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25 results on '"Singh, Rashim Pal"'

1. Identification of an optimized Receptor-Binding Domain Subunit Vaccine against SARS-CoV-2

Author

Yu, Hong, primary, Worrall, Liam J., additional, Berger, Thorsten, additional, Petric, Martin, additional, Lin, Bryan H., additional, Vuckovic, Marija, additional, Robb, Craig S., additional, Le, Quan, additional, Kenward, Calem, additional, Dai, Chuanbin, additional, Wakeham, Andrew, additional, Liu, Shaofeng, additional, Snow, Bryan, additional, Tobin, Chantal, additional, Budylowski, Patrick, additional, Guvenc, Furkan, additional, You-Ten, Annick, additional, Haight, Jillian, additional, Silvester, Jennifer, additional, Singh, Rashim Pal, additional, Ahn, Sang Kyun, additional, Sultana, Azmiri, additional, Poon, Betty, additional, Lam, Jessica, additional, Christie-Holmes, Natasha, additional, Ostrowski, Mario, additional, Gray-Owen, Scott D., additional, Kubli, Shawn, additional, Mak, Tak, additional, Strynadka, Natalie C. J., additional, and Brunham, Robert C., additional

Published
2023
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2. Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Author

Mitroulis, Ioannis, Chen, Lan-Sun, Singh, Rashim Pal, Kourtzelis, Ioannis, Economopoulou, Matina, Kajikawa, Tetsuhiro, Troullinaki, Maria, Ziogas, Athanasios, Ruppova, Klara, Hosur, Kavita, Maekawa, Tomoki, Wang, Baomei, Subramanian, Pallavi, Tonn, Torsten, Verginis, Panayotis, von Bonin, Malte, Wobus, Manja, Bornhauser, Martin, Grinenko, Tatyana, Di Scala, Marianna, Hidalgo, Andres, Wielockx, Ben, Hajishengallis, George, and Chavakis, Triantafyllos

Subjects
Hematopoietic stem cells -- Health aspects, Health care industry
Abstract

Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by [beta] integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis., Introduction Hematopoietic stem cells (HSC) lie at the core of the hematopoietic and immune systems and have a unique capacity for self-renewal and differentiation to multipotent and lineage-committed hematopoietic progenitors, [...]

Published
2017
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4. Iron- and erythropoietin-resistant anemia in a spontaneous breast cancer mouse model

Author

Bregolat, Nuria Fabregas, Ruetten, Maja, Da Silva, Milene Costa, Aboouf, Mostafa A, Ademi, Hyrije, von Büren, Nadine, Armbruster, Julia, Stirn, Martina, Altamura, Sandro, Marques, Oriana, Rodríguez, Josep M Monné, Samillan, Victor J, Singh, Rashim Pal, Wielockx, Ben, Muckenthaler, Martina U, Gassmann, Max; https://orcid.org/0000-0003-2750-8878, Thiersch, Markus; https://orcid.org/0000-0002-9118-8285, Bregolat, Nuria Fabregas, Ruetten, Maja, Da Silva, Milene Costa, Aboouf, Mostafa A, Ademi, Hyrije, von Büren, Nadine, Armbruster, Julia, Stirn, Martina, Altamura, Sandro, Marques, Oriana, Rodríguez, Josep M Monné, Samillan, Victor J, Singh, Rashim Pal, Wielockx, Ben, Muckenthaler, Martina U, Gassmann, Max; https://orcid.org/0000-0003-2750-8878, and Thiersch, Markus; https://orcid.org/0000-0002-9118-8285

Abstract

Anemia of cancer (AoC) with its multifactorial etiology and complex pathology is a poor prognostic indicator for cancer patients. One of the main causes of AoC is cancer-associated inflammation that activates mechanisms, commonly observed in anemia of inflammation, where functional iron deficiency and iron-restricted erythropoiesis is induced by increased hepcidin levels in response to IL-6 elevation. So far only a few AoC mouse models have been described, and most of them did not fully recapitulate the interplay of anemia, increased hepcidin levels and functional iron deficiency in human patients. To test if the selection and the complexity of AoC mouse models dictates the pathology or if AoC in mice per se develops independently of iron deficiency, we characterized AoC in Trp53floxWapCre mice that spontaneously develop breast cancer. These mice developed AoC associated with high IL-6 levels and iron deficiency. However, hepcidin levels were not increased and hypoferremia coincided with anemia rather than causing it. Instead, an early shift in the commitment of common myeloid progenitors from the erythroid to the myeloid lineage resulted in increased myelopoiesis and in the excessive production of neutrophils that accumulate in necrotic tumor regions. This process could neither be prevented by iron nor erythropoietin (EPO) treatment. Trp53floxWapCre mice are the first mouse model where EPO-resistant anemia is described and may serve as a disease model to test therapeutic approaches for a subpopulation of human cancer patients with normal or corrected iron levels that do not respond to EPO.

Published
2022

5. Iron- and erythropoietin-resistant anemia in a spontaneous breast cancer mouse model

Author

Bregolat, Nuria Fabregas, primary, Ruetten, Maja, additional, Da Silva, Milene Costa, additional, Aboouf, Mostafa A., additional, Ademi, Hyrije, additional, Büren, Nadine von, additional, Armbruster, Julia, additional, Stirn, Martina, additional, Altamura, Sandro, additional, Marques, Oriana, additional, Rodriguez, Josep M. Monné, additional, Samillan, Victor J., additional, Singh, Rashim Pal, additional, Wielockx, Ben, additional, Muckenthaler, Martina U., additional, Gassmann, Max, additional, and Thiersch, Markus, additional

Published
2022
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10. Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal

Author

Singh, Rashim Pal, primary, Jeyaraju, Danny V., additional, Voisin, Veronique, additional, Hurren, Rose, additional, Xu, Changjiang, additional, Hawley, James R., additional, Barghout, Samir H., additional, Khan, Dilshad H., additional, Gronda, Marcela, additional, Wang, Xiaoming, additional, Jitkova, Yulia, additional, Sharon, David, additional, Liyanagae, Sanduni, additional, MacLean, Neil, additional, Seneviratene, Ayesh K., additional, Mirali, Sara, additional, Borenstein, Adina, additional, Thomas, Geethu E., additional, Soriano, Joelle, additional, Orouji, Elias, additional, Minden, Mark D., additional, Arruda, Andrea, additional, Chan, Steven M., additional, Bader, Gary D., additional, Lupien, Mathieu, additional, and Schimmer, Aaron D., additional

Published
2020
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12. Targeting the Mitochondrial Metallochaperone Cox17 Reduces DNA Methylation and Promotes AML Differentiation through a Copper Dependent Mechanism

Author

Singh, Rashim Pal, primary, Jeyaraju, Danny V., additional, Voisin, Veronique, additional, Xu, Changjiang, additional, Barghout, Samir H, additional, Khan, Dilshad H., additional, Hurren, Rose, additional, Gronda, Marcela, additional, Wang, Xiaoming, additional, Jitkova, Yulia, additional, Sharon, David, additional, Liyanage, Sanduni U., additional, Soriano, Joelle, additional, Lechman,, Eric R., additional, MacLean, Neil, additional, Minden, Mark D., additional, Chan, Steven M, additional, Dick, John E., additional, Bader, Gary D, additional, and Schimmer, Aaron, additional

Published
2018
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13. Hematopoietic stem cells but not multipotent progenitors drive erythropoiesis during chronic erythroid stress in EPO transgenic mice

Author

Singh, Rashim Pal, Grinenko, Tatyana, Ramasz, Beáta, Franke, Kristin, Lesche, Mathias, Dahl, Andreas, Gassmann, Max, Chavakis, Triantafyllos, Henry, Ian, Wielockx, Ben, Singh, Rashim Pal, Grinenko, Tatyana, Ramasz, Beáta, Franke, Kristin, Lesche, Mathias, Dahl, Andreas, Gassmann, Max, Chavakis, Triantafyllos, Henry, Ian, and Wielockx, Ben

Abstract

The hematopoietic stem cell (HSC) compartment consists of a small pool of cells capable of replenishing all blood cells. Although it is established that the hematopoietic system is assembled as a hierarchical organization under steady-state conditions, emerging evidence suggests that distinct differentiation pathways may exist in response to acute stress. However, it remains unclear how different hematopoietic stem and progenitor cell subpopulations behave under sustained chronic stress. Here, by using adult transgenic mice overexpressing erythropoietin (EPO; Tg6) and a combination of in vivo, in vitro, and deep-sequencing approaches, we found that HSCs respond differentially to chronic erythroid stress compared with their closely related multipotent progenitors (MPPs). Specifically, HSCs exhibit a vastly committed erythroid progenitor profile with enhanced cell division, while MPPs display erythroid and myeloid cell signatures and an accumulation of uncommitted cells. Thus, our results identify HSCs as master regulators of chronic stress erythropoiesis, potentially circumventing the hierarchical differentiation-detour.

Published
2018

15. Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in

Author

Rauner, Martina, Franke, Kristin, Murray, Marta, Singh, Rashim-Pal, Hiram-Bab, Sahar, Platzbecker, Uwe, Gassmann, Max, Socolovsky, Merav, Neumann, Drorit, Gabet, Yankel, Chavakis, Triantafyllos, Hofbauer, Lorenz-C., and Wielockx, Ben

Subjects
OSTEOCLAST, Mice, Knockout, purl.org/pe-repo/ocde/ford#3.02.18 [https], Erythropoietin/biosynthesis/genetics, Osteoblasts/metabolism/pathology, Bone Resorption/genetics/metabolism/pathology, purl.org/pe-repo/ocde/ford#3.03.11 [https], Mice, Bone Density/genetics, Hypoxia-Inducible Factor-Proline Dioxygenases/deficiency, BONE LOSS, PHD2, Animals, Osteoclasts/metabolism/pathology, Hematopoietic Stem Cells/metabolism/pathology, OSTEOBLAST, Bone Marrow/metabolism/pathology, ERYTHROPOIETIN
Abstract

The main oxygen sensor hypoxia inducible factor (HIF) prolyl hydroxylase 2 (PHD2) is a critical regulator of tissue homeostasis during erythropoiesis, hematopoietic stem cell maintenance, and wound healing. Recent studies point toward a role for the PHD2‐erythropoietin (EPO) axis in the modulation of bone remodeling, even though the studies produced conflicting results. Here, we used a number of mouse strains deficient of PHD2 in different cell types to address the role of PHD2 and its downstream targets HIF‐1α and HIF‐2α in bone remodeling. Mice deficient for PHD2 in several cell lineages, including EPO‐producing cells, osteoblasts, and hematopoietic cells (CD68:cre‐PHD2f/f) displayed a severe reduction of bone density at the distal femur as well as the vertebral body due to impaired bone formation but not bone resorption. Importantly, using osteoblast‐specific (Osx:cre‐PHD2f/f) and osteoclast‐specific PHD2 knock‐out mice (Vav:cre‐ PHD2f/f), we show that this effect is independent of the loss of PHD2 in osteoblast and osteoclasts. Using different in vivo and in vitro approaches, we show here that this bone phenotype, including the suppression of bone formation, is directly linked to the stabilization of the α‐subunit of HIF‐2, and possibly to the subsequent moderate induction of serum EPO, which directly influenced the differentiation and mineralization of osteoblast progenitors resulting in lower bone density. Taken together, our data identify the PHD2:HIF‐2α:EPO axis as a so far unknown regulator of osteohematology by controlling bone homeostasis. Further, these data suggest that patients treated with PHD inhibitors or EPO should be monitored with respect to their bone status.

Published
2016

16. Increased epo levels are associated with bone loss in mice lacking phd2 in epo-producing cells

Author

Rauner, Martina, Franke, Kristin, Murray, Marta, Singh, Rashim Pal, Hiram-Bab, Sahar, Platzbecker, Uwe, Gassmann, Max, Socolovsky, Merav, Neumann, Drorit, Gabet, Yankel, Chavakis, Triantafyllos, Hofbauer, Lorenz C, Wielockx, Ben, University of Zurich, and Wielockx, Ben

Subjects
2712 Endocrinology, Diabetes and Metabolism, 2732 Orthopedics and Sports Medicine, bone loss, 10076 Center for Integrative Human Physiology, osteoclast, osteoblast, 570 Life sciences, biology, PHD2, erythropoietin, 10081 Institute of Veterinary Physiology
Published
2016

17. Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in EPO-Producing Cells

Author

Rauner, Martina, primary, Franke, Kristin, additional, Murray, Marta, additional, Singh, Rashim Pal, additional, Hiram-Bab, Sahar, additional, Platzbecker, Uwe, additional, Gassmann, Max, additional, Socolovsky, Merav, additional, Neumann, Drorit, additional, Gabet, Yankel, additional, Chavakis, Triantafyllos, additional, Hofbauer, Lorenz C, additional, and Wielockx, Ben, additional

Published
2016
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18. Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development

Author

Mamlouk, Soulafa, Kalucka, Joanna, Singh, Rashim Pal, Franke, Kristin, Muschter, Antje, Langer, Anika, Jakob, Christiane, Gassmann, Max, Baretton, Gustavo B, Wielockx, Ben, University of Zurich, and Wielockx, Ben

Subjects
RNA, Messenger/genetics, Antigens, CD/metabolism, Apoptosis, animal cell, Myeloid Cells/immunology, tumor-associated immune cells, Immunoenzyme Techniques, Mice, Cell Movement, purl.org/pe-repo/ocde/ford#3.02.21 [https], cytokine, T lymphocyte, prolylhydroxylase 2, 1306 Cancer Research, rat, Oligonucleotide Array Sequence Analysis, Mice, Knockout, Cytokines/genetics, Reverse Transcriptase Polymerase Chain Reaction, article, Flow Cytometry, 10081 Institute of Veterinary Physiology, unclassified drug, Hypoxia-Inducible Factor-Proline Dioxygenases/physiology, cell death, priority journal, 10076 Center for Integrative Human Physiology, Disease Progression, Antigens, Differentiation, Myelomonocytic/metabolism, 2730 Oncology, enzyme deficiency, Biomarkers, Tumor/genetics, down regulation, phenotype, Blotting, Western, animal experiment, cancer genetics, 610 Medicine & health, Real-Time Polymerase Chain Reaction, cancer growth, animal tissue, Carcinoma, Lewis Lung/genetics, Hypoxia-Inducible Factor 1, alpha Subunit/physiology, Animals, controlled study, cell lineage, mouse, Bone Marrow/metabolism, nonhuman, Gene Expression Profiling, animal model, T-Lymphocytes/immunology, ablation therapy, cytokines, oxygenase, Mice, Inbred C57BL, cell proliferation, Melanoma, Experimental/genetics, cancer size, prolyl hydroxylase-2, 570 Life sciences, biology, hematopoietic system, Integrases/metabolism, bone marrow cell
Abstract

The tumor microenvironment plays a pivotal role during cancer development and progression. The balance between suppressive and cytotoxic responses of the tumor immune microenvironment has been shown to have a direct effect on the final outcome in various human and experimental tumors. Recently, we demonstrated that the oxygen sensor HIF-prolyl hydroxylase-2 (PHD2) plays a detrimental role in tumor cells, stimulating systemic growth and metastasis in mice. In our current study, we show that the conditional ablation of PHD2 in the hematopoietic system also leads to reduced tumor volume, intriguingly generated by an imbalance between enhanced cell death and improved proliferation of tumor cells. This effect seems to rely on the overall downregulation of protumoral as well as antitumoral cytokines. Using different genetic approaches, we were able to confine this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. Taken together, our findings reveal a multifaceted role for PHD2 in several hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies in the future. What's new? Here the authors describe the complex role of the oxygen sensor PHD2 in tumor-associated immune cells in a conditional PHD2-deficient mouse line. They demonstrate that the observed reduced tumor volume is a consequence of opposing changes including the drastic down-regulation of numerous pro- as well as anti-tumoral genes and an imbalance between enhanced cell death and greater proliferation of tumor cells. They confined this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. The findings reveal a multifaceted role for PHD2 in hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies.

Published
2013

21. Loss of Epithelial Hypoxia-Inducible Factor Prolyl Hydroxylase 2 Accelerates Skin Wound Healing in Mice

Author

Kalucka, Joanna, primary, Ettinger, Andreas, additional, Franke, Kristin, additional, Mamlouk, Soulafa, additional, Singh, Rashim Pal, additional, Farhat, Katja, additional, Muschter, Antje, additional, Olbrich, Susanne, additional, Breier, Georg, additional, Katschinski, Dörthe M., additional, Huttner, Wieland, additional, Weidemann, Alexander, additional, and Wielockx, Ben, additional

Published
2013
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23. HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α–induced excessive erythropoiesis

Author

Franke, Kristin, primary, Kalucka, Joanna, additional, Mamlouk, Soulafa, additional, Singh, Rashim Pal, additional, Muschter, Antje, additional, Weidemann, Alexander, additional, Iyengar, Vasuprada, additional, Jahn, Steffen, additional, Wieczorek, Kathrin, additional, Geiger, Kathrin, additional, Muders, Michael, additional, Sykes, Alex M., additional, Poitz, David M., additional, Ripich, Tatsiana, additional, Otto, Teresa, additional, Bergmann, Sybille, additional, Breier, Georg, additional, Baretton, Gustavo, additional, Fong, Guo-Hua, additional, Greaves, David R., additional, Bornstein, Stefan, additional, Chavakis, Triantafyllos, additional, Fandrey, Joachim, additional, Gassmann, Max, additional, and Wielockx, Ben, additional

Published
2013
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24. Transduction of Primary AML Cells with Lentiviral Vector for In VitroStudy or In VivoEngraftment

Author

Schimmer, Aaron D., Singh, Rashim Pal, Seneviratne, Ayesh K., Thomas, Geethu E., MacLean, Neil, and Hurren, Rose

Abstract

We describe a method to silence genes in primary acute myeloid leukemia cells by transducing them with shRNA in lentiviral vectors. The transduction of primary non-adherent cells is particularly challenging. The protocol will aid in performing such experiments and is particularly helpful to prepare cells for in vivoengraftment studies. Use of a special medium supplemented with cytokines preserves the viability of the leukemic stem cells and their ability to engraft the marrow of immune-deficient mice.

Published
2020
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25. Hypoxia-mediated regulation of stem cell fate.

Author

Singh RP, Franke K, and Wielockx B

Subjects
Animals, Cell Differentiation, Hematopoietic Stem Cells metabolism, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Mesenchymal Stem Cells metabolism, Neoplastic Stem Cells metabolism, Neural Stem Cells metabolism, Oxygen metabolism, Hypoxia metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Signal Transduction, Stem Cells metabolism
Abstract

Hypoxia-mediated regulation of stem cell fate, or reduced oxygen availability, is a prominent feature during mammalian development and under physiological and pathological conditions in adults. Oxygen-sensing is therefore indispensable as it enables the cells to adapt instantaneously to an inappropriate pO(2). This machinery relies primarily on hypoxia inducible factor (HIF). Moreover, a growing body of evidence proposes that different types of stem cells exist in a very hypoxic microenvironment, which may be beneficial for the maintenance of these cells and ensures continuous replenishment of dead or damaged cells in virtually all tissues of the body. Recent reports have shown that HIF is a critical player in these responses. However, a better understanding of the different HIF-related mechanisms is of utmost importance for the improvement of therapeutic strategies for tissue regeneration as well as hematological malignancies.

Published
2012
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