Forced LMX1A expression induces dorsal neural fates and disrupts patterning of human embryonic stem cells into ventral midbrain dopaminergic neurons
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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; Kajtez, Janko; Christiansen, Josefine Rågård; Schörling, Alrik; Rathore, Gaurav Singh; Wolf, Daniel A; Heuer, Andreas; Kirkeby, Agnete.
In: Stem Cell Reports, Vol. 19, No. 6, 2024, p. 830-838.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Forced LMX1A expression induces dorsal neural fates and disrupts patterning of human embryonic stem cells into ventral midbrain dopaminergic neurons
AU - Rifes, Pedro
AU - Kajtez, Janko
AU - Christiansen, Josefine Rågård
AU - Schörling, Alrik
AU - Rathore, Gaurav Singh
AU - Wolf, Daniel A
AU - Heuer, Andreas
AU - Kirkeby, Agnete
N1 - Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1016/j.stemcr.2024.04.010
DO - 10.1016/j.stemcr.2024.04.010
M3 - Journal article
C2 - 38759646
VL - 19
SP - 830
EP - 838
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 6
ER -
ID: 392610931