Chromaffin cells probably are the most intensively studied of the neural crest derivates. They are closely related to the nervous system, share with neurons some fundamental mechanisms and thus were the ideal model to study the basic mechanisms of neurobiology for many years. The lessons we have learned from chromaffin cell biology as a peripheral model for the brain and brain diseases pertain more than ever to the cutting edge research in neurobiology. Here, we highlight how studying this cell model can help unravel the basic mechanisms of cell renewal and regeneration both in the central nervous system (CNS) and neuroendocrine tissue and also can help in designing new strategies for regenerative therapies of the CNS.
Chromaffin cells form perhaps the most interesting cellular system in the human body. They are closely related to sympathetic neurons and are one of the most intensively studied of the neural crest derivates. As an evolutionary hybrid of both the endocrine and nervous system they have served as a model to explore the basic mechanisms of neurophysiology, regulated secretion and pharmacology. Thus, adrenal chromaffin cells can be considered as the peripheral brain as they share with neurons some fundamental mechanisms: (1) Receive inputs of electrical and chemical nature; (2) are able to decode and recognize these signals; (3) possess the machinery to generate and elaborate pattern of responses such as the release of catecholamines and other messengers. In conclusion, the chromaffin cells, such as a neuron can be viewed as a secretory cell that releases its secretion at large distance from cell body where macromolecules are synthesized, provide for rapid communication between widely separated parts of the body. In addition, the adrenal medulla with its chromaffin cells serves through the release of catecholamines for communication with all the most important organs such as the heart, vascular apparatus, lungs, kidney and also the brain.
More importantly, chromaffin cells located in the center of an easily accessible peripheral organ have served for many years as a window into the functions of the brain. Chromaffin cells served as the model to identify the basic concept of neurochemical transmission. The first secretory organelles were isolated from chromaffin cells, and chromaffin vesicles served as the model neurotransmitter-containing vesicle. Many of the major vesicle-associated proteins involved in the process of exocytosis were characterized in chromaffin vesicles.1, 2, 3, 4, 5
Sharing the same ectodermic (neural crest) origin, chromaffin cells are part of the so called Erspamer's triangle (skin, gut and brain), which possess the same neurotransmitters, neuropeptides, transduction mechanisms.6 Much of today's understanding of the physiology and pathophysiology of neuropeptide and monoamine neurotransmitter systems is owed to studies utilizing chromaffin cell model systems. The rat pheochromocytoma (PC12) cell line developed by Greene and Tischler7 over 35 years ago remains one of the most well studied and to this day continues to provide a powerful model for the understanding of neuronal systems. This cell line and other chromaffin model systems have been particularly useful for studies of exocytotic mechanisms, including the operation of ion channels, vesicular dynamics and stimulus-secretion coupling. Associated methodological advances in electrophysiology, from development of the patch clamp to more sophisticated techniques combining electrophysiological and electrochemical methods (for example, patch amperometry) have been largely facilitated by the availability of such model systems.
In cat's adrenal gland perfused in situ it was clearly demonstrated by using different receptorial stimuli (acetylcholine, nicotine, dimethylphenylpiperazimium and so on) that chromaffin cells posses two distinct neurosecretory granules (the noradrenergic and the adrenergic ones), thus ruling out the idea that the noradrenergic ones were the precursor cells in which phenylethanolamine-N-methyltransferase functions to turn them into adrenergic chromaffin cells. In addition, also at the brain level D-amphetamine particularly increase the release of noradrenaline.8, 9
In addition to improving understanding of neural development processes, chromaffin cell systems have been extremely important for studies of neurodegenerative processes, tumorigenesis and drug development.
Furthermore, due to the close relation of chromaffin cells to catecholaminergic neurons they have even been used for the treatment of neurodegenerative brain disorders such as Parkinson's disease.10 Between 1988 and 2001, >300 Parkinsonian patients were treated by autologous adrenal transplants with some improvement of the clinical symptoms. However, the survival rates of grafted adult chromaffin cells were only short-term and clinical improvements disappeared 1–2 years after transplantation.11, 12 A serious limitation in the application of adult adrenal medulla probably was the post-mitotic nature of most cells transplanted.
At the same time, endocrinologists have explored the role of several central releasing hormones and neuropeptides within the chromaffin cell systems.13 Interestingly, the adrenal medulla in the periphery expresses a similar set of neuropeptides that occur in the brain involved in stress regulation, energy homeostasis, anxiety and pain.14, 15 The concept of ectopic hormone production was among others described and refined in these cells. This includes the expression of corticotropin-releasing hormone, adrenocorticotropin, pro-opiomelanocortin and other neuropeptides in the adrenal medulla. The intense crosstalk of endocrine cells, the paracrine and neurocrine pathways of endocrine communication, were established particularly in the adrenal gland.16 Here, again the complex but accessible microenvironment of the adrenal mimics the microenvironment of the brain with respect to the crosstalk of neuronal structures with different endocrine cell types.17 Furthermore, the action of steroids and neurosteroids occurring in the brain has been widely studied in chromaffin cell systems.18, 19 The strict interaction between the cortical and the medullary part of the adrenal gland was demonstrated since long time. In fact, the inhibition of biosynthesis of adrenal glucocorticoids by the specific inhibitor aminoglutethimide determined both in cats and rats a significant decrease of catecholamines at the medullary level without changes between the two types of chromaffin cells. Therefore, glucocorticoids excert a permissive role on the chromaffin system through a double mechanism, a direct one at the chromaffin cells and an indirect one via the inhibition of CRH release at the hypothalamic levels.20, 21
Whereas the peripheral nitric-oxide system occurs in the adrenal cortex, chromaffin cells express the nitric-oxide system of the brain. Thus, the basic mechanisms of the nitric-oxide regulation both for neurons and endocrine cells have been identified in chromaffin cells.22 Similarly, the pituitary and the adrenal medulla contain the highest amount of vitamin C in the human body, and mechanisms of the of role vitamin C uptake and regulation of neurotransmitters were identified in chromaffin cells.23
The broad role of nerve growth factor (NGF) in the living organism was first discovered in the adrenal medulla.24 Indeed, Unsicker et al.25 at that time at the Johns Hopkins University found that immature chromaffin cells obtained from the adrenal medulla cultured in the presence of NGF acquire the biochemical and morphological properties of sympathetic neurons.
Furthermore, experiments carried out in the CNR (Italian Council for Research) laboratory of cell biology in Rome by Aloe and Levi-Montalcini26 demonstrated in vivo that application of NGF into the rat fetus and continued for 3 weeks after birth induced the differentiation of chromaffin cells into sympathetic neurones within the adrenal gland. This clearly established that NGF had a much wider role in the living organisms than had been supposed so far.
The central medulla markedly increased in volume as a result of the differentiation of adrenal cells into sympathetic neurons, which sprout a large number of widely branching fibers.
Given the outstanding role the chromaffin cell system has had in the past, it would be a mistake not to use the system for the current issues of brain research.
We have entered a new era of regenerative medicine also for neurodegenerative diseases of the brain. Chromaffin cells could again take the lead to explore some of the mechanisms of regeneration that pertain in a similar way to the more complex central nervous system (CNS) disorders. Chromaffin cell lines are now being used to explore the role of NGF in Alzheimer's disease. Indeed, proteins from chromaffin granules promote survival of neurons,27 which may be due to a number of known or yet unknown neurotrophin factors. Thus, NGF deprivation from differentiated PC12 cells caused overproduction of amyloid-β peptides, which are the most toxic protein fragments directly implicated in the development of Alzheimer's disease, concomitantly with cell death by apoptosis.28 The tight connection between NGF deprivation and activation of the amyloidogenic pathway has been extended to hippocampal neurons.29 These studies have revealed a new property of TrkA, the high affinity NGF receptor. When deprived of NGF TrakA switches from a prosurvival to a proapoptotic cell signaling system. It is reasonable to hypothesize that such property is also operative in chromaffin neurons bearing NGF receptor and underly new avenues for cell signaling machineries in these cells.29
NGF also promotes cell survival during endoplasmic reticulum stress in PC12 cells.30 Moreover, PC12 cells are now widely used to study the effect and signaling pathways of numerous other neurotrophic and neuroprotective peptides in brain regeneration. This includes pituitary adenylate cyclase-activating polypeptide,31, 32 bone morphogenetic protein 733 and cerebral dopamine neurotrophic factor,34 which may restore dopaminergic neurons in degenerative diseases of the brain such as Parkinson's disease. Sequence variations in the BDNF gene have been associated with major depression and antidepressant treatment success,35 and the role of BDNF in mediating the neuroprotective role of antidepressants has been recently explored in chromaffin cell lines.36
Furthermore, mounting evidence suggests the existence of multipotent neural crest-derived progenitor cells in the adult adrenal medulla.37 Their recent identification and isolation38 sparks off new hopes for their potential use in regenerative treatment of neurodegenerative diseases such as Parkinson's disease.39, 40, 41 Chromaffin progenitor cells share significant properties with neural stem cells. Similar to neurospheres, when prevented from adherence to the culture dish, chromaffin progenitor cells grow in spheres with self-renewing capacity, which we named chromospheres. They express the neural progenitor markers nestin, vimentin, musashi 1 and NGF receptor, as well as Sox1 and Sox10,38 Mash137 and proteins of the Notch pathway (Vukicevic and colleagues, under revision). Furthermore, they are able to differentiate to mature catecholaminergic neurons38 (Vukicevic and colleagues, under revision). Similar to differentiating neural stem cells, where Notch is a key regulator of neural stem cell maintenance in the developing nervous system,42, 43 the shift toward neuronal differentiation of chromosphere cells is accompanied by a reduction of neural progenitor markers including Notch-2, Hes (hairy and enhancer of split) 1, Hes 5 and nestin (Vukicevic and colleagues, under revision).
Finally, it should not been forgotten that enterochromaffin cells derive also from the neural crest, and represent the site in which Vittorio Erspamer discovered in 1930s enteramine,44 which later was found identical to serotonin (5-HT)45 present in CNS.46 A large number of papers exist in the literature that show that other neurotransmitters, neuropeptides and the same transduction mechanisms present in the brain exist also in the gastrointestinal chromaffin cells where they have important roles.47
Thus, chromaffin cells and brain neurons and their precursor cells share similar signaling pathways and again constitute an ideal model to identify the innate pathways and targets for brain regeneration.
Recent efforts probing the endogenous regenerative and repair potential of the adult CNS are met with great difficulties, which are based on the system's rigidity and limited access to pharmaceuticals. The blood–brain barrier limits the number of factors that can be tested systemically and necessitates invasive alternatives such as direct injections into the brain. Rigidity comes from the subtle plasticity exhibited, possibly as a means of preserving homeostasis and memory. The adrenal gland, in stark contrast, is a remarkably plastic organ that reacts in marked fashion to many physical and emotional stresses. For the scientist researching state change, the adrenal gland is an outstanding tool case. Within it, the canary in the coal mine is the chromaffin cell and its precursor cell. Physical and emotional insults alter the function, properties and numbers of these cells in a way, which is easy to assess and manipulate. The relevance to neuroscience is direct: chromaffin precursor cells share many common features with their bona fide CNS brethren; they can be cultured in much the same way (Figure 1), they express many common markers including components of the cytoskeleton and transcription factors and, critically, they respond to many treatments similarly. As a research system to the neuroscientist, the adrenal gland is a model of the brain, outside the blood–brain barrier, exhibiting augmented reactions. Within it, chromaffin precursor cells are an accessible and measurable window to the workings of CNS neural stem cells. At a time when scientists strive to not pigeon-hole themselves within one organ, but search for clues that will lead to novel therapeutic approaches in as many places as possible, the chromaffin cell system is an outstanding research companion to its more esoteric CNS counterpart.
In the CNS, a role of endogenous neural stem cells (eNSCs) in generating new neurons is only recognized in two areas, the subventricular zone and the dentate gyrus of the hippocampus. Yet, populations of eNSCs have been discovered throughout the brain and spinal cord of adult rodents and primates. A widespread population can be identified using expression of the transcription factor Hes3.48 Such observations have raised roles for eNSCs other than cell replacement. Hes3 is regulated by a non-canonical Notch pathway branch that involves the sequential activation of the Notch receptor, phosphorylation of the signaling molecule signal transducer and activator of transcription 3 on its serine residue and induction of Hes3 transcription.49 Other factors that regulate this pathway at different points including insulin,50 inhibitors of the p38MAP and Janus kinases, the Tie2 receptor ligand angiopoietin 2 and the cholera toxin51 also increase stem cell numbers. Individually, some of these factors have adverse effects on the vasculature (some are pro- and others anti-angiogenic).52 When combined into a particular mixture containing Delta4, angiopoietin2, insulin and a Janus kinase inhibitor, maximal increases of eNSC numbers are achieved with minimal vascular side effects. In rats subjected to experimental Parkinsonism, a single injection of this mixture promotes long-term rescue of dopamine neurons, which would otherwise die and motor skill recovery. These results suggest that eNSCs have a role in protecting compromised neurons. Many of these pathway components may be shared with the chromaffin cell system and work has already shown a general involvement of the Notch receptor and several common transcription factors (see above). In addition, the highly vascularised environment of the adrenal gland suggests that angiogenic cytokines may regulate adrenomedullary precursor cells as well. Although the involvement of chromaffin precursor cells in cell replenishment in the adrenal medulla is established, data from the CNS suggest that additional regulatory and possibly pro-survival roles of chromaffin cells in the adrenal medulla await discovery.
In summary, the lessons we have learned from chromaffin cell biology as a peripheral model for brain and brain disease pertain more than ever to the cutting edge research in neurobiology. We should continue and intensify the use of this model to unravel the mechanisms of regeneration both in the CNS and neuroendocrine tissue. It will not only help to explore the basic mechanisms of cell renewal and regeneration but also help to design new strategies for regenerative therapies of the brain in the future.
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This work was supported by grants of the Deutsche Forschungsgemeinschaft: KFO 252/1 (SRB, MEB, AAT, GE), SFB 655 (MEB, SRB) and the Center for Regenerative Therapies Dresden Cluster of Excellence to (SRB, MEB).
The authors declare no conflict of interest.
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Bornstein, S., Ehrhart-Bornstein, M., Androutsellis-Theotokis, A. et al. Chromaffin cells: the peripheral brain. Mol Psychiatry 17, 354–358 (2012). https://doi.org/10.1038/mp.2011.176
- adrenal medulla
- neuronal differentiation
- stem cells
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