Cellule souches, Vieillissement et Mécanismes de Réponse au Stress / Stem Cells, Aging and Stress Response Mechanisms

Séminaire co-organisé par Emmanuelle Passegué (Columbia University, New York, USA) et Shahragim Tajbakhsh (Institut Pasteur, Paris, France) du 7 au 12 Octobre 2019.

 

Résumé

La réunion a rassemblé dix-neuf scientifiques internationaux de renom pour discuter des progrès à la croisée des chemins entre les cellules souches, les mécanismes de réponse au stress et le vieillissement. Dix chercheurs étaient européens et neuf internationaux (États-Unis et Japon), avec deux professeurs juniors et une excellente parité entre les sexes avec 10 femmes et 9 hommes présents. La rédactrice en chef de la revue Nature Communication était également présente tout au long de la réunion et elle a détaillé plusieurs nouvelles initiatives de publication destinées à améliorer la rigueur et reproductibilité des travaux scientifiques. Les présentations ont couvert un large éventail de recherches sur les effets intrinsèques (régulations métaboliques, cassure à l’ADN, la senescence et les mécanismes de la reprogrammation cellulaire, la dérégulation transcriptionnelle et épigénétique, etc.) et extrinsèques (la niche, l’hétérogénéité cellulaire, les facteur systémiques, etc.) du vieillissement. La discussion a porté sur la notion que la suractivation des mécanismes de réponse au stress ou la réponse dérégulée au stress est au cœur du vieillissement des cellules souches et de la dérégulation des tissus liée à l’âge. Ces travaux offrent de nouvelles opportunités intéressantes pour les interventions anti-âge et de rajeunissement.

 

Summary

The meeting gathered nineteen renowned international scientists to discuss advances at the crossroads between stem cells, stress response mechanisms and aging. Ten researchers were European and nine were international (USA and Japan), with two junior faculty and an excellent gender parity with 10 women and 9 men presenting. The editor-in-chief from the journal Nature Communication was also in attendance and she introduced several new publishing initiatives to enhance rigor and reproducibility. The presentations covered a broad spectrum of research on the cell-intrinsic (e.g., metabolic regulation, DNA damage, senescence and cellular reprogramming, transcriptional and epigenetic deregulation, etc.) and cell-extrinsic (e.g., niche, cellular heterogeneity, systemic factors, etc.) effects on aging. The discussion centered on the notion that overactivation of stress response mechanisms or deregulated response to stress is at the core of stem cell aging and age-related tissue deregulation, which provide new exciting opportunities for anti-aging and rejuvenation interventions.

 

Compte-Rendu (en anglais) / Report

Dr. Emmanuelle Passegué (Columbia University, USA) started the meeting by discussing how hematopoietic stem cells (HSCs) lose their ability to regenerate the blood system, and promote disease development with age. Many cell intrinsic drivers of HSC aging have been identified so far, but it remains unclear what promotes their deregulation and whether they could be reversed for rejuvenation interventions. Moreover, the contribution of the aging bone marrow (BM) niche microenvironment to blood aging and HSC dysfunction is still in large part unexplored. Dr. Passegué presented ongoing work from her laboratory addressing the contribution of replication stress and autophagy to HSC aging as well as the role of the inflamed BM niche microenvironment in driving blood aging. She also discussed the reversibility of these cell intrinsic or extrinsic deregulations as strategies for combating the effects of old age and HSC dysfunction.

Dr. Omer Yilmaz (MIT, USA) presented work on how fat-rich diets and fasting enhance intestinal stem cell (ISC) function through engagement of fatty acid oxidation and its downstream metabolites. Ketogenesis is a metabolic process that occurs downstream of fatty acid oxidation (FAO) and results from the breakdown of fatty acids and ketogenic amino acids to generate a group of metabolites collectively known as ketone bodies. Dr. Yilmaz showed that expression of ketogenic enzymes distinguished Lgr5+ ISCs from progenitors. Furthermore, his group found that abrogation of HMGCS2, the rate limiting enzyme of ketogenesis, compromised ISC numbers (by promoting their differentiation) and ISC-mediated post-injury repair. Mechanistically, the ketone body β-hydroxybutyrate (βOHB) acted as a signaling metabolite that amplified NOTCH signaling through the inhibition of histone deacetylases (HDACs). With respect to diet, a high fat ketogenic diet boosted ISC function and post-injury regeneration through βOHB-mediated NOTCH signaling, whereas a glucose supplemented diet had the opposite effects. This fascinating finding links a metabolite downstream of FAO to a fundamental developmental pathway and raised many exciting future directions: 1) the cancer consequences of this model, 2) the energetic and NOTCH-independent signaling roles of ketone bodies in regulating stemness, and 3) the non-cell-autonomous roles of ISC-derived ketone bodies on stromal, immune and microbial commensals in the stem cell microenvironment.

Dr. Allison Bardin (Curie Institute, France) followed on her work addressing how stem cell DNA damage can cause functional decline of stem cell-based tissue renewal during aging. Endogenous cellular events, such as replication fork collapse, or exogenous agents, such as ultraviolet light, modify the DNA leading to altered bases or DNA breaks, “DNA damage,” that needs to be repaired. Repair, in turn, can be accurate and prevent mutation, or imprecise and result in genome mutation. In addition, transposable element (TE) de-repression during aging can be a source of functional decline of adult stem cells and tissues. Consistent with this, TEs (LINE elements) were demonstrated to give rise to de novo insertions in the mammalian brain and are proposed to generate diversity leading to “unique properties” of the targeted neurons. Historically, it has been difficult to measure genome-wide rates of DNA mutation in adult stem cells as individual mutations are only present in a fraction of cells. However, consistent with the notion that DNA damage drives aging, there is an increase in marks of DNA damage during aging in many stem cells. To address the extent to which DNA damage arises and the impact that it has, Dr. Bardin’s group use the adult Drosophila intestinal stem cell model, which they have previously shown to acquire mutations leading to neoplasia formation. She presented evidence for frequent LTR element mobility leading to de novo inserts and large gene deletion events. Using novel long-read sequencing technology, her group found tissue-specific mobilization of an LTR. Interestingly, the evidence suggests that distinct types of mutations have different kinetics during aging, raising the possibility for differential impact on development and aging.

Dr. Manuel Serrano (IRB, Spain) presented recent data from his laboratory on cellular senescence and cellular reprogramming in relation to aging and age-associated diseases. A major advance in the field of aging research has been the demonstration that senescent cells play a key role and, even more importantly, the discovery of small pharmacological compounds that can kill senescent cells within the organism resulting in improved health. Dr. Serrano presented evidence that senescent cells are necessary and sufficient to produce some degenerative diseases. He also proposed a possible pathophysiological origin for the appearance of senescent cells in degenerative diseases. During the past 5 years, his laboratory has also devoted a large effort to understand how reprogramming driven by the Yamanaka factors (OSKM) occurs in vivo, leading to the discovery of the essential function of interleukin IL6, a finding that has been corroborated by various laboratories. His work is now focused on the early phases of in vivo reprogramming, when cells partially lose their identity and tissues alter their histology, but can still recover homeostasis upon switching off the expression of the OSKM cassette. The Belmonte laboratory has reported that serial periods of transient reprogramming can rejuvenate cells and animals, and Dr. Serrano presented results in mice indicating that a single transient period of OSKM expression can produce epigenetic rejuvenation in vivo.

Dr. Sara Wickström (HILS, Finland) discussed the role of the niche and in particular niche-derived mechanical stress in stem cell regulation and aging. Using mouse hair follicle as paradigm for stem cell regulation she showed how age-related changes in the extracellular matrix proteome impacted the mechanical properties of the hair follicle stem cell niche and how these mechanical forces attenuated in particular the expression of genes with poised promoter states. She further discussed data on how extrinsic mechanical strain directly acts on cell nuclei to trigger alterations in the epigenetic state of in particular heterochromatin. Collectively, the talk highlighted the importance of niche mechanics in regulating the state and potency of stem cells and the potential relevance of mechanical stress as a factor in aging.

Dr. Saul Villeda (UCSF, USA) spoke about systemic interventions to reverse age-related regenerative and cognitive decline in the aged brain. He surveyed the state of the field on the effect of heterochronic parabiosis and young plasma administration on neural stem cells, neuroinflammation, synaptic plasticity and cognition. In unpublished data, he showed that administration of circulating blood factors in plasma transfers rejuvenating effects of exercise on adult neurogenesis and cognition in aged mice. He identified glycosylphosphatidylinositol specific phospholipase D1 (Gpld1) as a liver-derived exercise blood factor – the plasma levels of which correlate with improved cognitive function in aged mice, and the levels of which are increased in active healthy elderly humans. Lastly, he demonstrated that increasing liver-derived systemic Gpld1 in aged mice ameliorates age-related regenerative and cognitive impairments by altering signaling cascades downstream of glycosylphosphatidylinositol (GPI)-anchored substrate cleavage in the aging systemic milieu.

Dr. Amy Wagers (Harvard University, USA) discussed new insights into the molecular regulators of very early events in the activation of muscle stem cells (also known as satellite cells), a stage of myogenesis that reprograms these normally quiescent cells to a state of myogenic competency and rapid proliferative activity and which is rate-limiting for recovery from muscle damage. She described the work of her laboratory identifying a prominent FOS signature in recently activated muscle stem cells, and demonstrating the requirement for FOS activation in efficient entry of muscle stem cells into cell cycle, proliferative expansion, and induction of a robust regenerative response to muscle injury. She also presented evidence implicating the FOS-activated target gene, mono-ADP Ribosyl-Transferase 1 (Art1), as a key molecular mediator of these effects and potential integrator of systemic metabolic cues with injury-induced satellite cell activation and muscle repair. Finally, she discussed the broad impact of blood-circulating factors in both driving and reversing age-related dysfunction in a variety of organ systems, and provided an update on our ongoing work evaluating one such blood-circulating factor, the Growth Differentiation Factor 11 (GDF11) for its role in age-related loss of muscle regenerative function.

Dr. Toshio Suda (CSI, Singapore) discussed how the metabolic requirements for adaptations of stem cells to their niches still remain largely unknown. He used the paradigm of blood-forming hematopoietic stem cells (HSCs) where cell metabolism can be quite different in quiescent and cycling states. Most of HSCs within the bone marrow are in a quiescent state. By contrast, upon stress hematopoiesis, HSCs actively divide to regenerate the hematopoietic system with the appropriate balance between self-renewal and differentiation divisions. It is reported that with aging, HSC metabolic change with increased oxidative phosphorylation. Dr. Suda compared mitochondrial metabolism between the quiescent state and cycling state in various conditions. First, he showed that suppression of Ca2+ influx and subsequent mitochondrial membrane potential contributes to the maintenance of HSCs by slowing cell divisions. Next, during stress hematopoiesis as induced by thrombopoietin (Thpo) administration or oppositely, in Thpo-deficient mice, he demonstrated drastic changes in the cell metabolism accompanying by a shift in an HSC subpopulation. Finally, using ATG7-deficient mice, he suggested that autophagy is involved in maintaining quiescence in adult HSCs, but not in neonatal HSCs, which show significant differences in the nature of their cell metabolism compared to adult quiescent HSCs. Dr. Suda proposed two types of self-renewing HSCs (dormant and cycling), and stressed the need for more extensive examination of mitochondrial function in aging HSCs.

Dr. Pura Muñoz-Cánoves (ICREA and Pompeu Fabra University, Spain) described how aging is characterized by the progressive dysfunction of most tissues and organs, which has been linked to the regenerative decline of their resident stem cells over time. Skeletal muscle provides a stark example of this decline. Its stem cells, also called satellite cells, sustain muscle regeneration throughout life, but at advanced age they fail for largely undefined reasons. She discussed her current understanding of the molecular processes regulating satellite-cell maintenance throughout life and how age-related failure of these processes contributes to muscle aging. In particular, she put special emphasis on the following specific unsolved questions: i) what maintains muscle stem cell quiescence in adult life; ii) what drives loss of bona fide quiescence during aging; iii) what are the consequences on muscle regenerative functions; iv) what strategies can reverse loss of quiescence and muscle regeneration; and v) how does muscle stem cell diversity evolve throughout a lifetime, from birth through geriatric age. Dr. Muñoz-Cánoves found that the relative expression of CD34 can distinguish two satellite cell states with distinct molecular and functional characteristics and unveiled some regulatory mechanisms of their separation. Finally, she also highlighted the emerging field of rejuvenating biology to restore features of youthfulness in satellite cells, with the ultimate goal of slowing down or reversing the age-related decline in muscle regeneration.

Dr. Henri Jasper (Genentech, USA) presented recent studies on the regulation and age-related decline of intestinal stem cell (ISC) function in Drosophila. Previous studies in his and other labs had established that Drosophila ISCs are mostly quiescent in homeostatic conditions, but become rapidly activated in response to tissue damage. The signals and response pathways that control this activation step are largely understood, but it remains unclear how ISC metabolism is modulated to ensure proper adaptation of energy production to the needs of activated stem cells. Recent work in Dr. Jasper’s lab identified mitochondrial Calcium (Ca2+) uptake as a required step in the adaptation of ISC metabolism to the increased energetic demand of regenerative activity. Using a series of in vivo reporters for metabolites and oxygen radicals he showed that mitochondrial Ca2+ regulates Complex I of the electron transport chain to provide increased NADH oxidation capacity and restore normal ATP levels in activated ISCs. Dr. Jasper further discussed a model for age-related decline in ISC function that has emerged based on a series of studies over the last decade. Critically, a progressive decline in intestinal homeostasis can be attributed to a metaplasia that emerges in the gastric epithelium and that results in changes in the pH of the gastric lumen. Microbial dysbiosis is a consequence of these changes and results in a secondary inflammatory response in turn causes ISC dysplasia and loss of barrier function. Various interventions have been designed based on this model and were shown to successfully delay the onset of such age-related changes and to extend lifespan.

Dr. Emi K. Nishimura (Tokyo University, Japan) talked about stem cell fate changes in melanocyte stem cells, hair follicle stem cells and epidermal stem cells during ageing. Her studies with melanocyte stem cells and hair follicle stem cells in hair follicles have revealed that dynamic elimination of the aged stem cells underlies typical hair ageing phenotypes such as hair graying and hair thinning in mammalian hair follicles. She presented recent results from her laboratory showing that the expression of the hemidesmosome component collagen XVII (COL17A1) by epidermal stem cells fluctuates physiologically through genomic/oxidative stress-induced proteolysis, and that the resulting differential expression of COL17A1 in individual stem cells generated a driving force for cell competition to eliminate unfit cells. In particular, in vivo clonal analysis in mice and in vitro 3D modelling showed that clones that express high levels of COL17A1, which divide symmetrically, outcompete and eliminate adjacent stressed clones that express low levels of COL17A1, which divide asymmetrically. Stem cells with higher potential or quality are thus selected for homeostasis, but their eventual loss of COL17A1 limits their competition, thereby causing ageing. Conversely, the forced maintenance of COL17A1 rescues skin organ ageing, thereby indicating potential new angles for anti-ageing therapeutic intervention.

Dr. Linda Partridge (Max Planck Institute, Germany) described work on the geroprotective effects of the drug rapamycin. The drug induces a remarkable memory effect in both Drosophila and mice. In the fly, elevated autophagy in the enterocytes, but not the stem cells, of the gut persists after the drug is withdrawn, or after genetic induction of autophagy; and elevated autophagy in enterocytes is necessary and sufficient to maintain gut health and extend lifespan. In the mouse, effects on Paneth cells, tight junctions and gut leakage all persist 6 months after the drug is withdrawn. These findings both raise many questions and imply that the full geroprotective effects of rapamycin can be achieved with brief treatment.

Dr. Salvador Aznar Benitah (IRB, Spain) discussed how adult stem cells maintain tissue homeostasis, and why and how their striking regenerative capacity is altered during aging and cancer. He showed that adult stem cells are under robust circadian control. This not only allows stem cells to anticipate correct functions according to the time of the day, but also to temporally segregate functions that would be harmful if coincident. Importantly, his and other labs have shown that stem cell circadian arrhythmia leads to a premature ageing phenotype and shortened lifespan. Dr. Benitah’s also showed that the oscillating transcriptome is extensively reprogrammed in physiologically aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses. Importantly, circadian reprogramming during aging is strongly prevented by caloric restriction (6 months long) and exacerbated by a short-term high fat diet (3 months long). One finding is that the timed regulation of stem cell function depends on tissue-autonomous mechanisms and extrinsic factors (both niche-derived and systemic). However, the nature of these functions, and what factors regulate them remain unknown. At the cellular level, clock regulation is established by a self-sustained Bmal1-dependent transcriptional oscillator network, yet how different tissues achieve a synchronized rhythmic physiology remains unclear. Do they respond independently to environmental signals, or require interactions with each other to do so? His laboratory found that unexpectedly light synchronizes the Bmal1-dependent circadian machinery in single tissues in the absence of Bmal1 in all other tissues. Strikingly, light-driven tissue autonomous clocks occur without rhythmic feeding behavior, and are lost in constant darkness. Tissue-autonomous Bmal1 partially sustains homeostasis in otherwise arrhythmic and prematurely-aging animals. His results therefore support a two-branched model for the daily synchronization of tissues: an autonomous response branch, whereby light entrains circadian clocks without any commitment of other Bmal1-dependent clocks; and a memory branch, using other Bmal1-dependent clocks to “remember” time in the absence of external cues. This work will allow identification of the nature of the signals that different stem cells receive from their local environment and systemically to regulate their daily timed functions.

Dr. Anne Brunet (Stanford University, USA) focused on the proteomic and metabolic regulation of adult neural stem cells during aging. She reported that the quiescent and activated NSCs in the adult brain exhibited differences in their protein homeostasis network. She showed that quiescent NSCs contained large lysosomes whereas activated NSCs use the proteasome. Quiescent NSCs from young mice accumulated protein aggregates, and many of these aggregates were stored in large lysosomes but could be degraded upon nutrient starvation. She also showed that during aging, quiescent NSCs displayed defects in their lysosomes, increased accumulation of protein aggregates, and reduced ability to activate. She reported that enhancement of the lysosome pathway in old quiescent NSCs cleared protein aggregates and ameliorated the ability of quiescent NSCs to activate, allowing them to regain a more youthful state. She showed preliminary data on the characterization of protein aggregates and metabolism in lysosomes of young and old NSCs. Together these results help identify mechanisms by which the old neurogenic niche could be ‘rejuvenated’, with the goal of counteracting decline in brain function with aging.

Dr. Shahragim Tajbakhsh (Pasteur Institute, France) presented work on heterogeneity in the quiescent state showing that Pax7-GFP^Hi and Pax7-GFP^Lo muscle stem cells (MuSCs) have distinct properties. The former are in a deeper (dormant) quiescence state, have lower mitochondrial activity, and take about 10 hours longer to execute their first mitosis after activation. In spite of these differences, self-renewal properties following serial transplantation in immunocompromised mice did not reveal major differences between these two populations, although their differentiation potential was not examined. He speculated that MuSCs might consist of a homogenous population of cells, where their anatomical location within the niche (ex. proximal or distal to vessels) would promote distinct properties. Metabolic analysis of young, aged and post-mortem MuSCs was also presented, where mitochondrial activity was compromised in the aged, but not post-mortem cells compared to young MuSCs. In other studies, simultaneous methylome and transcriptome profiling of Pax7-GFP^Hi single cells showed chaotic transcription in aged mice compared to the young (collaboration W. Reik lab, UK). This deregulated transcription correlated in part to increased heterogeneity and reduced methylation in promoters. Finally, Dr. Tajbakhsh showed data on symmetric and asymmetric cells divisions directly in muscle for the first time, where clonal labeling and cell fates were monitored by Pax7 (stem) and Myogenin (differentiated) expression. This readout coupled with non-random segregation of old and new DNA provides in vivo assays and a framework to examine the extent to which symmetry and asymmetry are altered during ageing and in myopathic conditions.

Dr. Ana Martin-Villalba (DKFZ, Germany) discussed recent data on how adult neural stem cells perform in the adult young and old brain. Whereas active neural stem cells show a similar potential to divide and generate progeny as their older counterparts, quiescent stem cells are much harder to activate in the old than in the young brain. Dr. Martin-Villalba’s laboratory found that coordination of cell cycle exit and a drop of mTORC1 activity are required for young and old neural stem cells to exit stemness and start differentiation into neurons. On the other end, an increase in interferon type I signaling in the old brain prevents activation of quiescent stem cells. This increase in quiescence prevents depletion of the stem cell pool at very old ages. At the same time, the increase in quiescence impairs stem cell homeostasis and repair. Notably, acute modulation of inflammatory cytokines facilitates stem cell activation. How much quiescence is good and when to block it to get the best performance of stem cells in the young and the old brain remain open questions for future studies.

Dr. Hiromitsu Nakauchi (Stanford University, USA) discovered a significant (>10 fold) increase of phenotypically-defined hematopoietic stem cells (pHSCs) in aged mouse bone marrow (BM). However, limiting dilution analysis revealed only ~2.9 fold increase in functional HSCs (fHSCs). This discrepancy was largely due to a huge expansion of myeloid-restricted stem/progenitor cells in aged mouse pHSC compartment. Also in aged BM, “latent HSCs” were identified, which showed only myeloid reconstitution in primary recipients but upon secondary transplantation, they reconstituted all 5-lineages including T- and B-lymphocytes. These results question the conventional dogma of HSC aging and our current approaches to assay and define HSCs. Single cell RNA sequence of young and aged mouse pHSCs was performed and bioinformatic analysis is currently in progress to clarify the mechanism(s) underlying the expansion and heterogeneity of pHSCs in aged mouse BM.

Dr. Laure Bally-Cuif (Pasteur Institute, France) is using the zebrafish adult brain, which hosts large amounts of neural stem cells (NSCs), to understand the mechanisms of stem cell maintenance. She specifically presented work addressing the temporal and spatial coordination of NSC fate decisions over time. Combining long-term clonal and populational genetic lineage tracing with intra-vital imaging, she showed that NSC pools behave as systems whose maintenance relies on populational, rather than single-cell, mechanisms. She specifically illustrated the organization of the telencephalic NSC population into sub-functionalized sub-pools selectively responsible for amplification, self-renewal or neurogenesis potential. She also showed how long distance and temporally delayed NSC-NSC interactions generate and propagate the positioning of NSC activation events across the NSC pool to homogenize the spatial distribution of NSC recruitment. These results together support the notion of an intrinsic niche, where self-organized coordination properties emerge from stem cell pools to permit the maintenance of their spatio-temporal homeostasis at long-term.

Dr. Alex Gould (CRICK Institute, UK) ended the meeting by detailing his research aimed at understanding the molecular nuts and bolts of how early-life environmental stresses alter gene expression, metabolism and physiology. His laboratory uses the genetic model Drosophila, and more recently mice and human cells, and employs a range of different technologies, including genetics to find out how genes work, and mass spectrometry imaging to see where metabolites are located inside cells and organs. In his presentation, he showed how the Alk and Insulin signaling pathways play local and systemic roles respectively to drive the proliferation of neural and epidermal stem cells during nutrient stress and hypoxia. In the case of stressed Drosophila neural stem cells, the niche not only provides ligand to activate the Alk receptor but it also protects the redox balance of the stem cell itself. This redox protection in stem cells is mediated, at least in part, via the induction of lipid droplets in the adjacent cells of the niche. He detailed ongoing work suggesting that the “antioxidant” role of lipid droplets is widespread and may extend to hypoxic neural tumors such as glioblastoma. 

 

Communications

• Salvador AZNAR-BENITAH (Institute for Research in Biomedicine, Barcelona, Spain) – Stem cell communication from different tissues through clocks: impact on homeostasis and aging
• Laure BALLY-CUIF (Pasteur Institute, Paris, France) – Mechanisms driving the construction and maintenance of adult neural stem cell ensembles
• Allison BARDIN (Curie Institute, Paris, France) – Stem cell DNA damage
• Anne BRUNET (Stanford University, Palo Alto, USA) – Mechanisms of stem cell aging
• Alex GOULD (CRICK Institute, London, UK) – Coping with a stressful start in life
• Heinrich JASPER (Genentech, San Francisco, USA) – Stem Cell Energetics and Aging: lessons from Drosophila
• Ana MARTIN-VILLALBA (Deutsches Krebsforschungszentrum, Heidelberg, Germany) – Molecular interrogation of neural stem cells in the aging brain
• Pura MUÑOZ-CÁNOVES (ICREA and Pompeu Fabra University, Barcelona, Spain) – Muscle stem cells and aging
• Hiromitsu NAKAUCHI (Stanford University, USA) – Dietary control of stem cells in physiology and disease
• Emi NISHIMURA (Tokyo Medical and Dental University , Tokyo, Japan) – Stem cell fate changes in skin organ aging
• Linda PARTRIDGE (Max Planck Institute for Biology of Ageing, Cologne, Germany) – Drugging Ageing
• Emmanuelle PASSEGUÉ (Columbia University, New York, USA) – Inflammation of the aged bone marrow niche microenvironment
• Manuel SERRANO (Institute for Research in Biomedicine, Barcelona, Spain) – Cellular plasticity and rejuvenation by in vivo reprogramming
• Toshio SUDA (Cancer Science Institute, National University of Singapore, Singapore and　 IRCMS, Kumamoto University, Japan) – Mitochondrial metabolism in hematopoietic stem cells
• Shahragim TAJBAKHSH (Pasteur Institute, Paris, France) – Stem cell and niche interactions in comfort and stress
• Saul VILLEDA (UCSF, San Francisco, USA) – Mechanisms of Regeneration Decline in the Aging Brain
• Amy WAGERS (Harvard University, Boston, USA) – In vivo editing of stem cell genomes
• Sara WICKSTRÖM (Helsinki Institute of Life Science, Helsinki, Finland) – Regulation of stem cell fate by niche-derived signals and forces
• Omer YILMAZ (Massachusetts Institute of Technology, Boston, USA) – Dietary control of stem cells in physiology and disease

Invited Journalist

• Natalie LE BOT (Editor-in-Chief), Nature Communication, London, UK

 

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