Antonica, Francesco

Costagliola, Sabine

Dumitrescu, Alexandra Mihaela

Kasprzyk, Dominika Figini

Kyba, Michael

lacovino, Michelina

Liao, Xiao-Hui

Manto, Mario

Opitz, Robert

Peremans, Kathelijne

Refetoff, Samuel

Ghent University Academic Bibliography

Embryonic	  Stem	  cell-­‐derived	  thyroid	  follicles	  rescue	  hypothyroidism	  in	  athyroid	  mice.	  	  Francesco	  Antonica1,	  Dominika	  Figini	  Kasprzyk1,	  Robert	  Opitz1,	  Michelina	  Iacovino2,	  Xiao-­‐Hui	  Liao3,	  Alexandra	  Mihaela	  Dumitrescu3,	  Samuel	  Refetoff3,4,	  Kathelijne	  Peremans5,	  Mario	  Manto6,	  Michael	  Kyba2	  and	  Sabine	  Costagliola1	  	  1IRIBHM	  (Institute	  of	  Interdisciplinary	  Research	  in	  Molecular	  Human	  Biology),	  Université	  Libre	  de	  Bruxelles,	  808	  route	  de	  Lennik,	  1070	  Brussels,	  Belgium.	  2Lillehei	  Heart	  Institute	  and	  Department	  of	  Pediatrics,	  University	  of	  Minnesota,	  Minneapolis,	  MN,	  USA.	  3Department	  of	  Medicine,	  The	  University	  of	  Chicago,	  Chicago,	  IL,	  USA.	  4Departments	  of	  Pediatrics	  and	  Genetics,	  The	  University	  of	  Chicago,	  Chicago,	  IL,	  USA.	  5Department	  of	  Veterinary	  Medical	  Imaging	  and	  Small	  Animal	  Orthopaedics,	  Faculty	  of	  Veterinary	  Medicine,	  Ghent	  University,	  Belgium.	  6FNRS,	  ERASME,	  Université	  Libre	  de	  Bruxelles,	  808	  Route	  de	  Lennik,	  1070	  Brussels,	  Belgium.	  	  Induced	  overexpression	  of	  defined	  transcription	  factors	  has	  been	  shown	  to	  have	  a	  directing	  effect	  on	   the	   differentiation	   of	   Embryonic	   Stem	   Cells	   (ESCs)	   into	   specific	   cell	   types.	   Nevertheless,	  protocols	  promoting	  coordinated	  self-­‐assembly	  of	  differentiated	  cells	   into	  distinct	  morphological	  units	  with	  functional	  properties	  reminiscent	  of	  organs	  and	  tissues	  in	  vivo	  are	  still	  very	  sparse.	  Here	  we	  report	  efficient	  rescue	  of	  hypothyroidism	  in	  athyroid	  mice	  transplanted	  with	  functional	  thyroid	  follicles	  generated	  from	  mouse	  embryonic	  stem	  cells	  (mESC)	  in	  vitro.	  	  We	  show	  that	  a	  transient	  overexpression	  of	  the	  transcription	  factors	  NKX2.1	  and	  PAX8	  is	  sufficient	  to	  direct	  mESC	  differentiation	  into	  thyroid	  follicular	  cells	  (TFC)	  and	  promotes	  in	  vitro	  self-­‐assembly	  of	  TFC	   into	  three-­‐dimensional	   follicular	  structures,	  when	  associated	  to	  a	  subsequent	  thyrotropin	  (TSH)	   treatment.	   Cells	   differentiated	   by	   this	   protocol	   showed	   significant	   iodide	   organification	  activity,	  a	  hallmark	  of	  thyroid	  tissue	  function.	  	  Importantly,	   athyroid	   mice	   grafted	   with	   mESC-­‐derived	   thyroid	   follicles	   show	   normalization	   of	  plasma	   T4	   levels	  with	   concomitant	   decrease	   of	   plasma	   TSH.	   In	   addition,	   a	   full	   normalization	   of	  body	   temperature	   at	   4	  weeks	   after	   transplantation	  was	   observed.	   Together,	   these	   data	   clearly	  demonstrate	   that	   grafting	   of	   our	  mESC-­‐derived	   thyroid	   cells	   rescues	   the	   hypothyroid	   state	   and	  triggers	  symptomatic	  recovery	  along	  with	  the	  normalization	  of	  plasma	  hormone	  concentrations. The	  high	  efficiency	  of	  TFC	  differentiation	  and	  follicle	  morphogenesis	  in	  our	  system	  will	  provide	  an	  unprecedented	   opportunity	   for	   future	   studies	   to	   decipher	   regulatory	   mechanisms	   involved	   in	  embryonic	   thyroid	  development,	   a	  major	   research	  need	   towards	  an	   improved	  understanding	  of	  the	  molecular	  mechanisms	  underlying	   congenital	   hypothyroidism,	   the	  most	   common	   congenital	  endocrine	  disorder	  in	  humans.	  	  

Embryonic stem cell-derived thyroid follicles rescue hypothyroidism in athyroid mice

https://biblio.ugent.be/publication/3149965/file/3149973

Embryonic stem cell-derived thyroid follicles rescue hypothyroidism in athyroid mice

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Ghent University Academic Bibliography