Mouse heart development arises from
-expressing cardiovascular progenitors (CPs) that are specified during gastrulation. The molecular processes that control early regional and lineage segregation of ...CPs have been unclear. We performed single-cell RNA sequencing of wild-type and
-null CPs in mice. We showed that populations of
CPs are molecularly distinct and span the continuum between epiblast and later mesodermal cells, including hematopoietic progenitors. Single-cell transcriptome analysis of
-deficient CPs showed that Mesp1 is required for the exit from the pluripotent state and the induction of the cardiovascular gene expression program. We identified distinct populations of
CPs that correspond to progenitors committed to different cell lineages and regions of the heart, identifying the molecular features associated with early lineage restriction and regional segregation of the heart at the early stage of mouse gastrulation.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
The ability of the skin to grow in response to stretching has been exploited in reconstructive surgery
. Although the response of epidermal cells to stretching has been studied in vitro
, it remains ...unclear how mechanical forces affect their behaviour in vivo. Here we develop a mouse model in which the consequences of stretching on skin epidermis can be studied at single-cell resolution. Using a multidisciplinary approach that combines clonal analysis with quantitative modelling and single-cell RNA sequencing, we show that stretching induces skin expansion by creating a transient bias in the renewal activity of epidermal stem cells, while a second subpopulation of basal progenitors remains committed to differentiation. Transcriptional and chromatin profiling identifies how cell states and gene-regulatory networks are modulated by stretching. Using pharmacological inhibitors and mouse mutants, we define the step-by-step mechanisms that control stretch-mediated tissue expansion at single-cell resolution in vivo.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The mammary gland is composed of basal cells and luminal cells. It is generally believed that the mammary gland arises from embryonic multipotent progenitors, but it remains unclear when lineage ...restriction occurs and what mechanisms are responsible for the switch from multipotency to unipotency during its morphogenesis. Here, we perform multicolour lineage tracing and assess the fate of single progenitors, and demonstrate the existence of a developmental switch from multipotency to unipotency during embryonic mammary gland development. Molecular profiling and single cell RNA-seq revealed that embryonic multipotent progenitors express a unique hybrid basal and luminal signature and the factors associated with the different lineages. Sustained p63 expression in embryonic multipotent progenitors promotes unipotent basal cell fate and was sufficient to reprogram adult luminal cells into basal cells by promoting an intermediate hybrid multipotent-like state. Altogether, this study identifies the timing and the mechanisms mediating early lineage segregation of multipotent progenitors during mammary gland development.
Cardiac development arises from two sources of mesoderm progenitors, the first heart field (FHF) and the second (SHF). Mesp1 has been proposed to mark the most primitive multipotent cardiac ...progenitors common for both heart fields. Here, using clonal analysis of the earliest prospective cardiovascular progenitors in a temporally controlled manner during early gastrulation, we found that Mesp1 progenitors consist of two temporally distinct pools of progenitors restricted to either the FHF or the SHF. FHF progenitors were unipotent, whereas SHF progenitors were either unipotent or bipotent. Microarray and single-cell PCR with reverse transcription analysis of Mesp1 progenitors revealed the existence of molecularly distinct populations of Mesp1 progenitors, consistent with their lineage and regional contribution. Together, these results provide evidence that heart development arises from distinct populations of unipotent and bipotent cardiac progenitors that independently express Mesp1 at different time points during their specification, revealing that the regional segregation and lineage restriction of cardiac progenitors occur very early during gastrulation.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Twist1 promotes epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and cancer stem cell (CSC) properties. However, it remains unclear whether Twist1 is also required for tumor ...initiation and whether Twist1-induced cancer stemness and EMT are functionally linked. Using a conditional deletion of Twist1 at different stages of skin carcinogenesis, we show that Twist1 is required for skin tumor initiation and progression in a gene-dosage-dependent manner. Moreover, conditional ablation of Twist1 in benign tumors leads to increased apoptosis, reduced cell proliferation, and defective tumor maintenance and propagation independently of its EMT-inducing abilities. Concomitant deletion of Twist1 and p53 rescues the apoptotic response, but not the cell proliferation and propagation defects. These results reveal that Twist1 is required for tumor initiation and maintenance in a p53-dependent and -independent manner. Importantly, our findings also indicate that tumor stemness and EMT can be regulated by distinct mechanisms.
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•Twist1 is required for skin tumor initiation•Twist1 controls tumor initiation and progression in a gene-dosage-dependent manner•Twist1 controls apoptosis and propagation in a p53-dependent and -independent manner•Twist1 controls tumor maintenance and stemness independently of its EMT function
Twist1 promotes tumor stemness and EMT. It remains unclear whether Twist1 also controls tumor initiation and whether the different Twist1 functions are linked. Using Twist1 deletion at different stages of skin tumorigenesis, Beck et al. show that Twist1 is required for tumor initiation, stemness, and progression in a gene-dosage-dependent manner.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The head and neck tumor microenvironment (TME) is highly infiltrated with macrophages. More specifically, tumor-associated macrophages (TAM/M2-like) are one of the most critical components associated ...with poor overall survival in head and neck cancers (HNC). Two extreme states of macrophage phenotypes are described as conducting pro-inflammatory/anti-tumoral (M1) or anti-inflammatory/pro-tumoral (M2) activities. Moreover, specific metabolic pathways as well as oxidative stress responses are tightly associated with their phenotypes and functions. Hence, due to their plasticity, targeting M2 macrophages to repolarize in the M1 phenotype would be a promising cancer treatment. In this context, we evaluated macrophage infiltration in 60 HNC patients and demonstrated the high infiltration of CD68+ cells that were mainly related to CD163+ M2 macrophages. We then optimized a polarization protocol from THP1 monocytes, validated by specific gene and protein expression levels. In addition, specific actors of glutamine pathway and oxidative stress were quantified to indicate the use of glutaminolysis by M2 and the production of reactive oxygen species by M1. Finally, we evaluated and confirmed the plasticity of our model using M1 activators to repolarize M2 in M1. Overall, our study provides a complete reversible polarization protocol allowing us to further evaluate various reprogramming effectors targeting glutaminolysis and/or oxidative stress in macrophages.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Epithelial-to-mesenchymal transition (EMT) has been proposed to be important for metastatic dissemination. However, recent studies have challenged the requirement of EMT for metastasis. Here, we ...assessed in different models of primary skin squamous cell carcinomas (SCCs) whether EMT is associated with metastasis. The incidence of metastasis was much higher in SCCs presenting EMT compared to SCCs without EMT, supporting the notion that a certain degree of EMT is required to initiate the metastatic cascade in primary skin SCCs. Most circulating tumor cells presented EMT, whereas most lung metastasis did not present EMT, showing that mesenchymal-to-epithelial transition is important for metastatic colonization. In contrast, immunodeficient mice transplanted with SCCs, whether displaying EMT or not, presented metastasis. Altogether, our data demonstrate that the association of EMT and metastasis is model dependent, and metastasis of primary skin SCCs is associated with EMT.
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•Primary skin SCCs with EMT have a high incidence of metastasis•Primary skin SCCs without EMT have no metastasis•Circulating tumor cells present EMT in primary tumors with metastasis•Transplanted tumors present metastasis regardless of EMT
The role of epithelial-to-mesenchymal transition (EMT) during metastasis remains controversial. Revenco et al. show that in models of primary skin tumors, only EMT tumors are associated with metastasis. In contrast, EMT is not required to induce metastasis following the subcutaneous transplantation of tumor cells, demonstrating the context dependency of EMT for metastasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Psoriasis is a common chronic skin disorder characterized by keratinocyte hyperproliferation with altered differentiation accompanied by inflammation and increased angiogenesis. It remains unclear ...whether the first events that initiate psoriasis development occur in keratinocytes or inflammatory cells. Here, using different psoriasis mouse models, we showed that conditional deletion of
or
in epidermal cells inhibited psoriasis mediated by
overexpression or
deletion. Administration of anti-Nrp1 antibody reverted the psoriasis phenotype. Using transcriptional and chromatin profiling of epidermal cells following
overexpression together with
or
deletion, we identified the gene regulatory network regulated by
/
/
during psoriasis development and uncovered a key role of Fosl1 in regulating the chromatin remodeling mediated by
overexpression in keratinocytes. In conclusion, our study identifies an epidermal autonomous function of Vegfa/Nrp1/Flt1 that mediates psoriatic-like disease and demonstrates the clinical relevance of blocking Vegfa/Nrp1/Flt1 axis in psoriasis.
While chemerin has been shown to increase proliferation and migration of systemic vascular smooth muscle cells (SMCs) contributing therefore to the development of hypertension, this remains to be ...clarified for the pulmonary circulation.
Expression of chemerin and its three receptors (CMKRL1, CCRL2, GPR1) was examined by immunohistochemistry and RTq-PCR in lungs, pulmonary artery, and thoracic aorta from Wistar rats. Primary cultured rat pulmonary artery and thoracic aorta SMCs treated with recombinant chemerin (tested from 5.10
to 10
mol/L) were assessed for proliferation and migration (both with 10
mol/L endothelin-1), as well as for staurosporine-induced apoptosis.
In pulmonary artery and thoracic aorta, CMKLR1 expression was detected in both endothelial cells and SMCs. In primary cultured pulmonary artery SMCs, chemerin and its three receptors were expressed, and CMKLR1 expression was higher than those of CCRL2 and GPR1. Chemerin added to endothelin-1 increased pulmonary artery SMC proliferation, while chemerin or endothelin-1 alone did not. This effect was less pronounced in thoracic aorta SMCs. Chemerin induced pulmonary artery and thoracic aorta SMC migration, which was exacerbated by endothelin-1 and more pronounced in thoracic aorta SMCs. Chemerin concentration-dependently reduced staurosporine-induced apoptosis in both pulmonary artery and thoracic aorta SMCs. In pulmonary artery SMCs, endothelin-1 treatment increased the expression of CMKLR1, CCRL2, and GPR1, while these expressions were not altered in thoracic aorta SMCs.
Chemerin/CMKRL1 signaling, in conjunction with a key mediator in the pathogenesis of pulmonary hypertensive diseases, endothelin-1, stimulated proliferation and migration, and increased resistance to apoptosis in rat primary cultured pulmonary artery SMCs. Our results suggest that this signaling could play a role in pulmonary artery remodeling observed in pulmonary hypertension.
The mammary gland (MG) is composed of three main epithelial lineages, the basal cells (BC), the estrogen receptor (ER) positive luminal cells (ER+ LC), and the ER negative LC (ER− LC). Defining the ...cell identity of each lineage and how it is modulated throughout the different stages of life is important to understand how these cells function and communicate throughout life. Here, we used transgenic mice specifically labelling ER+ LC combined to cell surface markers to isolate with high purity the 3 distinct cell lineages of the mammary gland and defined their expression profiles and chromatin landscapes by performing bulk RNAseq and ATACseq of these isolated populations in puberty, adulthood and mid-pregnancy. Our analysis identified conserved genes, ligands and transcription factor (TF) associated with a specific lineage throughout life as well as genes, ligands and TFs specific for a particular stage of the MG. In summary, our study identified genes and TF network associated with the identity, function and cell-cell communication of the different epithelial lineages of the MG at different stages of life.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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