Project C07

Generation of human steroid-producing cells from pluripotent stem cells

Gerard Ruiz-Babot, PhD                               
Gerard.Ruiz-Babot(at)uniklinikum-dresden.de
Medical Clinic and Polyclinic III
Universitätsklinikum Carl Gustav Carus Dresden

Scientific Staff:

Maria Malyukov – Veterinarian

Linda Friedrich – MTA

Uta Lehnert – MTA

Project description:

The proposed research aims to generate hormone-producing cells as a novel and alternative treatment for patients affected by adrenal insufficiency. The methodology consists on testing steroidogenic cells differentiated from human pluripotent stem cells (hPSCs) in rodent in vivo models of adrenal insufficiency. Current protocols allows the generation of steroid-producing cells from hPSCs after overexpression of the transcription factor steroidogenic factor 1 (SF1) using lentiviral particles. To enhance ACTH responsiveness, those cells also overexpress ACTH receptor/co-receptor (MC2R/MRAP). The resulting cells, named human induced steroidogenic cells (hiSCs), produce cortisol and they are ACTH responsive. hiSCs will be implanted under the kidney capsule or encapsulated into immunoisolating devices developed at TU Dresden. The goal is to assess the ability to restore adrenal steroid levels and reverse adrenal insufficiency in a preclinical setting leading to a step forward towards cellular therapies for patients suffering from adrenal insufficiency.

Aims

(I) Optimization of in vitro cell culture conditions to enhance functionality of hiSCs

(II) Cell transplantation of hiSCs into rodent models of adrenal insufficiency.

(III) Test of immune isolating encapsulation devices.

Awards:

2020           

IFCAH funding renewal. Value of the award: €100.000.

Funding organization: International Fund for Congenital Adrenal Hyperplasia (IFCAH).

2020

Privat funding Mr. Mark Quinlivan: €115.725.

2019

Marie Curie Individual Global Fellowship. Value of the award €239.860 

Funding organization: European Commission

2018

IFCAH funding 2018. Value of the award: €150.000.

Funding organization: International Fund for Congenital Adrenal Hyperplasia (IFCAH).

Publications:

Bornstein SR, Malyukov M, Heller C, Ziegler CG, Ruiz-Babot G, Schedl A, Ludwig B, Steenblock C. New Horizons: Novel Adrenal Regenerative Therapies. 2020 J Clin Endocrinol Metab.

Mariniello K, Ruiz-Babot G, McGaugh EC, Nicholson JG, Gualtieri A, Gaston-Massuet C, Nostro MC, Guasti L. Stem Cells, Self-Renewal, and Lineage Commitment in the Endocrine System. 2019 Front Endocrinol (Lausanne).

Bornstein SRSteenblock CChrousos GPSchally AVBeuschlein FKline GKrone NPLicinio JWong MLUllmann ERuiz-Babot GBoehm BOBehrens ABrennand ASantambrogio ABerger IWerdermann MSancho RLinkermann ALenders JWEisenhofer GAndoniadou CL. Stress-inducible-stem cells: a new view on endocrine, metabolic and mental disease? 2018 Mol Psychiatry

Balyura M, Gelfgat E, Steenblock C, Androutsellis-Theotokis A, Ruiz-Babot G, Guasti L, Werdermann M, Ludwig B, Bornstein T, Schally AV, Brennand A, Bornstein SR.  Expression of progenitor markers is associated with the functionality of a bioartificial adrenal cortex. 2018 PLOS One

Ruiz-Babot G, Balyura M, Hadjidemetriou I, Ajodha SJ, Tylor DR, Ghataore L, Taylor NF, Schubert U, Ziegler CG, Storr HL, Druce MR, Gevers EF, Drake WM, Srirangalingam U, Conway GS, King PJ, Metherell LA, Bornstein SR, Guasti L. Modeling congenital adrenal hyperplasia and testing interventions for adrenal insufficiency using donor- specific reprogrammed cells. 2018 Cell Reports

Poliandri A, Miller D, Howard S, Nobles M, Ruiz-Babot G, Harmer S, Tinker A, McKay T, Guasti L, Dunkel L. Generation of kisspeptin-responsive GnRH neurons from human pluripotent stem cells. 2017 Mol Cell Endocrinol.

Ruiz-Babot G, Hadjidemetriou I, King PJ, Guasti L. New directions for the treatment of adrenal insufficiency. 2015 Front Endocrinol (Lausanne). Review.