title: Differentiation of chromaffin progenitor cells to dopaminergic neurons.
abstract: The differentiation of dopamine-producing neurons from chromaffin progenitors might represent a new valuable source for replacement therapies in Parkinson's disease. However, characterization of their differentiation potential is an important prerequisite for efficient engraftment. Based on our previous studies on isolation and characterization of chromaffin progenitors from adult adrenals, this study investigates their potential to produce dopaminergic neurons and means to enhance their dopaminergic differentiation. Chromaffin progenitors grown in sphere culture showed an increased expression of nestin and Mash1, indicating an increase of the progenitor subset. Proneurogenic culture conditions induced the differentiation into neurons positive for neural markers β-III-tubulin, MAP2, and TH accompanied by a decrease of Mash1 and nestin. Furthermore, Notch2 expression decreased concomitantly with a downregulation of downstream effectors Hes1 and Hes5 responsible for self-renewal and proliferation maintenance of progenitor cells. Chromaffin progenitor-derived neurons secreted dopamine upon stimulation by potassium. Strikingly, treatment of differentiating cells with retinoic and ascorbic acid resulted in a twofold increase of dopamine secretion while norepinephrine and epinephrine were decreased. Initiation of dopamine synthesis and neural maturation is controlled by Pitx3 and Nurr1. Both Pitx3 and Nurr1 were identified in differentiating chromaffin progenitors. Along with the gained dopaminergic function, electrophysiology revealed features of mature neurons, such as sodium channels and the capability to fire multiple action potentials. In summary, this study elucidates the capacity of chromaffin progenitor cells to generate functional dopaminergic neurons, indicating their potential use in cell replacement therapies.
authors.affiliation: Molecular Endocrinology, Medical Clinic III, University Clinic Dresden, Dresden University of Technology, Fetscherstrasse 74, Dresden, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vukicevic
authors.forename: Janine
authors.initials: J
authors.lastname: Schmid
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
authors.forename: Sven
authors.initials: S
authors.lastname: Lange
authors.forename: Nan
authors.initials: N
authors.lastname: Qin
authors.forename: Linda
authors.initials: L
authors.lastname: Gebauer
authors.forename: Kuei-Fang
authors.initials: KF
authors.lastname: Chunk
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: Alexander
authors.initials: A
authors.lastname: Storch
authors.forename: Marius
authors.initials: M
authors.lastname: Ader
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: Monika
authors.initials: M
authors.lastname: Ehrhart-Bornstein
mesh_terms: D000818:Animals; D002417:Cattle; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000166:cytology* / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism
chemical_list: D014212:Tretinoin