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First Description of Serotonin Neuron Production from Pluripotent Stem Cells

Review of “Generation of serotonin neurons from human pluripotent stem cells” from Nature Biotechnology by Stuart P. Atkinson

The monoamine neurotransmitter serotonin plays a key role in the central nervous system and the misregulation of its release or uptake has been implicated in multiple psychiatric disorders [1]. However, functional serotonin neurons for in vitro assessment are not readily available. One possible strategy to rectify this problem is to differentiate these neurons from human pluripotent stem cell (PSC) sources; a task that researchers from the laboratory of Su-Chun Zhang (University of Wisconsin, USA) sought to undertake [2].

This new strategy used both embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) and involved:

  • Differentiation of PSCs to rostral hindbrain neural stem cells (NSCs) via transforming growth factor (TGF)-β inhibitor SB431542, BMP inhibitor DMH1, and GSK3-β inhibitor CHIR99021 treatment
  • Specification of rostral hindbrain NSCs into ventral hindbrain serotonergic neuronal progenitors via treatment with high levels of SHH followed by FGF4 treatment
  • Differentiation of serotonergic progenitors into serotonergic neurons via treatment with morphogen-free neural differentiation medium 
      • 80% became Tuj1+ Neurons, with 60% of these identified as serotonin-positive

A large proportion of resultant neural cells tested demonstrated the characteristic functional features of serotonergic neurons, whilst also having the ability to release serotonin in response to specific stimuli. Furthermore, the authors highlighted the possible application of these cells to validate serotonin releasers or selective serotonin reuptake inhibitors by confirming the expected results in response to two US Food and Drug Administration (FDA)-approved drugs - tramadol, a mu-opiate agonist, inhibitor of monoamine (including serotonin) reuptake, and serotonin releaser that is used to treat pain, and escitalopram oxalate, a selective serotonin reuptake inhibitor used for treatment of major depressive disorder and generalized anxiety disorder.

Not only does this new strategy represent a great tool to research the patient-specific molecular basis of multiple psychiatric disorders but will also represent a great resource to test new and more effective drugs.


  1. Deneris ES and Wyler SC Serotonergic transcriptional networks and potential importance to mental health. Nat Neurosci 2012;15:519-527.
  2. Lu J, Zhong X, Liu H, et al. Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol 2016;34:89-94.