Chromaffin progenitor cells in adrenal tissue formation
Final Report Abstract
Chromaffin cells of the adrenal gland are historically interesting to both scientists who study the roles of this organ in homeostasis and stress adaptation as well as to neuroscientists who have utilized them for decades as a more manageable model system to study the brain and its progenitorcells. Chromaffin cells are closely related to the nervous system, being dervatives of the neural crest. Today, in the age of stem cell biology, it is essential to study the fundamental properties of chromaffin cells and their progenitors; not simply as a means of regenerating the organ from daily wear-and-tear, but to understand how their “stemness” properties contribute to health and disease. Because the adrenal medulla is a major mediator of stress responses, synthesizing and quickly releasing epinephrine (adrenaline), norepinephrine (noradrenaline), and a small amount of dopamine in response to stimulation by sympathetic preganglionic neurons, we had the opportunity to introduce vast knowledge from our work on neural stem cell biology into the control of adrenomedullary progenitor cells and, ultimately, adaptation to stress. In our interdisciplinary project, we took two main parallel approaches. First, we utilized a reporter mouse line that allow the identification of cells that express nestin. Nestin is type VI intermediate filament protein and it is a biomarker of both neural stem cells in the brain and adrenomedullary chromaffin progenitors. With this mouse line we were able to show that, in the adult living mouse, stress strongly regulates these progenitors in the adrenal medulla. Specifically, these cells are glia-like with features of adrenomedullary sustentacular cells, are multipotent, and are able to differentiate into chromaffin cells and neurons. Stress induces their activation and differentiation into new chromaffin cells. Second, we took a more molecular approach to characterize these cells regarding their signal transduction pathway requirements, in order to identify novel molecular mechanisms that both explain how they are regulated and provide a blueprint to future pharmacological manipulation. Using cultured bovine adrenomedullary chromaffin progenitors as well as tissue from mice, we demonstrated that these cells operate the STAT3-Ser/Hes3 Signaling Axis. This is a molecular mechanism that we previously discovered in neural stem cells and that regulates their number in vitro and in vivo. The cells express the transcription factor Hes3, a key component of the pathway. When the cells are induced to differentiate, Hes3 expression is lost. Pharmacological activation of the pathway increased cell number in culture, without significantly affecting catecholamine content levels. Treatment with cholera toxin, another pathway manipulator, does not significantly affect cell number but changes the relative ratios of the hormone content of the cells. Overall, our data suggest the contribution of stem and progenitor cells in the adaptation of neuroendocrine tissue function in general and provide a novel, complex molecular mechanism that contributes to our understanding of these cells. The cellular and in vivo systems we developed may also be used in drug discovery programs as they allow for the quantification of the effects of many treatments on different aspects of the adrenal gland.
Publications
- Chromaffin cells: the peripheral brain. Mol Psychiatry. 2012 Apr;17(4):354-8
Bornstein SR, Ehrhart-Bornstein M, Androutsellis-Theotokis A, Eisenhofer G, Vukicevic V, Licinio J, Wong ML, Calissano P, Nisticò G, Preziosi P, Levi-Montalcini R
(See online at https://doi.org/10.1038/mp.2011.176) - Common features between chromaffin and neural progenitor cells. Mol Psychiatry. 2012 Apr;17(4):351
Androutsellis-Theotokis A, Rubin de Celis MF, Ehrhart-Bornstein M, Bornstein SR
(See online at https://doi.org/10.1038/mp.2012.18) - Neurovascular signals suggest a propagation mechanism for endogenous stem cell activation along blood vessels. CNS Neurol Disord Drug Targets. 2012 Nov 1;11(7):805-17
Masjkur J, Rueger MA, Bornstein SR, McKay R, Androutsellis-Theotokis A
(See online at https://doi.org/10.2174/1871527311201070805) - Expression profiles of the nuclear receptors and their transcriptional coregulators during differentiation of neural stem cells. Horm Metab Res. 2013 Feb;45(2):159-68
Androutsellis-Theotokis A, Chrousos GP, McKay RD, DeCherney AH, Kino
(See online at https://doi.org/10.1055/s-0032-1321789) - A defined, controlled culture system for primary bovine chromaffin progenitors reveals novel biomarkers and modulators. Stem Cells Transl Med. 2014 Jul;3(7):801-8
Masjkur J, Levenfus I, Lange S, Arps-Forker C, Poser S, Qin N, Vukicevic V, Chavakis T, Eisenhofer G, Bornstein SR, Ehrhart-Bornstein M, Androutsellis-Theotokis A
(See online at https://doi.org/10.5966/sctm.2013-0211) - Expression of the transcription factor Hes3 in the mouse and human ocular surface, and in pterygium. Int J Radiat Biol. 2014 Aug;90(8):700-9
Economopoulou M, Masjkur J, Raiskup F, Ebermann D, Saha S, Karl MO, Funk R, Jaszai J, Chavakis T, Ehrhart-Bornstein M, Pillunat LE, Kunz-Schughart L, Kurth I, Dubrovska A, Androutsellis-Theotokis A
(See online at https://doi.org/10.3109/09553002.2014.892228) - Adrenomedullary progenitor cells: isolation and characterization of a multi-potent progenitor cell population. Mol Cell Endocrinol. 2015 Jun 15;408:178-84
Vukicevic V, Rubin de Celis MF, Pellegata NS, Bornstein SR, Androutsellis-Theotokis A, Ehrhart-Bornstein M
(See online at https://doi.org/10.1016/j.mce.2014.12.020) - Multipotent glia-like stem cells mediate stress adaptation. Stem Cells. 2015 Jun;33(6):2037-51
Rubin de Celis MF, Garcia-Martin R, Wittig D, Valencia GD, Enikolopov G, Funk RH, Chavakis T, Bornstein SR, Androutsellis-Theotokis A, Ehrhart-Bornstein M
(See online at https://doi.org/10.1002/stem.2002) - Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology. Diabetes. 2016 Feb;65(2):314-30
Masjkur J, Poser SW, Nikolakopoulou P, Chrousos G, McKay RD, Bornstein SR, Jones PM, Androutsellis-Theotokis A
(See online at https://doi.org/10.2337/db15-1099) - STAT3-Ser/Hes3 signaling: a new molecular component of the neuroendocrine system? Horm Metab Res. 2016 Feb;48(2):77-82
Nikolakopoulou P, Poser SW, Masjkur J, Fernandez Rubin de Celis M, Toutouna L, Andoniadou CL, McKay RD, Chrousos G, Ehrhart-Bornstein M, Bornstein SR, Androutsellis-Theotokis A
(See online at https://doi.org/10.1055/s-0041-111699) - The effects of stress on brain and adrenal stem cells. Mol Psychiatry. 2016 May;21(5):590-3. Erratum in: Mol Psychiatry. 2016 May;21(5):722. de Celis, MFR [Corrected to Rubin de Celis, MF]
Rubin de Celis MF, Bornstein SR, Androutsellis-Theotokis A, Andoniadou CL, Licinio J, Wong ML, Ehrhart-Bornstein M
(See online at https://doi.org/10.1038/mp.2015.230 https://doi.org/10.1038/mp.2016.26) - The effects of stress on brain and adrenal stem cells. Mol Psychiatry. 2016 May;21(5):722
de Celis MF, Bornstein SR, Androutsellis-Theotokis A, Andoniadou CL, Licinio J, Wong ML, Ehrhart-Bornstein M
(See online at https://doi.org/10.1038/mp.2016.26) - Adrenal cortical and chromaffin stem cells: Is there a common progeny related to stress adaptation? Mol Cell Endocrinol. 2017 Feb 5;441:156-163
Steenblock C, Rubin de Celis MF, Androutsellis-Theotokis A, Sue M, Delgadillo Silva LF, Eisenhofer G, Andoniadou CL, Bornstein SR
(See online at https://doi.org/10.1016/j.mce.2016.09.011)
