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Forced LMX1A expression induces dorsal neural fates and disrupts patterning of human embryonic stem cells into ventral midbrain dopaminergic neurons

Rifes, Pedro LU ; Kajtez, Janko LU orcid ; Christiansen, Josefine Rågård ; Schörling, Alrik LU orcid ; Rathore, Gaurav Singh ; Wolf, Daniel A. LU ; Heuer, Andreas LU and Kirkeby, Agnete LU (2024) In Stem Cell Reports 19(6). p.830-838
Abstract

The differentiation of human pluripotent stem cells into ventral mesencephalic dopaminergic (DA) fate is relevant for the treatment of Parkinson's disease. Shortcuts to obtaining DA cells through direct reprogramming often include forced expression of the transcription factor LMX1A. Although reprogramming with LMX1A can generate tyrosine hydroxylase (TH)-positive cells, their regional identity remains elusive. Using an in vitro model of early human neural tube patterning, we report that forced LMX1A expression induced a ventral-to-dorsal fate shift along the entire neuroaxis with the emergence of roof plate fates despite the presence of ventralizing molecules. The LMX1A-expressing progenitors gave rise to grafts containing roof... (More)

The differentiation of human pluripotent stem cells into ventral mesencephalic dopaminergic (DA) fate is relevant for the treatment of Parkinson's disease. Shortcuts to obtaining DA cells through direct reprogramming often include forced expression of the transcription factor LMX1A. Although reprogramming with LMX1A can generate tyrosine hydroxylase (TH)-positive cells, their regional identity remains elusive. Using an in vitro model of early human neural tube patterning, we report that forced LMX1A expression induced a ventral-to-dorsal fate shift along the entire neuroaxis with the emergence of roof plate fates despite the presence of ventralizing molecules. The LMX1A-expressing progenitors gave rise to grafts containing roof plate-derived choroid plexus cysts as well as ectopically induced TH-positive neurons of a forebrain identity. Early activation of LMX1A prior to floor plate specification was necessary for the dorsalizing effect. Our work suggests using caution in employing LMX1A for the induction of DA fate, as this factor may generate roof plate rather than midbrain fates.

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Please use this url to cite or link to this publication:
@article{c9526cee-054d-467c-bea9-3bd26d65c60f,
  abstract     = {{<p>The differentiation of human pluripotent stem cells into ventral mesencephalic dopaminergic (DA) fate is relevant for the treatment of Parkinson's disease. Shortcuts to obtaining DA cells through direct reprogramming often include forced expression of the transcription factor LMX1A. Although reprogramming with LMX1A can generate tyrosine hydroxylase (TH)-positive cells, their regional identity remains elusive. Using an in vitro model of early human neural tube patterning, we report that forced LMX1A expression induced a ventral-to-dorsal fate shift along the entire neuroaxis with the emergence of roof plate fates despite the presence of ventralizing molecules. The LMX1A-expressing progenitors gave rise to grafts containing roof plate-derived choroid plexus cysts as well as ectopically induced TH-positive neurons of a forebrain identity. Early activation of LMX1A prior to floor plate specification was necessary for the dorsalizing effect. Our work suggests using caution in employing LMX1A for the induction of DA fate, as this factor may generate roof plate rather than midbrain fates.</p>}},
  author       = {{Rifes, Pedro and Kajtez, Janko and Christiansen, Josefine Rågård and Schörling, Alrik and Rathore, Gaurav Singh and Wolf, Daniel A. and Heuer, Andreas and Kirkeby, Agnete}},
  issn         = {{2213-6711}},
  keywords     = {{cell replacement therapy; dopamine; human embryonic stem cells; induced neurons; neural tube ventral patterning; Parkinson's disease; reprogramming; transplantation}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{6}},
  pages        = {{830--838}},
  publisher    = {{Cell Press}},
  series       = {{Stem Cell Reports}},
  title        = {{Forced LMX1A expression induces dorsal neural fates and disrupts patterning of human embryonic stem cells into ventral midbrain dopaminergic neurons}},
  url          = {{http://dx.doi.org/10.1016/j.stemcr.2024.04.010}},
  doi          = {{10.1016/j.stemcr.2024.04.010}},
  volume       = {{19}},
  year         = {{2024}},
}