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  1. Article ; Online: Angiocrine endothelium

    Jennifer Pasquier / Pegah Ghiabi / Lotfi Chouchane / Kais Razzouk / Shahin Rafii / Arash Rafii

    Journal of Translational Medicine, Vol 18, Iss 1, Pp 1-

    from physiology to cancer

    2020  Volume 17

    Abstract: Abstract The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The significance of endothelial ...

    Abstract Abstract The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The significance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogenesis that is critical for tumor initiation and growth. Nevertheless, the identification of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profiling studies have demonstrated distinctive expression patterns in tumor-associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identified which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies.
    Keywords Angiocrine ; Endothelium ; Cancer ; Cancer microenvironment ; Angiogenesis ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response

    Pradeep Ramalingam / Michael C. Gutkin / Michael G. Poulos / Taylor Tillery / Chelsea Doughty / Agatha Winiarski / Ana G. Freire / Shahin Rafii / David Redmond / Jason M. Butler

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 20

    Abstract: Abstract Aging associated defects within stem cell-supportive niches contribute towards age-related decline in stem cell activity. However, mechanisms underlying age-related niche defects, and whether restoring niche function can improve stem cell ... ...

    Abstract Abstract Aging associated defects within stem cell-supportive niches contribute towards age-related decline in stem cell activity. However, mechanisms underlying age-related niche defects, and whether restoring niche function can improve stem cell fitness, remain unclear. Here, we sought to determine whether aged blood stem cell function can be restored by rejuvenating their supportive niches within the bone marrow (BM). We identify Netrin-1 as a critical regulator of BM niche cell aging. Niche-specific deletion of Netrin-1 induces premature aging phenotypes within the BM microenvironment, while supplementation of aged mice with Netrin-1 rejuvenates aged niche cells and restores competitive fitness of aged blood stem cells to youthful levels. We show that Netrin-1 plays an essential role in maintaining active DNA damage responses (DDR), and that aging-associated decline in niche-derived Netrin-1 results in DNA damage accumulation within the BM microenvironment. We show that Netrin-1 supplementation is sufficient to resolve DNA damage and restore regenerative potential of the aged BM niche and blood stem cells to endure serial chemotherapy regimens.
    Keywords Science ; Q
    Subject code 612
    Language English
    Publishing date 2023-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Endothelial Jak3 expression enhances pro-hematopoietic angiocrine function in mice

    José Gabriel Barcia Durán / Tyler Lu / Sean Houghton / Fuqiang Geng / Ryan Schreiner / Jenny Xiang / Shahin Rafii / David Redmond / Raphaël Lis

    Communications Biology, Vol 4, Iss 1, Pp 1-

    2021  Volume 14

    Abstract: Barcia Durán et al. show that the tyrosine kinase gene Jak3 is expressed in multiple endothelial cell types in the mouse, including in non-hematopoietic organs, with particularly high expression in the bone marrow. Using mice lacking Jak3, they show that ...

    Abstract Barcia Durán et al. show that the tyrosine kinase gene Jak3 is expressed in multiple endothelial cell types in the mouse, including in non-hematopoietic organs, with particularly high expression in the bone marrow. Using mice lacking Jak3, they show that Jak3 expressed in the bone marrow niche is important for maintaining long-term repopulating hematopoietic stem cells.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Engineering a niche supporting hematopoietic stem cell development using integrated single-cell transcriptomics

    Brandon Hadland / Barbara Varnum-Finney / Stacey Dozono / Tessa Dignum / Cynthia Nourigat-McKay / Adam M. Heck / Takashi Ishida / Dana L. Jackson / Tomer Itkin / Jason M. Butler / Shahin Rafii / Cole Trapnell / Irwin D. Bernstein

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 17

    Abstract: Here, the authors use single cell RNA-sequencing to generate an atlas of signaling interactions regulating embryonic hematopoietic stem cell (HSC) development and apply this knowledge to engineer a niche sufficient to support HSC maturation in vitro. ...

    Abstract Here, the authors use single cell RNA-sequencing to generate an atlas of signaling interactions regulating embryonic hematopoietic stem cell (HSC) development and apply this knowledge to engineer a niche sufficient to support HSC maturation in vitro.
    Keywords Science ; Q
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Attenuation of apoptotic cell detection triggers thymic regeneration after damage

    Sinéad Kinsella / Cindy A. Evandy / Kirsten Cooper / Lorenzo Iovino / Paul C. deRoos / Kayla S. Hopwo / David W. Granadier / Colton W. Smith / Shahin Rafii / Jarrod A. Dudakov

    Cell Reports, Vol 37, Iss 1, Pp 109789- (2021)

    2021  

    Abstract: Summary: The thymus, which is the primary site of T cell development, is particularly sensitive to insult but also has a remarkable capacity for repair. However, the mechanisms orchestrating regeneration are poorly understood, and delayed repair is ... ...

    Abstract Summary: The thymus, which is the primary site of T cell development, is particularly sensitive to insult but also has a remarkable capacity for repair. However, the mechanisms orchestrating regeneration are poorly understood, and delayed repair is common after cytoreductive therapies. Here, we demonstrate a trigger of thymic regeneration, centered on detecting the loss of dying thymocytes that are abundant during steady-state T cell development. Specifically, apoptotic thymocytes suppressed production of the regenerative factors IL-23 and BMP4 via TAM receptor signaling and activation of the Rho-GTPase Rac1, the intracellular pattern recognition receptor NOD2, and micro-RNA-29c. However, after damage, when profound thymocyte depletion occurs, this TAM-Rac1-NOD2-miR29c pathway is attenuated, increasing production of IL-23 and BMP4. Notably, pharmacological inhibition of Rac1-GTPase enhanced thymic function after acute damage. These findings identify a complex trigger of tissue regeneration and offer a regenerative strategy for restoring immune competence in patients whose thymic function has been compromised.
    Keywords thymus ; T cell development ; tissue regeneration ; apoptotic cell death ; NOD2 ; Rac1 GTPase ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: A computational approach to identify cellular heterogeneity and tissue-specific gene regulatory networks

    Ankit Jambusaria / Jeff Klomp / Zhigang Hong / Shahin Rafii / Yang Dai / Asrar B. Malik / Jalees Rehman

    BMC Bioinformatics, Vol 19, Iss 1, Pp 1-

    2018  Volume 15

    Abstract: Abstract Background The heterogeneity of cells across tissue types represents a major challenge for studying biological mechanisms as well as for therapeutic targeting of distinct tissues. Computational prediction of tissue-specific gene regulatory ... ...

    Abstract Abstract Background The heterogeneity of cells across tissue types represents a major challenge for studying biological mechanisms as well as for therapeutic targeting of distinct tissues. Computational prediction of tissue-specific gene regulatory networks may provide important insights into the mechanisms underlying the cellular heterogeneity of cells in distinct organs and tissues. Results Using three pathway analysis techniques, gene set enrichment analysis (GSEA), parametric analysis of gene set enrichment (PGSEA), alongside our novel model (HeteroPath), which assesses heterogeneously upregulated and downregulated genes within the context of pathways, we generated distinct tissue-specific gene regulatory networks. We analyzed gene expression data derived from freshly isolated heart, brain, and lung endothelial cells and populations of neurons in the hippocampus, cingulate cortex, and amygdala. In both datasets, we found that HeteroPath segregated the distinct cellular populations by identifying regulatory pathways that were not identified by GSEA or PGSEA. Using simulated datasets, HeteroPath demonstrated robustness that was comparable to what was seen using existing gene set enrichment methods. Furthermore, we generated tissue-specific gene regulatory networks involved in vascular heterogeneity and neuronal heterogeneity by performing motif enrichment of the heterogeneous genes identified by HeteroPath and linking the enriched motifs to regulatory transcription factors in the ENCODE database. Conclusions HeteroPath assesses contextual bidirectional gene expression within pathways and thus allows for transcriptomic assessment of cellular heterogeneity. Unraveling tissue-specific heterogeneity of gene expression can lead to a better understanding of the molecular underpinnings of tissue-specific phenotypes.
    Keywords Gene set enrichment ; Systems biology ; Tissue specificity ; Gene expression ; Transcriptional networks ; Transcription factor binding motifs ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2018-06-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Multipotent progenitors and hematopoietic stem cells arise independently from hemogenic endothelium in the mouse embryo

    Tessa Dignum / Barbara Varnum-Finney / Sanjay R. Srivatsan / Stacey Dozono / Olivia Waltner / Adam M. Heck / Takashi Ishida / Cynthia Nourigat-McKay / Dana L. Jackson / Shahin Rafii / Cole Trapnell / Irwin D. Bernstein / Brandon Hadland

    Cell Reports, Vol 36, Iss 11, Pp 109675- (2021)

    2021  

    Abstract: Summary: During embryogenesis, waves of hematopoietic progenitors develop from hemogenic endothelium (HE) prior to the emergence of self-renewing hematopoietic stem cells (HSCs). Although previous studies have shown that yolk-sac-derived erythromyeloid ... ...

    Abstract Summary: During embryogenesis, waves of hematopoietic progenitors develop from hemogenic endothelium (HE) prior to the emergence of self-renewing hematopoietic stem cells (HSCs). Although previous studies have shown that yolk-sac-derived erythromyeloid progenitors and HSCs emerge from distinct populations of HE, it remains unknown whether the earliest lymphoid-competent progenitors, multipotent progenitors, and HSCs originate from common HE. In this study, we demonstrate by clonal assays and single-cell transcriptomics that rare HE with functional HSC potential in the early murine embryo are distinct from more abundant HE with multilineage hematopoietic potential that fail to generate HSCs. Specifically, HSC-competent HE are characterized by expression of CXCR4 surface marker and by higher expression of genes tied to arterial programs regulating HSC dormancy and self-renewal. Taken together, these findings suggest a revised model of developmental hematopoiesis in which the initial populations of multipotent progenitors and HSCs arise independently from HE with distinct phenotypic and transcriptional properties.
    Keywords hematopoietic stem cell ; HSC ; multipotent progenitor ; MPP ; aorta-gonad-mesonephros ; AGM ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Completely ES cell-derived mice produced by tetraploid complementation using inner cell mass (ICM) deficient blastocysts.

    Duancheng Wen / Nestor Saiz / Zev Rosenwaks / Anna-Katerina Hadjantonakis / Shahin Rafii

    PLoS ONE, Vol 9, Iss 4, p e

    2014  Volume 94730

    Abstract: Tetraploid complementation is often used to produce mice from embryonic stem cells (ESCs) by injection of diploid (2n) ESCs into tetraploid (4n) blastocysts (ESC-derived mice). This method has also been adapted to mouse cloning and the derivation of mice ...

    Abstract Tetraploid complementation is often used to produce mice from embryonic stem cells (ESCs) by injection of diploid (2n) ESCs into tetraploid (4n) blastocysts (ESC-derived mice). This method has also been adapted to mouse cloning and the derivation of mice from induced pluripotent stem (iPS) cells. However, the underlying mechanism(s) of the tetraploid complementation remains largely unclear. Whether this approach can give rise to completely ES cell-derived mice is an open question, and has not yet been unambiguously proven. Here, we show that mouse tetraploid blastocysts can be classified into two groups, according to the presence or absence of an inner cell mass (ICM). We designate these as type a (presence of ICM at blastocyst stage) or type b (absence of ICM). ESC lines were readily derived from type a blastocysts, suggesting that these embryos retain a pluripotent epiblast compartment; whereas the type b blastocysts possessed very low potential to give rise to ESC lines, suggesting that they had lost the pluripotent epiblast. When the type a blastocysts were used for tetraploid complementation, some of the resulting mice were found to be 2n/4n chimeric; whereas when type b blastocysts were used as hosts, the resulting mice are all completely ES cell-derived, with the newborn pups displaying a high frequency of abdominal hernias. Our results demonstrate that completely ES cell-derived mice can be produced using ICM-deficient 4n blastocysts, and provide evidence that the exclusion of tetraploid cells from the fetus in 2n/4n chimeras can largely be attributed to the formation of ICM-deficient blastocysts.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Akt-activated endothelium promotes ovarian cancer proliferation through notch activation

    Jessica Hoarau-Véchot / Cyril Touboul / Najeeb Halabi / Morgane Blot-Dupin / Raphael Lis / Charbel Abi Khalil / Shahin Rafii / Arash Rafii / Jennifer Pasquier

    Journal of Translational Medicine, Vol 17, Iss 1, Pp 1-

    2019  Volume 11

    Abstract: Abstract Background One main challenge in ovarian cancer rests on the presence of a relapse and an important metastatic disease, despite extensive surgical debulking and chemotherapy. The difficulty in containing metastatic cancer is partly due to the ... ...

    Abstract Abstract Background One main challenge in ovarian cancer rests on the presence of a relapse and an important metastatic disease, despite extensive surgical debulking and chemotherapy. The difficulty in containing metastatic cancer is partly due to the heterotypic interaction of tumor and its microenvironment. In this context, evidence suggests that endothelial cells (EC) play an important role in ovarian tumor growth and chemoresistance. Here, we studied the role of tumor endothelium on ovarian cancer cells (OCCs). Methods We evaluated the effect of activated endothelial cells on ovarian cancer cell proliferation and resistance to chemotherapy and investigated the survival pathways activated by endothelial co-culture. Results The co-culture between OCCs and E4+ECs, induced an increase of OCCs proliferation both in vitro and in vivo. This co-culture induced an increase of Notch receptors expression on OCC surface and an increase of Jagged 1 expression on E4+ECs surface and activation of survival pathways leading to chemoresistance by E4+ECs. Conclusion The targeting of aberrant NOTCH signaling could constitute a strategy to disrupt the pro-tumoral endothelial niche.
    Keywords Ovarian cancer ; Tumor microenvironment ; Cell–cell interactions ; Endothelial cells ; Medicine ; R
    Subject code 570
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Epigenetic profiles signify cell fate plasticity in unipotent spermatogonial stem and progenitor cells

    Ying Liu / Eugenia G. Giannopoulou / Duancheng Wen / Ilaria Falciatori / Olivier Elemento / C. David Allis / Shahin Rafii / Marco Seandel

    Nature Communications, Vol 7, Iss 1, Pp 1-

    2016  Volume 13

    Abstract: Spermatogonial stem cells (SSCs) spontaneously convert to multipotent adult spermatogonial-derived stem cells (MASCs). Here, the authors reveal the dynamics of bivalent histone H3-lysine4 and -lysine27 methylation signatures at somatic gene promoters in ... ...

    Abstract Spermatogonial stem cells (SSCs) spontaneously convert to multipotent adult spermatogonial-derived stem cells (MASCs). Here, the authors reveal the dynamics of bivalent histone H3-lysine4 and -lysine27 methylation signatures at somatic gene promoters in SSCs and ESC-like promoter chromatin states in MASCs.
    Keywords Science ; Q
    Language English
    Publishing date 2016-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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