Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Tissue-Specific Stress
The correct timing of adult stem cell function is essential for tissue homeostasis. Our group was among the first to show that circadian rhythms segregate important stem cell functions along the day. For instance, in mouse epidermal stem cells this mechanism ensures that their proliferation occurs a...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/457961 |
| Acceso en línea: | http://hdl.handle.net/10803/457961 |
| Access Level: | acceso abierto |
| Palabra clave: | Cèl·lules mare Células madre Stem cells Envelliment Envejecimiento Aging Ritmes circadiaris Ritmos circadianos Circadian rhythms Ciències de la Salut 616 |
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Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Tissue-Specific Stress |
| title |
Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Tissue-Specific Stress |
| spellingShingle |
Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Tissue-Specific Stress Peixoto, Francisca de Oliveira Cèl·lules mare Células madre Stem cells Envelliment Envejecimiento Aging Ritmes circadiaris Ritmos circadianos Circadian rhythms Ciències de la Salut 616 |
| title_short |
Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Tissue-Specific Stress |
| title_full |
Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Tissue-Specific Stress |
| title_fullStr |
Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Tissue-Specific Stress |
| title_full_unstemmed |
Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Tissue-Specific Stress |
| title_sort |
Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Tissue-Specific Stress |
| dc.creator.none.fl_str_mv |
Peixoto, Francisca de Oliveira |
| author |
Peixoto, Francisca de Oliveira |
| author_facet |
Peixoto, Francisca de Oliveira |
| author_role |
author |
| dc.contributor.none.fl_str_mv |
Aznar Benitah, Salvador Universitat de Barcelona. Facultat de Farmàcia |
| dc.subject.none.fl_str_mv |
Cèl·lules mare Células madre Stem cells Envelliment Envejecimiento Aging Ritmes circadiaris Ritmos circadianos Circadian rhythms Ciències de la Salut 616 |
| topic |
Cèl·lules mare Células madre Stem cells Envelliment Envejecimiento Aging Ritmes circadiaris Ritmos circadianos Circadian rhythms Ciències de la Salut 616 |
| description |
The correct timing of adult stem cell function is essential for tissue homeostasis. Our group was among the first to show that circadian rhythms segregate important stem cell functions along the day. For instance, in mouse epidermal stem cells this mechanism ensures that their proliferation occurs at night and not during day, when maximal oxidation takes place. Likewise, circadian rhythms separate DNA replication from the time when human epidermal stem cells are exposed to UV radiation. Importantly, circadian control of stem cells is a general mechanism operating in hematopoietic, mesenchymal, muscle, neural, and intestinal stem cells, as shown by others. A current dogma in the field is that circadian rhythms dampen during ageing, and that this dampening is in fact a major cause of many traits associated to ageing. With this in mind we decided to ask: is the timing of stem cell function altered during ageing? If so, how is it perturbed? Are the changes common, or stem cell-specific? To study these questions, we have performed a large-scale analysis of the circadian transcriptome of FACS-sorted stem cells from adult and aged mice, which has provided us with an unprecedented understanding of how their physiology changes during ageing. We chose two types of stem cells for our study, those from the epidermis and the skeletal muscle, since they represent two populations with very different behaviours (the former being highly proliferative, while the latter remaining predominantly quiescent throughout the lifetime of the mouse). Unexpectedly, we find that aged mice remain behaviourally circadian, and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components (Bmal1, or Period-1 and Period-2) did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological ageing. Normal homeostatic functions of adult stem cells have rhythmic daily oscillations that are believed to become arrhythmic during ageing. Age-associated rewiring of the oscillatory diurnal transcriptome is significantly prevented by long- term caloric restriction in aged mice. This striking effect further highlights the anti-ageing benefits of this type of diet. Conversely, although a high-fat diet strongly reprograms the circadian output of both stem cells, there is little overlap with the age-related rewired oscillating transcriptome. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific age- related traits. |
| publishDate |
2017 |
| dc.date.none.fl_str_mv |
2017 2017 2018 |
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info:eu-repo/semantics/doctoralThesis info:eu-repo/semantics/publishedVersion |
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doctoralThesis |
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publishedVersion |
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http://hdl.handle.net/10803/457961 |
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http://hdl.handle.net/10803/457961 |
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Inglés |
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Inglés |
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info:eu-repo/semantics/openAccess |
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openAccess |
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145 p. application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Universitat de Barcelona |
| publisher.none.fl_str_mv |
Universitat de Barcelona |
| dc.source.none.fl_str_mv |
TDX (Tesis Doctorals en Xarxa) reponame:TDR. Tesis Doctorales en Red instname:CBUC, CESCA |
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CBUC, CESCA |
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TDR. Tesis Doctorales en Red |
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TDR. Tesis Doctorales en Red |
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1869404557052739584 |
| spelling |
Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Tissue-Specific StressPeixoto, Francisca de OliveiraCèl·lules mareCélulas madreStem cellsEnvellimentEnvejecimientoAgingRitmes circadiarisRitmos circadianosCircadian rhythmsCiències de la Salut616The correct timing of adult stem cell function is essential for tissue homeostasis. Our group was among the first to show that circadian rhythms segregate important stem cell functions along the day. For instance, in mouse epidermal stem cells this mechanism ensures that their proliferation occurs at night and not during day, when maximal oxidation takes place. Likewise, circadian rhythms separate DNA replication from the time when human epidermal stem cells are exposed to UV radiation. Importantly, circadian control of stem cells is a general mechanism operating in hematopoietic, mesenchymal, muscle, neural, and intestinal stem cells, as shown by others. A current dogma in the field is that circadian rhythms dampen during ageing, and that this dampening is in fact a major cause of many traits associated to ageing. With this in mind we decided to ask: is the timing of stem cell function altered during ageing? If so, how is it perturbed? Are the changes common, or stem cell-specific? To study these questions, we have performed a large-scale analysis of the circadian transcriptome of FACS-sorted stem cells from adult and aged mice, which has provided us with an unprecedented understanding of how their physiology changes during ageing. We chose two types of stem cells for our study, those from the epidermis and the skeletal muscle, since they represent two populations with very different behaviours (the former being highly proliferative, while the latter remaining predominantly quiescent throughout the lifetime of the mouse). Unexpectedly, we find that aged mice remain behaviourally circadian, and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components (Bmal1, or Period-1 and Period-2) did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological ageing. Normal homeostatic functions of adult stem cells have rhythmic daily oscillations that are believed to become arrhythmic during ageing. Age-associated rewiring of the oscillatory diurnal transcriptome is significantly prevented by long- term caloric restriction in aged mice. This striking effect further highlights the anti-ageing benefits of this type of diet. Conversely, although a high-fat diet strongly reprograms the circadian output of both stem cells, there is little overlap with the age-related rewired oscillating transcriptome. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific age- related traits.El control temporal de las funciones de las células madre es esencial para la homeostasis de los tejidos. Nuestro grupo de investigación fue uno de los primeros en mostrar como los ritmos circadianos coordinan distintas funciones celulares importantes a lo largo del día en las células madre epidérmicas de ratón. Además, tal y como han demostrado otros grupos, el control circadiano de las células madre, constituye un mecanismo de vital importancia en el caso de las células madre hematopoyéticas, mesenquimales, musculares, neurales e intestinales. Actualmente, en este campo de investigación, el dogma prevalente es la existencia de un desajuste progresivo de los ritmos circadianos durante el envejecimiento. Este desajuste se cree que puede ser el causante de muchas de las manifestaciones asociadas con el envejecimiento. Considerando todos estos aspectos, nos cuestionamos ¿está el control temporal de la función de las células madre alterado durante el envejecimiento? Y en caso de estar afectado, ¿de qué forma está perturbado?, ¿Existen cambios comunes durante el envejecimiento o estos cambios son específicos de cada tejido? Para resolver estas incógnitas hemos realizado un análisis a gran escala del transcriptoma circadiano de células madre de epidermis y músculo esquelético de ratones adultos y de edad avanzada. Estas células se obtuvieron a través de FACS (Fluorescence-Activated Cell Sorting) y los resultados obtenidos de este transcriptoma nos han permitido entender los cambios fisiológicos que ocurren durante el envejecimiento en estos tipos celulares tan dispares: la epidermis es altamente proliferativa mientras que en el músculo esquelético las células madres permanecen quiescentes durante la vida del ratón. Sorprendentemente, observamos que los ratones de edad más avanzada permanecen con un comportamiento circadiano, y que sus células madre epidérmicas y de músculo esquelético presentan una maquinaria circadiana robusta. A pesar de ello, el transcriptoma oscilatorio está reprogramado de una forma extensa en las células madres de más edad, cambiando los genes involucrados en homeostasis por aquellos asociados a estrés específico de tejido, como el daño celular o la autofagia ineficiente. Cabe destacar que la deleción de componentes del reloj circadiano (BmaI1 o Period-1 i Period-2) no reproduce las marcas distintivas de esta reprogramación sino que causa arritmia circadiana, que está asociada con envejecimiento fisiológico. Así pues, las funciones homeostáticas de las células madre adultas tienen unas oscilaciones rítmicas diarias alteradas - aunque no perdidas - durante el envejecimiento. La reprogramación del transcriptoma oscilatorio diurno asociada con la edad está significativamente reducida en los ratones sometidos a una restricción calórica a largo plazo. Este efecto tan dramático resalta los beneficios antienvejecimiento de este tipo de dieta. En cambio, a pesar de que una dieta rica en grasas reprograma el ritmo circadiano de ambas células madre (epidérmicas y de músculo esquelético), hay poca superposición con la reprogramación debida al envejecimiento. Así pues, las células madre reprograman sus funciones diurnas para adaptarse a las señales metabólicas y a las características específicas de tejido asociadas con el envejecimiento.Universitat de BarcelonaAznar Benitah, SalvadorUniversitat de Barcelona. Facultat de Farmàcia201720182017info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion145 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/457961TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/4579612026-06-14T12:46:07Z |
| score |
15,300719 |