iPSCs-derived model to study Klinefelter syndrome

Scope of the method

The Method relates to
  • Human health
The Method is situated in
  • Basic Research
  • Translational - Applied Research
Type of method
  • In vitro - Ex vivo
This method makes use of
  • Human derived cells / tissues / organs
Specify the type of cells/tissues/organs
Skin fibroblasts from KS patient


Method keywords
  • Primordial germ cells
  • Germ cell differentiation
  • Post-meiotic cells
  • Klinefelter syndrome iPSCs
Scientific area keywords
  • Klinefelter syndrome
  • Male infertility
  • Induced pluripotent stem cells
  • Disease modelling
Method description

We developed an innovative model to study the effect of the supernumerary X chromosome on KS features. The model was generated using induced pluripotent stem cells (iPSCs) from patients with Klinefelter syndrome (KS) i.e. with a 47, XXY karyotype. In order to compare the potentials of both 47XXY-iPSCs and 46XY-iPSCs to differentiate into the germ cell lineage, we developed a directed differentiation protocol by testing different combinations of factors including bone morphogenetic protein 4 (BMP4), glial-derived neurotrophic factor (GDNF), retinoic acid (RA) and stem cell factor (SCF) for 42 days. Importantly, we found a reduced ability of 47XXY-iPSCs to differentiate into germ cells when compared to 46XY-iPSCs. In particular, upon germ cell differentiation of 47XXY-iPSCs, we found a reduced proportion of cells positive for BOLL, a protein required for germ cell development and spermatogenesis, as well as a reduced proportion of cells positive for MAGEA4, a spermatogonia marker. This reduced ability to generate germ cells was not associated with a decrease of proliferation of 47XXY-iPSC-derived cells but rather with an increase of cell death upon germ cell differentiation as revealed by an increase of LDH release and of capase-3 expression in 47XXY-iPSC-derived cells.

Lab equipment
  • - Cell irradiation for mitotic inactivation ;
  • - Culture facility.
Method status
  • Published in peer reviewed journal

Pros, cons & Future potential


Applicable to different cell lines for comparative studies.


Define culture conditions to obtain sufficient amount of cells.

  • - Not for the generation of iPSCs ;
  • - Ongoing studies to define optimized culture conditions.
Future & Other applications

Provides an excellent in vitro model to unravel the pathophysiology and to design potential treatments for KS patients.

References, associated documents and other information


Botman O, Hibaoui Y, Giudice MG, Ambroise J, Creppe C, Feki A and Wyns C (2020) Modeling Klinefelter Syndrome Using Induced Pluripotent Stem Cells Reveals Impaired Germ Cell Differentiation. Front. Cell Dev. Biol. 8:567454. doi: 10.3389/fcell.2020.567454

Wyns C, Botman O. Induced pluripotent stem cell potential in medicine, specifically focused on reproductive medicine. Front Surg. 2014; 1: 5. Published online 2014 March 24

Gynaecology research group

Contact person

Christine Wyns


Université Catholique de Louvain (UCL)
Institut de recherche expérimentale et Clinique
Brussels Region


Geneva University Hospitals