Identification and characterisation of a novel SOX2+ progenitor population in the adrenal medulla
PhD student: Alice Santambrogio
Supervisor at TUD: Charlotte Steenblock, Stefan Bornstein
Supervisor at KCL: Cynthia Andoniadou
Start date: 01.09.2017
The adrenal glands are two major endocrine organs responsible for multiple physiological processes, including the stress response, the immune system and metabolism. The adrenal is composed of an outer cortex and an inner medulla with distinct developmental origin and function. While tissue-specific stem/progenitor population of the adrenal cortex have been widely identified and characterised, the presence of a functional stem/progenitor population in the medulla is unclear. Establishing cell hierarchy of the adrenal medulla essential to understand normal homeostasis and disease pathogenesis, therefore the identification of a stem/progenitor population would provide an important starting point for further basic and translational studies. Cell composition of the adrenal medulla includes three main cell types: chromaffin cells, that secrete catecholamines, neurons, which stimulate catecholamine production, and a third cell type with an unspecified “support” function called sustentacular cells.
Using transcriptomics and genetic approaches in mouse, I established that a population of sustentacular cells express the stem/progenitor marker SOX2. These cells are present throughout life and have a developmental origin congruent with the rest of the gland. Through genetic lineage-tracing using the Sox2CreERT2 strain, I demonstrate that SOX2+ are an expanding population, capable of giving rise to chromaffin cells, consistent with a stem/progenitor role in vivo. I further demonstrate the self-renewal potential of SOX2+ cells through in vitro isolation and expansion, using a Sox2eGFP mouse line. Analysis of SOX2+ cells in organ challenge and metabolic stress suggests potential involvement of these cells in the response to perturbation of normal homeostasis. Through analysis of FFPE sections of human adrenals, I confirm the presence of SOX2+ cells in the normal adult organ, as well as in pheochromocytomas.
Taken together, these data support the identification of a previously undescribed stem/progenitor cell in the mammalian adrenal medulla and confirm its functional relevance.
Publications:
Prognostic utility of HPV specific testing in addition to p16 immunohistochemistry in oropharyngeal squamous cell carcinoma. H.P. Sathasivam, A. Santambrogio, C.L. Andoniadou, M. Robinson, S. Thavaraj. Ann Oncol. 2018;29:2144-2145.
Isolation and characterization of adrenocortical progenitors involved in the adaptation to stress. C. Steenblock, M.F. Rubin de Celis, L.F. Delgadillo Silva, V. Pawolski, A. Brennand, M. Werdermann, I. Berger, A. Santambrogio, M. Peitzsch, C.L. Andoniadou, A.V. Schally, S.R. Bornstein. Proc Natl Acad Sci U S A. 2018;115:12997-13002.
Adrenal cortex–medulla interactions in adaptation to stress and disease. S.R. Bornstein, I. Berger, L. Scriba, A. Santambrogio, C. Steenblock. Curr Opin Endocr Metab Res. 2019;8:9-14.
Stress-inducible-stem cells: a new view on endocrine, metabolic and mental disease? S.R. Bornstein, C. Steenblock, G.P. Chrousos, A.V. Schally, F. Beuschlein, G. Kline, N.P. Krone, J. Licinio, M.L. Wong, E. Ullmann, G. Ruiz-Babot, B.O. Boehm, A. Behrens, A. Brennand, A. Santambrogio, I. Berger, M. Werdermann, R. Sancho, A. Linkermann, J.W. Lenders, G. Eisenhofer, C.L. Andoniadou. Mol Psychiatry. 2019;24:2-9.
Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade. E.J. Lodge, A. Santambrogio, J.P. Russell, P. Xekouki, T.S. Jacques, R.L. Johnson, S. Thavaraj, S.R. Bornstein, C.L. Andoniadou. Elife. 2019;8.
Non-secreting pituitary tumours characterised by enhanced expression of YAP/TAZ. P. Xekouki, E.J. Lodge, J. Matschke, A. Santambrogio, J.R. Apps, A. Sharif, T.S. Jacques, S. Aylwin, V. Prevot, R. Li, J. Flitsch, S.R. Bornstein, M. Theodoropoulou, C.L. Andoniadou. Endocr Relat Cancer. 2019;26:215-225.
RNA in situ hybridization for human papillomavirus testing in oropharyngeal squamous cell carcinoma on a routine clinical diagnostic platform. R. Henley-Smith, A. Santambrogio, C.L. Andoniadou, E. Odell, S. Thavaraj. Journal of oral pathology & medicine: official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2020.
Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development. E.J. Lodge, P. Xekouki, T.S. Silva, C. Kochi, C.A. Longui, F.R. Faucz, A. Santambrogio, J.L. Mills, N. Pankratz, J. Lane, D. Sosnowska, T. Hodgson, A.L. Patist, P. Francis-West, F. Helmbacher, C. Stratakis, C.L. Andoniadou. JCI Insight. 2020;5:e134310.
Cancer Stem Cells in Pheochromocytoma and Paraganglioma. L.D. Scriba, S.R. Bornstein, A. Santambrogio, G. Mueller, A. Huebner, J. Hauer, A. Schedl, B. Wielockx, G. Eisenhofer, C.L. Andoniadou, C. Steenblock. Front Endocrinol (Lausanne). 2020;11:79.
Single-cell molecular profiling of all three components of the HPA axis reveals adrenal ABCB1 as a regulator of stress adaptation. J.P. Lopez, E. Brivio, A. Santambrogio, C. De Donno, A. Kos, M. Peters, N. Rost, D. Czamara, T.M. Brückl, S. Roeh, M.L. Pöhlmann, C. Engelhardt, A. Ressle, R. Stoffel, A. Tontsch, J.M. Villamizar, M. Reincke, A. Riester, S. Sbiera, M. Fassnacht, H.S. Mayberg, W.E. Craighead, B.W. Dunlop, C.B. Nemeroff, M.V. Schmidt, E.B. Binder, F.J. Theis, F. Beuschlein, C.L. Andoniadou, A. Chen. Sci Adv. 2021;7(5):eabe4497.
Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells. J.P. Russell, X. Lim, A. Santambrogio, V. Yianni, Y. Kemkem, B. Wang, M. Fish, S. Haston, A. Grabek, S. Hallang, E.J. Lodge, A.L. Patist, A. Schedl, P. Mollard, R. Nusse, C.L. Andoniadou. Elife. 2021;10. pii: 59142.
Insulin and obesity transform hypothalamic-pituitary-adrenal axis stemness and function in a hyperactive state. M. Werdermann, I. Berger, L.D. Scriba, A. Santambrogio, P. Schlinkert, H. Brendel, H. Morawietz, A. Schedl, M. Peitzsch, A.J.F. King, C.L. Andoniadou, S.R. Bornstein, C. Steenblock. Mol Metab. 2021;43:101112.