Direct generation of functional dopaminergic neurons from mouse and human fibroblasts

Massimiliano Caiazzo, Maria Teresa Dell'Anno, Elena Dvoretskova, Dejan Lazarevic, Stefano Taverna, Damiana Leo, Tatyana D. Sotnikova, Andrea Menegon, Paola Roncaglia, Giorgia Colciago, Giovanni Russo, Piero Carninci, Gianni Pezzoli, Raul R. Gainetdinov, Stefano Gustincich, Alexander Dityatev, Vania Broccoli

Research output: Contribution to journalArticle

633 Citations (Scopus)

Abstract

Transplantation of dopaminergic neurons can potentially improve the clinical outcome of Parkinson's disease, a neurological disorder resulting from degeneration of mesencephalic dopaminergic neurons. In particular, transplantation of embryonic-stem-cell-derived dopaminergic neurons has been shown to be efficient in restoring motor symptoms in conditions of dopamine deficiency. However, the use of pluripotent-derived cells might lead to the development of tumours if not properly controlled. Here we identified a minimal set of three transcription factors-Mash1 (also known as Ascl1), Nurr1 (also known as Nr4a2) and Lmx1a-that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic (iDA) cells release dopamine and show spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The three factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson's disease patients. Direct generation of iDA cells from somatic cells might have significant implications for understanding critical processes for neuronal development, in vitro disease modelling and cell replacement therapies.

Original languageEnglish
Pages (from-to)224-227
Number of pages4
JournalNature
Volume476
Issue number7359
DOIs
Publication statusPublished - Aug 11 2011

Fingerprint

Dopaminergic Neurons
Fibroblasts
Parkinson Disease
Dopamine
Transplantation
Embryonic Stem Cells
Cell- and Tissue-Based Therapy
Nervous System Diseases
Transcription Factors
Stem Cells
Tissue Donors
Brain
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Caiazzo, M., Dell'Anno, M. T., Dvoretskova, E., Lazarevic, D., Taverna, S., Leo, D., ... Broccoli, V. (2011). Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature, 476(7359), 224-227. https://doi.org/10.1038/nature10284

Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. / Caiazzo, Massimiliano; Dell'Anno, Maria Teresa; Dvoretskova, Elena; Lazarevic, Dejan; Taverna, Stefano; Leo, Damiana; Sotnikova, Tatyana D.; Menegon, Andrea; Roncaglia, Paola; Colciago, Giorgia; Russo, Giovanni; Carninci, Piero; Pezzoli, Gianni; Gainetdinov, Raul R.; Gustincich, Stefano; Dityatev, Alexander; Broccoli, Vania.

In: Nature, Vol. 476, No. 7359, 11.08.2011, p. 224-227.

Research output: Contribution to journalArticle

Caiazzo, M, Dell'Anno, MT, Dvoretskova, E, Lazarevic, D, Taverna, S, Leo, D, Sotnikova, TD, Menegon, A, Roncaglia, P, Colciago, G, Russo, G, Carninci, P, Pezzoli, G, Gainetdinov, RR, Gustincich, S, Dityatev, A & Broccoli, V 2011, 'Direct generation of functional dopaminergic neurons from mouse and human fibroblasts', Nature, vol. 476, no. 7359, pp. 224-227. https://doi.org/10.1038/nature10284
Caiazzo M, Dell'Anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature. 2011 Aug 11;476(7359):224-227. https://doi.org/10.1038/nature10284
Caiazzo, Massimiliano ; Dell'Anno, Maria Teresa ; Dvoretskova, Elena ; Lazarevic, Dejan ; Taverna, Stefano ; Leo, Damiana ; Sotnikova, Tatyana D. ; Menegon, Andrea ; Roncaglia, Paola ; Colciago, Giorgia ; Russo, Giovanni ; Carninci, Piero ; Pezzoli, Gianni ; Gainetdinov, Raul R. ; Gustincich, Stefano ; Dityatev, Alexander ; Broccoli, Vania. / Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. In: Nature. 2011 ; Vol. 476, No. 7359. pp. 224-227.
@article{67e1429af229402c8e35afbe982cc9cc,
title = "Direct generation of functional dopaminergic neurons from mouse and human fibroblasts",
abstract = "Transplantation of dopaminergic neurons can potentially improve the clinical outcome of Parkinson's disease, a neurological disorder resulting from degeneration of mesencephalic dopaminergic neurons. In particular, transplantation of embryonic-stem-cell-derived dopaminergic neurons has been shown to be efficient in restoring motor symptoms in conditions of dopamine deficiency. However, the use of pluripotent-derived cells might lead to the development of tumours if not properly controlled. Here we identified a minimal set of three transcription factors-Mash1 (also known as Ascl1), Nurr1 (also known as Nr4a2) and Lmx1a-that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic (iDA) cells release dopamine and show spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The three factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson's disease patients. Direct generation of iDA cells from somatic cells might have significant implications for understanding critical processes for neuronal development, in vitro disease modelling and cell replacement therapies.",
author = "Massimiliano Caiazzo and Dell'Anno, {Maria Teresa} and Elena Dvoretskova and Dejan Lazarevic and Stefano Taverna and Damiana Leo and Sotnikova, {Tatyana D.} and Andrea Menegon and Paola Roncaglia and Giorgia Colciago and Giovanni Russo and Piero Carninci and Gianni Pezzoli and Gainetdinov, {Raul R.} and Stefano Gustincich and Alexander Dityatev and Vania Broccoli",
year = "2011",
month = "8",
day = "11",
doi = "10.1038/nature10284",
language = "English",
volume = "476",
pages = "224--227",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7359",

}

TY - JOUR

T1 - Direct generation of functional dopaminergic neurons from mouse and human fibroblasts

AU - Caiazzo, Massimiliano

AU - Dell'Anno, Maria Teresa

AU - Dvoretskova, Elena

AU - Lazarevic, Dejan

AU - Taverna, Stefano

AU - Leo, Damiana

AU - Sotnikova, Tatyana D.

AU - Menegon, Andrea

AU - Roncaglia, Paola

AU - Colciago, Giorgia

AU - Russo, Giovanni

AU - Carninci, Piero

AU - Pezzoli, Gianni

AU - Gainetdinov, Raul R.

AU - Gustincich, Stefano

AU - Dityatev, Alexander

AU - Broccoli, Vania

PY - 2011/8/11

Y1 - 2011/8/11

N2 - Transplantation of dopaminergic neurons can potentially improve the clinical outcome of Parkinson's disease, a neurological disorder resulting from degeneration of mesencephalic dopaminergic neurons. In particular, transplantation of embryonic-stem-cell-derived dopaminergic neurons has been shown to be efficient in restoring motor symptoms in conditions of dopamine deficiency. However, the use of pluripotent-derived cells might lead to the development of tumours if not properly controlled. Here we identified a minimal set of three transcription factors-Mash1 (also known as Ascl1), Nurr1 (also known as Nr4a2) and Lmx1a-that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic (iDA) cells release dopamine and show spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The three factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson's disease patients. Direct generation of iDA cells from somatic cells might have significant implications for understanding critical processes for neuronal development, in vitro disease modelling and cell replacement therapies.

AB - Transplantation of dopaminergic neurons can potentially improve the clinical outcome of Parkinson's disease, a neurological disorder resulting from degeneration of mesencephalic dopaminergic neurons. In particular, transplantation of embryonic-stem-cell-derived dopaminergic neurons has been shown to be efficient in restoring motor symptoms in conditions of dopamine deficiency. However, the use of pluripotent-derived cells might lead to the development of tumours if not properly controlled. Here we identified a minimal set of three transcription factors-Mash1 (also known as Ascl1), Nurr1 (also known as Nr4a2) and Lmx1a-that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic (iDA) cells release dopamine and show spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The three factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson's disease patients. Direct generation of iDA cells from somatic cells might have significant implications for understanding critical processes for neuronal development, in vitro disease modelling and cell replacement therapies.

UR - http://www.scopus.com/inward/record.url?scp=80051674431&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051674431&partnerID=8YFLogxK

U2 - 10.1038/nature10284

DO - 10.1038/nature10284

M3 - Article

C2 - 21725324

AN - SCOPUS:80051674431

VL - 476

SP - 224

EP - 227

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7359

ER -