Project

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Molecular and cellular network regulating stem cell activity and neurogenesis in the olfactory epithelium

English title Molecular and cellular network regulating stem cell activity and neurogenesis in the olfactory epithelium
Applicant Fritschy Jean-Marc
Number 128112
Funding scheme NRP 63 Stem cells and regenerative medicine
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.03.2010 - 28.02.2015
Approved amount 564'304.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Cellular Biology, Cytology

Keywords (3)

neurogenesis; olfaction; stem cell

Lay Summary (English)

Lead
Lay summary
Nerve stem cells: Control and communication

The human nose contains anything from 10 to 30 million receptor cells which can recognize thousands of different smells. Nerve stem cells ensure that dead receptor cells are constantly replaced. However, these stem cells could also be used for medical purposes.

Background
In the olfactory epithelium located in the nasal cavity, smell receptor cells are constantly regenerated over a person’s lifetime. Olfactory stem cells are responsible for this and they are an ideal model to examine how stem cells are regulated. Furthermore, they are available in abundance and easily accessible - important preconditions for any later medical application.

These nerve stems cells could be used against a variety of ailments such as the loss of hearing and sight, Parkinson’s and stroke. However one of the challenges is that stem cells trans-planted in the brain do not assimilate very well and as a result rarely survive. To overcome this obstacle, this research project tries to get a better understanding of the stem cells’ direct surroundings because only in the right surroundings can stem cells perform their work as desired.

Aim
The aim is to study the different mechanisms which lead to old receptor cells dying and new ones being established. The project builds on the discovery of a particular cell type, the microvillar cells, which can recognize when smell receptor cells die. The microvillar cells pass this death notice on to the stem cells, which then begin to produce new smell cells. This projects aims at understanding how microvillar cells communicate with stem cells.

Significance
The project offers a possibility of investigating complex cell networks, which control the activity of stem cells. It should offer clues as to how nerve stem cells could be used for transplantations.


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Novel role of cystic fibrosis transmembrane conductance regulator in maintaining adult mouse olfactory neuronal homeostasis.
Pfister Sandra, Weber Tamara, Härtig Wolfgang, Schwerdel Cornelia, Elsaesser Rebecca, Knuesel Irene, Fritschy Jean-Marc (2015), Novel role of cystic fibrosis transmembrane conductance regulator in maintaining adult mouse olfactory neuronal homeostasis., in The Journal of comparative neurology, 523(3), 406-30.
Characterization and turnover of CD73/IP(3)R3-positive microvillar cells in the adult mouse olfactory epithelium.
Pfister Sandra, Dietrich Maren G, Sidler Corinne, Fritschy Jean-Marc, Knuesel Irene, Elsaesser Rebecca (2012), Characterization and turnover of CD73/IP(3)R3-positive microvillar cells in the adult mouse olfactory epithelium., in Chemical senses, 37(9), 859-68.

Collaboration

Group / person Country
Types of collaboration
University of Leipzig Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Hannover Medical School Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting of the Society for Neuroscience Poster Cystic fibrosis transmembrane conductance regulator (CFTR) contributes to neuronal homeostasis in the mouse olfactory epithelium by regulating the function of microvillar cells 17.11.2013 San Diego, United States of America Elsässer Rebecca; Pfister Sandra; Fritschy Jean-Marc;
8th FENS Forum Poster CFTR contributes to neuronal homeostasis in the olfactory epithelium by regulating the function of microvillar cells 08.07.2012 Barcelona, Spain Pfister Sandra; Fritschy Jean-Marc; Elsässer Rebecca;


Abstract

Neurons lost after injury or in neurodegenerative diseases are not replaced, causing irreversible functional impairments. Regenerative medicine using neural stem cells potentially promises effective treatment for these conditions. Despite progress in our understanding of the biology of stem cells, major obstacles faced by regenerative medicine are the poor survival and integration of transplanted cells. So far, we only inadequately understand the cellular microenvironment vital for neural stem cells. Since neuronal replacement continuously occurs throughout adult life in the olfactory epithelium, it is an ideal model system to elucidate the underlying mechanisms on a systemic level. Moreover, as olfactory stem cells are abundant and easily accessible, the olfactory epithelium is a potential source for future autotransplantation stem cell therapy. Olfactory neurons continuously degenerate by apoptosis and as a consequence of cellular damage. They are replaced by new neurons arising from a pool of adult stem cells. Therefore, apoptosis and regeneration must be precisely coordinated to maintain the functional integrity of the epithelium. So far, the molecular and cellular mechanisms underlying this intricate coordination are largely unknown. Understanding regeneration in the olfactory epithelium might provide keys to overcome the limited regeneration capacity of brain neurons and exploit the cell replacement potential of olfactory stem cells. The aim of my project is to contribute towards this goal by investigating mechanisms regulating neurogenesis in this model system. My preliminary work has identified a specialized olfactory cell type, so-called microvillar cells, which appears to coordinate a signaling network responsible for detecting degeneration of neurons and transducing this signal into adequate proliferation and differentiation cues. To further investigate the role of microvillar cells, I will perform an unbiased analysis of genes involved at different stages of the regenerative process. To this end, I will determine the transcriptional profile of olfactory stem cells and microvillar cells isolated by FACS from tissue in which neurodegeneration has been experimentally induced and compare the data to the expression profile of microvillar cells isolated from the unperturbed epithelium, which I already have determined. Transcripts that are up- or down-regulated upon degeneration will be characterized in vivo by in-situ-hybridization and immunohistochemistry, and their impact on cell proliferation and differentiation will be tested in vitro in primary cultures of the olfactory epithelium. Moreover, extrinsic factors regulating the excitability and function of microvillar cells will be characterized in vitro with calcium-imaging experiments and in vivo upon intranasal instillation. The same approach will be used to transduce the olfactory epithelium with viruses encoding selected genes to influence cell proliferation and differentiation. Finally, the role of key candidate components of the neurogenesis regulatory network will be confirmed in vivo in wild-type and knockout mice. My project allows the investigation of complex cellular networks regulating stem cell activity in response to physiological and pathophysiological stimuli in vivo. It will therefore provide important insights into the cellular microenvironment that regulates neuronal replacement in the olfactory epithelium in order to provide cues to be exploited in future neural stem cell transplantation approaches.
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