Browsing by Keyword "SELF-RENEWAL"
Now showing 1 - 7 of 7
Results Per Page
Sort Options
Publication Altered Metabolic and Stemness Capacity of Adipose Tissue-Derived Stem Cells from Obese Mouse and Human(Public Library of Science (PLOS), 2015) Perez, Laura M.; Bernal, Aurora; de Lucas, Beatriz; San Martin, Nuria; Mastrangelo, Annalaura; Garcia, Antonia; Barbas, Coral; Galvez, Beatriz G.; Ministerio de Ciencia e Innovación (España); Fundación ProCNIC; Ministerio de Economía y Competitividad (España)Adipose stem cells (ASCs) are an appealing source of cells for therapeutic intervention; however, the environment from which ASCs are isolated may impact their usefulness. Using a range of functional assays, we have evaluated whether ASCs isolated from an obese environment are comparable to cells from non-obese adipose tissue. Results showed that ASCs isolated from obese tissue have a reduced proliferative ability and a loss of viability together with changes in telomerase activity and DNA telomere length, suggesting a decreased self-renewal capacity. Metabolic analysis demonstrated that mitochondrial content and function was impaired in obese-derived ASCs resulting in changes in favored oxidative substrates. These findings highlight the impact of obesity on adult stem properties. Hence, caution should be exercised when considering the source of ASCs for cellular therapies since their therapeutic potential may be impaired.Publication Cardiac Bmi1(+) cells contribute to myocardial renewal in the murine adult heart(BioMed Central (BMC), 2015) Valiente-Alandi, I; Albo-Castellanos, Carmen; Herrero, Diego; Arza, Elvira; Garcia-Gomez, Maria; Segovia, Jose Carlos; Capecchi, Mario; Bernad, Antonio; Ministerio de Ciencia e Innovación (España); Comunidad de Madrid (España); Instituto de Salud Carlos III; Unión Europea. Comisión Europea; Ministerio de Economía y Competitividad (España)Introduction: The mammalian adult heart maintains a continuous, low cardiomyocyte turnover rate throughout life. Although many cardiac stem cell populations have been studied, the natural source for homeostatic repair has not yet been defined. The Polycomb protein BMI1 is the most representative marker of mouse adult stem cell systems. We have evaluated the relevance and role of cardiac Bmi1(+) cells in cardiac physiological homeostasis. Methods: Bmi1(CreER/+); Rosa26(YFP/+) (Bmi1-YFP) mice were used for lineage tracing strategy. After tamoxifen (TM) induction, yellow fluorescent protein (YFP) is expressed under the control of Rosa26 regulatory sequences in Bmi1(+) cells. These cells and their progeny were tracked by FACS, immunofluorescence and RT-qPCR techniques from 5 days to 1 year. Results: FACS analysis of non-cardiomyocyte compartment from TM-induced Bmi1-YFP mice showed a Bmi1 (+)-expressing cardiac progenitor cell (Bmi1-CPC: B-CPC) population, SCA-1 antigen-positive (95.9 +/- 0.4 \%) that expresses some stemness-associated genes. B-CPC were also able to differentiate in vitro to the three main cardiac lineages. Pulse-chase analysis showed that B-CPC remained quite stable for extended periods (up to 1 year), which suggests that this Bmi1(+) population contains cardiac progenitors with substantial self-maintenance potential. Specific immunostaining of Bmi1-YFP hearts serial sections 5 days post-TM induction indicated broad distribution of B-CPC, which were detected in variably sized clusters, although no YFP+ cardiomyocytes (CM) were detected at this time. Between 2 to 12 months after TM induction, YFP+ CM were clearly identified (3 +/- 0.6 \% to 6.7 +/- 1.3 \%) by immunohistochemistry of serial sections and by flow cytometry of total freshly isolated CM. B-CPC also contributed to endothelial and smooth muscle (SM) lineages in vivo. Conclusions: High Bmi1 expression identifies a non-cardiomyocyte resident cardiac population (B-CPC) that contributes to the main lineages of the heart in vitro and in vivo.Publication Neurovascular EGFL7 regulates adult neurogenesis in the subventricular zone and thereby affects olfactory perception(Nature Publishing Group, 2017) Bicker, Frank; Vasic, Verica; Horta, Guilherme; Ortega, Felipe; Nolte, Hendrik; Kavyanifar, Atria; Keller, Stefanie; Stankovic, Nevenka Dudvarski; Harter, Patrick N.; Benedito, Rui; Lutz, Beat; Baeuerle, Tobias; Hartwig, Jens; Baumgart, Jan; Krueger, Marcus; Radyushkin, Konstantin; Alberi, Lavinia; Berninger, Benedikt; Schmidt, Mirko H. H.; Deutsche Forschungsgemeinschaft (Alemania)Adult neural stem cells reside in a specialized niche in the subventricular zone (SVZ). Throughout life they give rise to adult-born neurons in the olfactory bulb (OB), thus contributing to neural plasticity and pattern discrimination. Here, we show that the neurovascular protein EGFL7 is secreted by endothelial cells and neural stem cells (NSCs) of the SVZ to shape the vascular stem-cell niche. Loss of EGFL7 causes an accumulation of activated NSCs, which display enhanced activity and re-entry into the cell cycle. EGFL7 pushes activated NSCs towards quiescence and neuronal progeny towards differentiation. This is achieved by promoting Dll4-induced Notch signalling at the blood vessel-stem cell interface. Fewer inhibitory neurons form in the OB of EGFL7-knockout mice, which increases the absolute signal conducted from the mitral cell layer of the OB but decreases neuronal network synchronicity. Consequently, EGFL7-knockout mice display severe physiological defects in olfactory behaviour and perception.Publication TGF-β induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression(Nature Publishing Group, 2018-05-10) Ottaviani, Silvia; Stebbing, Justin; Frampton, Adam E; Zagorac, Sladjana; Krell, Jonathan; de Giorgio, Alexander; Trabulo, Sara M; Nguyen, Van T M; Magnani, Luca; Feng, Hugang; Giovannetti, Elisa; Funel, Niccola; Gress, Thomas M; Jiao, Long R; Lombardo, Ylenia; Lemoine, Nicholas R; Heeschen, Christopher; Castellano, Leandro; Action Against Cancer; Pancreatic Cancer UK; Academy of Medical Sciences (Reino Unido); Royal College of Surgeons of Edinburgh; Colin McDavid Family Trust; No Surrender Cancer Trust; Ralph Bates Pancreatic Cancer Research Fund; Dutch Cancer Society (Holanda); Italian Association for Cancer Research; Tumour Institute of Tuscany (Italia); Regione Toscana "Progetto DIAMANTE"/FAS grant; Medical Research Council (Reino Unido)TGF-β/Activin induces epithelial-to-mesenchymal transition and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-β transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-β also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-β-mediated response indicating that these miRNAs are important TGF-β effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell-cell junctions' pathways. Together, we uncover that TGF-β induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis.Publication The hematopoietic stem-cell niche in health and leukemia(Springer, 2017) Sanchez-Aguilera, Abel; Mendez-Ferrer, Simon; Wellcome Trust; Medical Research Council (Reino Unido); Ministerio de Economía y Competitividad (España); Fundación ProCNIC; RETICS-Terapia Celular (TERCEL-ISCIII) (España); Comunidad de Madrid (España); Unión Europea. Comisión Europea; European Hematology Association; Howard Hughes Medical InstituteResearch in the last decade has shown that hematopoietic stem cells (HSCs) interact with and are modulated by a complex multicellular microenvironment in the bone marrow, which includes both the HSC progeny and multiple non-hematopoietic cell types. Intense work is gradually throwing light on the composition of the HSC niche and the molecular cues exchanged between its components, which has implications for HSC production, maintenance and expansion. In addition, it has become apparent that bidirectional interactions between leukemic cells and their niche play a previously unrecognized role in the initiation and development of hematological malignancies. Consequently, targeting of the malignant niche holds considerable promise for more specific antileukemic therapies. Here we summarize the latest insights into HSC niche biology and recent work showing multiple connections between hematological malignancy and alterations in the bone marrow microenvironment.Publication The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells(BMJ Publishing Group, 2015) Cioffi, Michele; Trabulo, Sara M.; Sanchez-Ripoll, Yolanda; Miranda-Lorenzo, Irene; Lonardo, Enza; Dorado, Jorge; Reis Vieira, Catarina; Ramirez, Juan Carlos; Hidalgo, Manuel; Aicher, Alexandra; Hahn, Stephan; Sainz, Jr., Bruno; Heeschen, Christopher; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Ministerio de Economía y Competitividad (España); Instituto de Salud Carlos III; Fundación La CaixaObjective Cancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes. Design Micro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs. Results We found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-beta 1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer. Conclusions Our findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs.Publication Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence(Impact Journals, 2015) Niu, Ping; Smagul, Aibek; Wang, Lu; Sadvakas, Aiman; Sha, Ying; Perez, Laura M.; Nussupbekova, Aliya; Amirbekov, Aday; Akanov, Akan A.; Galvez, Beatriz G.; Jordan, I. King; Lunyak, Victoria V.; Ministerio de Ciencia e Innovación (España)Inflammation is a double-edged sword with both detrimental and beneficial consequences. Understanding of the mechanisms of crosstalk between the inflammatory milieu and human adult mesenchymal stem cells is an important basis for clinical efforts. Here, we investigate changes in the transcriptional response of human adipose-derived stem cells to physiologically relevant levels of IL-2 (IL-2 priming) upon replicative senescence. Our data suggest that replicative senescence might dramatically impede human mesenchymal stem cell (MSC) function via global transcriptional deregulation in response to IL-2. We uncovered a novel senescence-associated transcriptional signature in human adipose-derived MSCs hADSCs after exposure to pro-inflammatory environment: significant enhancement of the expression of the genes encoding potent growth factors and cytokines with anti-inflammatory and migration-promoting properties, as well as genes encoding angiogenic and antiapoptotic promoting factors, all of which could participate in the establishment of a unique microenvironment. We observed transcriptional up-regulation of critical components of the nitric oxide synthase pathway (iNOS) in hADSCs upon replicative senescence suggesting, that senescent stem cells can acquire metastasis-promoting properties via stem cell-mediated immunosuppression. Our study highlights the importance of age as a factor when designing cell-based or pharmacological therapies for older patients and predicts measurable biomarkers characteristic of an environment that is conducive to cancer cells invasiveness and metastasis.