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Live Imaging of Hair Follicle Stem Cell Behaviors and Fate during Tissue Regeneration The hair follicle is comprised of both epithelial and mesenchymal populations. To visualize both cellular compartments in vivo, we utilized the transgenic mouse lines K14-H2BGFP (epithelial) and Lef1-RFP (mesenchymal). Combining these reporter lines with our multiphoton intravital imaging system, we have performed time-lapse recordings of hair follicles during both growth and regression phases of the hair cycle. We find that cell behaviors, including proliferation, migration, cell death, and phagocytosis, are all spatiotemporally restricted events within subcompartments of the hair follicle epithelium. Coordination of these tissue dynamics results is spatially regulated fate of epithelial stem cells with relation to the mesenchymal DP niche. Scale bar, 25mm.
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Most tissues in our bodies undergo constant cellular turnover. This process requires a dynamic balance between cell production and elimination. Stem cells have been shown in many of these tissues to be the major source of new cells. However, despite the tremendous advances made, it still remains unclear how stem cell behavior and activity are regul...
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... advantage of the hair follicle over other tissues lies both in its unique accessibility for investigation as well as its stereo- typic and continuous pattern of regeneration. This process relies on a stem cell pool that is maintained through the sequential phases of growth (Anagen), regression (Catagen), and rest (Telogen) of hair regeneration (Figure 1). These key features enable the field to use this model system to study the regulation of stem cell quiescence and activation in the context of a complete mini-organ. ...
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... the epithelial component of the follicle is highly compartmen- talized, which allows us to distinguish different cell types, such as distinct stem cell populations as well as their differentiated progeny, on the basis of their location, morphology, as well as molecular markers (Kretzschmar and Watt, 2014;Rogers, 2004;Schepeler et al., 2014). Specif- ically, within the hair follicle, the stem cell compartment is comprised of two spatially distinct epithelial populations: the bulge, which surrounds the base of the hair proper (called hair shaft), and the hair germ, which is located directly below the bulge stem cells and in direct contact with the mesenchymal dermal papilla (DP) niche (Cotsarelis et al., 1990;Ito et al., 2005;Jahoda et al., 1984;Panteleyev et al., 2001;Rahmani et al., 2014;Sennett and Rendl, 2012;Tumbar et al., 2004) (Figure 1). While previous data supported a bulge stem cell-centric model to initiate hair fol- licle growth, our work and that of others have opened up a new view that relies on the coexistence of two functionally distinct pools: the activated hair germ cells, which can more quickly respond to the environmental stimuli to engage in a new growth and the quiescent bulge stem cells. ...
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... capture be- haviors such as cell divisions and migrations within an intact organ, my group developed an intravital multi- photon imaging system, which allowed us to noninva- sively image the skin of live mice over time. To visualize the hair follicle in vivo, we utilized transgenic mouse lines that were previously made to label epithelial (K14-H2BGFP) and mesenchymal (Lef1-RFP) hair follicle populations ( Rendl et al., 2005;Tumbar et al., 2004) (Figure 1). Using these reporters in combination with our intravital imaging system, we have performed time-lapse recordings by gener- ating 3D-optical stacks of hair follicles at regular time inter- vals throughout the phases of hair follicle regeneration (Figure 1). ...
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... visualize the hair follicle in vivo, we utilized transgenic mouse lines that were previously made to label epithelial (K14-H2BGFP) and mesenchymal (Lef1-RFP) hair follicle populations ( Rendl et al., 2005;Tumbar et al., 2004) (Figure 1). Using these reporters in combination with our intravital imaging system, we have performed time-lapse recordings by gener- ating 3D-optical stacks of hair follicles at regular time inter- vals throughout the phases of hair follicle regeneration (Figure 1). These approaches allowed us to directly capture hair follicle growth beginning with spatially confined epithelial cell division, which occurs in the activated hair germ compartment at the interface with the mesenchymal DP niche. ...
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... the axes of these divisions are ori- ented perpendicular to the mesenchymal DP and parallel to the long axis of growth of the hair follicles ( Rompolas et al., 2012). These oriented divisions contribute to the newly formed inner differentiated layers, while the ex- panding basal epithelium (also called outer root sheath or ORS) is generated by a spatially restricted proliferation zone ( Rompolas et al., 2013;Sequeira and Nicolas, 2012) (Figure 1). While cell production and loss are often concur- rent events in several tissues, the hair follicle provides the advantage of studying them in isolation. ...
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... we found that epithelial cellular debris was not cleared by professional phagocytes. Rather, basal epithelial cells collectively act as phagocytes to clear dying epithelial neighbors (Mesa et al., 2015) ( Figure 1). These findings in the hair follicle, along with work in the mammary gland ( Monks et al., 2005), support a new paradigm of physiological epithelial self-clearance. ...
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... epithelial cells located in higher proximity of the mesenchymal DP niche have lower chances of surviving than cells located at further distances ( Mesa et al., 2015). Finally, revisits over several rounds of hair regeneration cycles revealed the stepwise progression of bulge stem cells in their differ- entiation path whereby lower bulge stem cells give rise to basal ORS cells and form the hair germ during a complete regeneration cycle and will eventually make differentiated cells during the subsequent regeneration cycle ( Rompolas et al., 2013) (Figure 1). ...
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... Elles exercent une influence majeure sur les fonctions des cellules souches et peuvent être définies par la somme des interactions cellules-cellules, cellule-matrice, cellules-facteurs solubles, dans un contexte de contraintes physiques et géométriques qu'une cellule rencontre à un temps précis » (Simian & Bissell, 2017). Il n'est pas certain que le caractère « souche » soit intrinsèque ou extrinsèque et qu'il puisse être définit en dehors de la niche (Mesa et al., 2015 ;Schofield, 1978). Une cellule souche sortant de sa niche peut perdre son caractère souche ; une cellule différenciée qui intègre ou colonise une niche peut reprendre une identité de cellule souche. ...
Cell therapies represent hope for millions of patients with chronic diseases or unmet medical needs. Pluripotent stem cells have emerged as the most promising cellular source to produce them. The bioproduction of stem cells is considered as the keystone of the industrialization processes. However, the technologies for culturing these stem cells are quite recent – Shinia Yamanaka's seminal work on induced pluripotent stem cells was awarded the Nobel Prize for Medicine in 2012.
The focus of this thesis is a fundamental industrial question: how to scale up human pluripotent stem cell bioproduction while preserving their identity and genetic integrity ?
We propose a biomimetic approach to encapsulate pluripotent stem cells that allows them to be grown in automated suspension culture in large-scale bioreactors. Thanks to a microfluidic high-throughput coextrusion device we are able to generate thousands of capsules per second per injector. The microcapsules produced (~400μm in diameter), are hollow and protect the cells during the production process. This inner space is partially liquid and allows us to engineer the cell micro-environment to mimic the in vivo cell niche.
In those biomimetic compartments, we observed self-organization of pluripotent stem cells as cystic 3D colonies reminiscent of the epiblast during embryogenesis. We call this culture strategy "encapsulated epiblastoids".
These encapsulated epiblastoids, cultured in bioreactor suspension (C-STEM), maintain pluripotency in culture in a homogeneous, reproducible and prolonged manner, while reaching unprecedented amplification factor for large culture volumes (282 fold in 6.5 days in 10 liter bioreactor).
We also have shown that selection of chromosomic mutation ‘20q11.21’ (by duplication of the large arm of chromosome 20) in long term culture is reduced by one order of magnitude compared to conventional culture systems.
The higher pluripotent stem cell viability (>98%) in our culture system, compared to traditional system, probably explains the improvement of the amplification factors and the decrease of pressure selection. We present preliminary results describing histological and biophysical findings of epiblastoids.
The encapsulation protects the cells from mechanical damage within the bioreactors and allows the reconstruction of a biomimetic niche at the microtissue level. Combining mechanical protection and biomimicry could help to overcome the current quantitative and qualitative limits of stem cell derived therapies bioproduction.
... All of these cells and their secreted paracrine factors, as well as the extracellular matrix, make up the stem cell microenvironment and play significant roles in fate decision of stem cells, tissue development, and homeostasis. 161 The stem cell microenvironment is diverse and dynamic, and the information it senses and conveys reflects the difference in tissue types and anatomic sites, as well as the state of differentiation. ...
The acquisition of genetic- and epigenetic-abnormalities during transformation has been recognized as the two fundamental factors that lead to tumorigenesis and determine the aggressive biology of tumor cells. However, there is a regularity that tumors derived from less-differentiated normal origin cells (NOCs) usually have a higher risk of vascular involvement, lymphatic and distant metastasis, which can be observed in both lymphohematopoietic malignancies and somatic cancers. Obviously, the hypothesis of genetic- and epigenetic-abnormalities is not sufficient to explain how the linear relationship between the cellular origin and the biological behavior of tumors is formed, because the cell origin of tumor is an independent factor related to tumor biology. In a given system, tumors can originate from multiple cell types, and tumor-initiating cells (TICs) can be mapped to different differentiation hierarchies of normal stem cells, suggesting that the heterogeneity of the origin of TICs is not completely chaotic. TIC’s epigenome includes not only genetic- and epigenetic-abnormalities, but also established epigenetic status of genes inherited from NOCs. In reviewing previous studies, we found much evidence supporting that the status of many tumor-related “epigenetic abnormalities” in TICs is consistent with that of the corresponding NOC of the same differentiation hierarchy, suggesting that they may not be true epigenetic abnormalities. So, we speculate that the established statuses of genes that control NOC’s migration, adhesion and colonization capabilities, cell-cycle quiescence, expression of drug transporters, induction of mesenchymal formation, overexpression of telomerase, and preference for glycolysis can be inherited to TICs through epigenetic memory and be manifested as their aggressive biology. TICs of different origins can maintain different degrees of innate stemness from NOC, which may explain why malignancies with stem cell phenotypes are usually more aggressive.
... The overall population HSC number (N) will fluctuate too, but only with a magnitude 1/N, which means these fluctuations are suppressed when the total number of HSCs is large. In normal homeostasis, feedback mechanisms likely exist to keep total HSC numbers fairly stable, for example from the stem cell niche [86][87][88] and extrinsic regulatory molecules 84,89,90 . In this model of HSC dynamics, mutations are acquired at a constant rate (µ), per year. ...
Acute myeloid leukaemia (AML) is an aggressive blood cancer which claims the lives of 70-80% of patients within 5 years of diagnosis. Like many other cancers, AML usually develops as a consequence of serial acquisition of somatic driver mutations; a process that starts many years, or even decades, before diagnosis. This raises the prospect that early detection of ‘pre-leukaemic’ mutations could be used to identify individuals at high risk of developing AML, in whom early intervention could halt the disease before it fully develops. One of the difficulties with early detection of AML is that clonally expanded leukaemia-associated mutations are also found in the blood of healthy individuals, a phenomenon termed ‘clonal haematopoiesis’. However, most individuals with clonal haematopoiesis will never progress to AML and so a key challenge is the identification of individuals most at risk. To do this, we need a better understanding of the evolutionary dynamics of clonal haematopoiesis in the years, or decades, before AML occurs and how this differs from the dynamics of clonal haematopoiesis in individuals that remain cancer-free. We sought to understand this process by first studying the acquisition and expansion of the initial clonal haematopoiesis driver mutation. Using blood sequencing data amassed from ~50,000 individuals, combined with insights from evolutionary theory, we developed a framework to quantify the mutation rates and fitness effects of clonal haematopoiesis variants down to single nucleotide resolution. This enabled us to build a league table of the fittest and potentially most pathogenic variants in blood. We also quantified the distribution of fitness across key clonal haematopoiesis genes and found the distribution to be highly skewed, with most mutations in these genes conferring either a weak or no fitness effect. Our framework also reveals that whilst cell-extrinsic effects are likely crucial in some situations, the combined effects of chance (when a mutation arises) and cell-intrinsic fitness differences are the major forces shaping clonal haematopoiesis. Mosaic chromosomal alterations (mCAs) can also be important drivers in AML and ~3\% of individuals aged ~40-70 have a clonally expanded mCA detectable in >1% of their blood cells. We therefore adapted our framework to quantify the mutation rates and fitness effects of mCAs in blood and applied this to data generated from ~500,000 individuals in UK Biobank. We find most mCAs confer growth rates of ~10-20\% per year and find correlation between mCA fitness and blood cancer risk. In contrast to the strong age dependence observed in single nucleotide variant prevalence in blood, we find mCA age dependence to be more variable, particularly in women, suggesting the risk of acquisition and/ or expansion of certain mCAs is non-uniform throughout life and is influenced by gender-specific factors. To determine how the dynamics of clonal haematopoiesis differs in individuals who progress to AML, we identified longitudinal blood samples that had been collected annually at multiple timepoints from individuals who subsequently developed AML, as well as age-matched controls who remained cancer free. We developed a custom error-corrected duplex sequencing platform to detect mutations in 34 clonal haematopoiesis/AML-associated genes, genome-wide mCAs and AML-associated translocations and used this to perform an integrative assessment of the genetic changes in these samples. We find there are four main evolutionary patterns in the years preceding AML diagnosis: linear evolution, evolution with clonal interference, static evolution and late evolution. We calculate the age at acquisition of the first and second mutations and, whilst the initial driver mutation is often acquired early in life, there are some very fit ‘uber drivers' which appear to occur as the initial event just ~4 years pre-diagnosis. We find that the variants we identified as ‘highly fit' in clonal haematopoiesis are significantly enriched pre-AML and we were able to determine how fitness effects changed with the acquisition of subsequent mutations. NPM1 mutations, which characteristically occur late in AML development and have never been seen in individuals who do not progress to AML, can be detected as early as 2 years pre-AML diagnosis, highlighting the benefit afforded by low VAF variant calling, particularly in high-risk individuals. This quantitative analysis of clonal haematopoiesis, combined with an integrated assessment of genetic changes in longitudinal blood samples from individuals who progress to AML, reveals important insights into the evolutionary dynamics of mutations in the years preceding AML. Understanding which features distinguish pre-malignant from benign clonal evolution is key for risk stratification of clonal haematopoiesis and will aid in the development of rational monitoring approaches and identification of those who may benefit from early intervention studies.
... Given that apoptosis is a physiological process during the regression phase (catagen) (Lindner et al, 1997;Mesa et al, 2015a), we hypothesized that the Bcl-2 EOE phenotype was linked to impaired apoptosis during catagen. Therefore, we first focused on the process of HF transition through catagen ( Fig EV1A). ...
... One explanation is that an abnormal HG impairs its intrinsic response to activating signals produced by the underlying DP (Greco et al, 2009). Another possibility is that the abnormal BSC and HG niche impacts on the molecular DP-HG crosstalk that is essential for anagen initiation (Mesa et al, 2015a). Finally, Bcl-2 overexpression and apoptosis defects may lead to an enhanced quiescence in BSCs, a hypothesis that is supported by the elevated expression of quiescent SC markers, including Nfatc1 and FoxC1. ...
Maintaining the architecture, size and composition of an intact stem cell (SC) compartment is crucial for tissue homeostasis and regeneration throughout life. In mammalian skin, elevated expression of the anti-apoptotic Bcl-2 protein has been reported in hair follicle (HF) bulge SCs (BSCs), but its impact on SC function is unknown. Here, we show that systemic exposure of mice to the Bcl-2 antagonist ABT-199/venetoclax leads to the selective loss of suprabasal BSCs (sbBSCs), thereby disrupting cyclic HF regeneration. RNAseq analysis shows that the pro-apoptotic BH3-only proteins BIM and Bmf are upregulated in sbBSCs, explaining their addiction to Bcl-2 and the marked susceptibility to Bcl-2 antagonism. In line with these observations, conditional knockout of Bcl-2 in mouse epidermis elevates apoptosis in BSCs. In contrast, ectopic Bcl-2 expression blocks apoptosis during HF regression, resulting in the accumulation of quiescent SCs and delaying HF growth in mice. Strikingly, Bcl-2-induced changes in size and composition of the HF bulge accelerate tumour formation. Our study identifies a niche-instructive mechanism of Bcl-2-regulated apoptosis response that is required for SC homeostasis and tissue regeneration, and may suppress carcinogenesis.
... The hair follicle has separate pools of long-term SCs [CD34 + (Blanpain et al., 2004), Gata6 + (Donati et al., 2017), Lgr5 + (Jaks et al., 2008), Lgr6 + (Snippert et al., 2010a), Lrig1 + (Jensen et al., 2009)] that are responsible for the homeostasis and the cycling regeneration of the hair follicle; and some of these subpopulations can contribute to the IFE for wounding regeneration, although they do not contribute to normal homeostasis maintenance of the IFE (Ito et al., 2005;Legué et al., 2012;Mesa et al., 2015;Liakath-Ali et al., 2018;Dekoninck and Blanpain, 2019;Abbasi et al., 2020). ...
Epithelial tissues are the most rapidly dividing tissues in the body, holding a natural ability for renewal and regeneration. This ability is crucial for survival as epithelia are essential to provide the ultimate barrier against the external environment, protecting the underlying tissues. Tissue stem and progenitor cells are responsible for self-renewal and repair during homeostasis and following injury. Upon wounding, epithelial tissues undergo different phases of haemostasis, inflammation, proliferation and remodelling, often resulting in fibrosis and scarring. In this review, we explore the phenotypic differences between the skin, the oesophagus and the oral mucosa. We discuss the plasticity of these epithelial stem cells and contribution of different fibroblast subpopulations for tissue regeneration and wound healing. While these epithelial tissues share global mechanisms of stem cell behaviour for tissue renewal and regeneration, the oral mucosa is known for its outstanding healing potential with minimal scarring. We aim to provide an updated review of recent studies that combined cell therapy with bioengineering exporting the unique scarless properties of the oral mucosa to improve skin and oesophageal wound healing and to reduce fibrotic tissue formation. These advances open new avenues toward the ultimate goal of achieving scarless wound healing.
... Stem cells rely on extrinsic signals from their specialized niches to balance self-renewal and lineage commitment (Jones and Wagers, 2008). The interactions between stem cells and niches also influence stem cell behaviors in aging and pathological conditions (Lukjanenko et al., 2016;Mesa et al., 2015). Identification and functional characterization of niche components and regulatory mechanisms are essential for elucidating the molecular basis of stem cell fate decisions. ...
... Stem cells rely on extrinsic signals from their specialized niches to balance self-renewal and lineage commitment (Jones and Wagers, 2008). The interactions between stem cells and niches also influence stem cell behaviors in aging and pathological conditions (Lukjanenko et al., 2016;Mesa et al., 2015). Identification and functional characterization of niche components and regulatory mechanisms are essential for elucidating the molecular basis of stem cell fate decisions. ...
Sertoli cells are the major component of the spermatogonial stem cell (SSC) niche; however, regulatory mechanisms in Sertoli cells that dictate SSC fate decisions remain largely unknown. Here we revealed features of the N 6-methyladenosine (m 6 A) mRNA modification in Sertoli cells and demonstrated the functions of WTAP, the key subunit of the m 6 A methyltransferase complex in spermatogenesis. m 6 A-sequencing analysis identified 21,909 m 6 A sites from 15,365 putative m 6 A-enriched transcripts within 6,122 genes, including many Ser-toli cell-specific genes. Conditional deletion of Wtap in Sertoli cells resulted in sterility and the progressive loss of the SSC population. RNA sequencing and ribosome nascent-chain complex-bound mRNA sequencing analyses suggested that alternative splicing events of transcripts encoding SSC niche factors were sharply altered and translation of these transcripts were severely dysregulated by Wtap deletion. Collectively, this study uncovers a novel regulatory mechanism of the SSC niche and provide insights into molecular interactions between stem cells and their cognate niches in mammals.
... This intimate association undoubtedly has a communicative significance as well [17,18]. The basement membrane that separates the epithelial cells of the SHG and mesenchymal cells of the FP 1 For details on HF cycling see [15] for mouse and [16] for human skin. ...
... Furthermore, in some publications these designations are used concurrently, thus producing a great deal of ambiguity. All in all, the currently prevailing view is that during telogen, the HF stem cell pool is composed of two compartments -the bulge and the SHG [9,14,18,31,77]. Consequently, the SHG is simply considered as a "second stem cell population" [e.g., 13] or, more specifically, as a population of "primed stem cells" [14,27,78]. ...
... The predetermination of SHG cells to a specific fate (formation of a new HF) implies three major aspects: 1) a selective sensitivity to anagen-inducing signals that emanate from the FP [18,114] or other sources like sensory nerves or subcutaneous fat [115][116]; 2) an exceptional proliferative potential, which, nevertheless, is held back by a number of restraining mechanisms maintaining the telogen SHG in a standby state; and 3) a strong morphogenetic commitment to produce the ascending compartment of the anagen HF through formation of the hair matrix ("germinative layer" [35]). ...
The secondary hair germ (SHG) – a transitory structure in the lower portion of the mouse telogen hair follicle (HF) ‐ is directly involved in anagen induction and eventual HF regrowth. Some crucial aspects of SHG functioning and ontogenetic relations with other HF parts, however, remain undefined. According to recent evidence (in contrast to previous bulge‐centric views), the SHG is the primary target of anagen‐inducing signaling and a source of both the outer root sheath (ORS) and ascending HF layers during the initial (morphogenetic) anagen sub‐phase. The SHG is comprised of two functionally distinct cell populations. Its lower portion (originating from lower HF cells that survived catagen) forms all ascending HF layers, while the upper SHG (formed by bulge‐derived cells) builds up the ORS. The predetermination of SHG cells to a specific morphogenetic fate contradicts their attribution to the “stem cell” category and supports SHG designation as a “germinative” or a “founder” cell population. The mechanisms of this predetermination driving transition of the SHG from “refractory” to the “competent” state during the telogen remain unknown. Functionally, the SHG serves as a barrier, protecting the quiescent bulge stem cell niche from the extensive follicular papilla/SHG signaling milieu. The formation of the SHG is a prerequisite for efficient “pre‐commitment” of these cells and provides for easier sensing and a faster response to anagen‐inducing signals. In general, the formation of the SHG is an evolutionary adaptation, which allowed the ancestors of modern Muridae to acquire a specific, highly synchronized pattern of hair cycling.
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... Le concept de la niche a été initialement proposé dans le contexte du système sanguin (Schofield, 1978) et il a été mis en évidence in vivo grâce aux études chez la Drosophile (Ferraro et al., 2010;Lin, 2002). Une niche fonctionnelle sert à maintenir l'équilibre de la quiescence et de l'activation des cellules souches (Mesa et al., 2015). Dans le cas des CSC, une « niche de cellules souches cancéreuses » est également présente et les interactions avec cette niche sont essentielles pour le maintien des CSC (Plaks et al., 2015). ...
Le cancer du sein est le cancer est le plus fréquent chez la femme. Les patientes traitées par chirurgie, radiothérapie et/ou chimiothérapie peuvent souffrir de rechute et de métastases à plus ou moins long terme. Il est à présent admis qu’une sous-population de cellules particulières dénommées cellules souches cancéreuses (CSC) jouent un rôle important dans ces événements. Il est donc crucial d’isoler et de caractériser ces cellules pour comprendre leurs propriétés particulières d’autorenouvellement et de résistance aux traitements, ce qui permettra de les cibler pour obtenir des traitements plus efficaces. C’est dans ce contexte que s’inscrit ma thèse. Au laboratoire, j’ai mis en place un modèle de souris bi-transgéniques (bi-Tg) en croisant les souris C3(1)-Tag qui est un modèle de tumorigenèse mammaire (et prostatique) bien établi, avec les souris Tg s-SHIP-GFP qui ont déjà permis l’isolement de CS normales mammaires (et prostatiques). Dans ces souris, le promoteur de s-SHIP contrôle l’expression de la protéine fluorescente GFP ce qui permet de marquer et d’isoler les cellules. Dans les tumeurs mammaires développées par ces souris biTg, j’ai isolé une population rare de cellules s-SHIP/GFP+ possédant des propriétés de CSC, surtout une capacité à former des sphères en culture non adhérente et à générer des tumeurs par transplantation en série très supérieure à celle des autres cellules de la tumeur. Une analyse transcriptomique globale qui compare les gènes dérégulés dans les cellules GFP+ et GFP- a mise en évidence le rôle d’un composant de la voie Notch dans le maintien de la pluripotence.Nous avons également dérivé plusieurs lignées cellulaires dénommées MAM (pour mammary) à partir des tumeurs mammaires. L’une d’entre, MAM326 est une lignée de cellules épithéliales cancéreuses avec environ 10 % de cellules GFP+ et j’ai démontré que les cellules GFP+ sont plus résistantes à différentes drogues anti-cancéreuses ainsi qu’à l’irradiation. Une analyse transcriptomique a été réalisée pour déterminer la signature moléculaire de cette résistance. Cette analyse a mis en évidence une vingtaine de gènes significativement surexprimés dans les cellules GFP+, et dont la nature et/ou la fonction est pertinente dans le contexte d’une résistance aux traitements antitumoraux. L'un de ces gènes est la synucléine-gamma dont le rôle dans la radiorésistance du cancer du sein a été suggéré mais non démontré expérimentalement. Par la surexpression ectopique et l’inhibition par siRNA, nous avons démontré que la synucléine gamma peut induire la radiorésistance dans plusieurs lignées cellulaires de cancer du sein. En conclusion, ces résultats démontrent que l’expression de s-SHIP est un marqueur de CSC mammaires chez la souris et son intérêt dans l’étude du cancer du sein.
... Cultivation of stem cells under traditional adherent two-dimensional (2D) conditions does not faithfully mimic the three-dimensional (3D) environment of tissue-specific stem cell niches [1]. Therefore, we should not expect stem cells grown in vitro in a 2D setting to behave appropriately given the lack of the spatial contacts and signals usually afforded to them by their in vivo 3D niche. ...
