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Modeling disorders of puberty with human pluripotent stem cells: a dream come true

I have been investigating the mechanisms of puberty since 1995. At that time (when I was 25) I couldn't imagine even in my wildest dreams that one day I'd be generating the key cells of puberty on a cell culture dish. But this is exactly what happened. (Read more) 

Puberty in the human is governed by a few thousand hypothalamic gonadotropin-releasing hormone (GnRH) neurons that transform cues from the central nervous system (CNS) and the environment to pulsatile secretion of GnRH decapeptide. This, in turn, augments gonadotropin secretion from the pituitary gland, which ultimately leads to sex steroid production and secretion by the gonads.

More than five years ago, I started to realize the possibilities of human pluripotent stem cells in the field of translational pediatrics. My friend, docent Timo Tuuri, was then doing his post-doctoral fellowship in the University of Sheffield, UK, and it turned out that some investigators there were modeling the otic placode with human embryonic stem cells. This was really fascinating news, since GnRH neurons are known to be born outside the CNS, in the close vicinity of another type of sensory placodes, the olfactory placode.

So, we decided to start modeling the ontogeny of these mysterious cells, but at the start had no clue on what to look for and where. The breakthrough was when we started to mimic the neurogenic niche, which is present in the olfactory pit: we first directed the cells to anterior neuronal progenitor cells by inhibiting TGFbeta and BMP signaling, and subsequently treated the cells with the key growth factor (FGF8) of GnRH neuron ontogeny. Final maturation of the cells was achieved by inhibiting Notch signaling. The protocol lasts approximately one month, and at the end of it, GnRH-positive cells secrete GnRH decapeptide robustly in the culture medium, express neuronal markers and display typical morphology of GnRH cells. The original paper can be found here and you may want to check this link as well.

But this is not the end of the story. In the current era of genome editing, we are extremely well-equipped to use this tool to model the mechanisms of human puberty and the role of different genetic factors therein. The biggest challenge now is to set the goal for the next 20 years to come.