","year":"2020","journal-title":"Stem Cell Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.reth.2020.06.002","article-title":"iPS cell-based therapy for parkinson\u2019s disease: a kyoto trial.","volume":"13","author":"Takahashi","year":"2020","journal-title":"Regen Ther"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1016\/j.stemcr.2018.01.010","article-title":"Neurons generated by mouse ESCs with hippocampal or cortical identity display distinct projection patterns when Co-transplanted in the adult brain.","volume":"10","author":"Terrigno","year":"2018","journal-title":"Stem Cell Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1126\/science.282.5391.1145","article-title":"Embryonic stem cell lines derived from human blastocysts.","volume":"282","author":"Thomson","year":"1998","journal-title":"Science"},{"key":"B39","first-page":"692","article-title":"Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli.","volume":"140","author":"Tornero","year":"2017","journal-title":"Brain"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2019.101429","article-title":"The in vivo timeline of differentiation of engrafted human neural progenitor cells.","volume":"37","author":"Vogel","year":"2019","journal-title":"Stem Cell Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.neuron.2007.01.033","article-title":"Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons.","volume":"53","author":"Wickersham","year":"2007","journal-title":"Neuron"},{"key":"B42","doi-asserted-by":"crossref","first-page":"112.e","DOI":"10.1016\/j.stem.2020.08.014","article-title":"Human stem cell-derived neurons repair circuits and restore neural function.","volume":"28","author":"Xiong","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B43","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.stem.2007.05.012","article-title":"Strategies and new developments in the generation of patient-specific pluripotent stem cells.","volume":"1","author":"Yamanaka","year":"2007","journal-title":"Cell Stem Cell"},{"key":"B44","doi-asserted-by":"publisher","first-page":"6571","DOI":"10.1523\/jneurosci.2010-18.2019","article-title":"optochemogenetic stimulation of transplanted iPS-NPCs enhances neuronal repair and functional recovery after ischemic stroke.","volume":"39","author":"Yu","year":"2019","journal-title":"J. Neurosci."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.662636\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T12:50:00Z","timestamp":1671799800000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.662636\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,6]]},"references-count":44,"alternative-id":["10.3389\/fcell.2021.662636"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.662636","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,6]]},"article-number":"662636"}}