Cytokine-induced conversion of mesencephalic-derived progenitor cells into dopamine neurons

Cell Tissue Res. 1999 May;296(2):235-46. doi: 10.1007/s004410051285.


We have previously shown that a combination of the cytokines interleukin (IL)-1, IL-11, leukemia inhibitory factor (LIF), and glial cell line-derived neurotrophic factor (GDNF) can convert rat fetal (E14.5) mesencephalic progenitor cells into tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in vitro. The experiments described here characterize the mesencephalic progenitor cells and their cytokine-induced conversion into dopamine (DA) neurons. For all experiments, we used bromodeoxyuridine (BrdU)-ir cultures of (E14.5) mesencephalic progenitor cells that had been expanded at least 21 days. We first demonstrated that IL-1 induced DA neuron conversion in mesencephalic progenitors, but not in striatal progenitors (P < 0.001). Thus, these cells should be classified as lineage-restricted progenitors, and not omnipotent stem cells. To further characterize cell populations in these cultures, we used monoclonal antibodies against Hu (an early marker for neurons), growth-associated protein (GAP)-43 (a marker for neuronal process extension), TH (a marker for DA neurons), and glial fibrillary acidic protein (GFAP, a marker for astrocytes). We assessed (E14.5) mesencephalic progenitor cell cultures (plated at 125,000 cells/cm2) incubated in the cytokine mixture (described above) or in complete media (CM, negative control). Following 7 days incubation, GFAP-positive cells formed a nearly confluent carpet in both types of cultures. However, numbers of Hu-ir and GAP-43-ir cells in the cytokine-incubated cultures far exceeded those in CM-incubated controls (P = 0.0003, P = 0.0001, respectively), while numbers of TH-ir cells were 58-fold greater in the cytokine-incubated cultures versus CM-incubated controls. The TH phenotype persisted for 7 days following withdrawal of the differentiation media. Numerous double-labeled cells that were BrdU-ir and also TH-ir, or Hu-ir and also TH-ir, were observed in the cytokine-incubated cultures. These data suggest that cytokines "drive" the conversion of progenitor cells into DA neurons.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Cell Differentiation / drug effects
  • Cytokines / pharmacology*
  • Dopamine / metabolism
  • Fetus
  • GAP-43 Protein / analysis
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Fibrillary Acidic Protein / analysis
  • Growth Inhibitors / pharmacology
  • Interleukin-6*
  • Leukemia Inhibitory Factor
  • Lymphokines / pharmacology
  • Mesencephalon / cytology
  • Mesencephalon / embryology*
  • Nerve Growth Factors / pharmacology*
  • Nerve Tissue Proteins / pharmacology
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / physiology*
  • Rats
  • Stem Cells / cytology*
  • Stem Cells / drug effects
  • Tyrosine 3-Monooxygenase / analysis


  • Brain-Derived Neurotrophic Factor
  • Cytokines
  • GAP-43 Protein
  • Gdnf protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Fibrillary Acidic Protein
  • Growth Inhibitors
  • Interleukin-6
  • Leukemia Inhibitory Factor
  • Lymphokines
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Tyrosine 3-Monooxygenase
  • Dopamine