scholarly journals TIMP-1 deficiency subverts cell-cycle dynamics in murine long-term HSCs

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6479-6488 ◽  
Author(s):  
Lara Rossi ◽  
Aysegul V. Ergen ◽  
Margaret A. Goodell
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Distribution ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Homeostatic Regulation ◽  
Intrinsic Cues ◽  
Stem Cell Quiescence ◽  
Cell Quiescence ◽  
Cell Cycle Dynamics

Abstract In addition to the well-recognized role in extracellular matrix remodeling, the tissue inhibitor of metalloproteinases-1 (TIMP-1) has been suggested to be involved in the regulation of numerous biologic functions, including cell proliferation and survival. We therefore hypothesized that TIMP-1 might be involved in the homeostatic regulation of HSCs, whose biologic behavior is the synthesis of both microenvironmental and intrinsic cues. We found that TIMP-1−/− mice have decreased BM cellularity and, consistent with this finding, TIMP-1−/− HSCs display reduced capability of long-term repopulation. Interestingly, the cell cycle distribution of TIMP-1−/− stem cells appears distorted, with a dysregulation at the level of the G1 phase. TIMP-1−/− HSCs also display increased levels of p57, p21, and p53, suggesting that TIMP-1 could be intrinsically involved in the regulation of HSC cycling dynamics. Of note, TIMP-1−/− HSCs present decreased levels of CD44 glycoprotein, whose expression has been proven to be controlled by p53, the master regulator of the G1/S transition. Our findings establish a role for TIMP-1 in regulating HSC function, suggesting a novel mechanism presiding over stem cell quiescence in the framework of the BM milieu.

TIMP-1 Deficiency Subverts Cell Cycle Dynamics in Long-Term HSCs.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2514-2514
Author(s):  
Lara Rossi ◽  
Margaret Goodell
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Biological Behavior ◽  
Cell Cycle Distribution ◽  
Matrix Remodeling ◽  
Hematopoietic Stem ◽  
Stem Cell Quiescence

Abstract Abstract 2514 Poster Board II-491 In addition to the consolidated role in extracellular matrix remodeling, the Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) has been suggested to be involved in the regulation of numerous biological functions, including cell proliferation and survival. We therefore hypothesized that TIMP-1 might be involved in the homeostatic regulation of hematopoietic stem cells (HSCs), whose biological behavior is the synthesis of both microenvironmental and intrinsic cues. We found that TIMP-1−/− mice have decreased HSC numbers and, consistent with this finding, TIMP-1−/− HSCs display reduced capability of long-term repopulation. Interestingly, the cell cycle distribution of TIMP-1−/− LT-HSCs is profoundly distorted, with a consistent proportion of the stem cell pool arrested in the G1 phase, suggesting that TIMP-1 is intrinsically involved in the regulation of the HSC proliferation dynamics. Indeed, HSCs exhibit a higher proliferation rate, leading to an increased formation of CFU-C in vitro and spleen colonies (CFU-S) after transplant. Of note, TIMP-1−/− HSCs present decreased levels of CD44 glycoprotein, whose expression has been proven to be controlled by p53, the master regulator of the G1/S transition. Our findings establish TIMP-1 role in HSC function, suggesting a novel mechanism presiding over stem cell quiescence and potentially involved in the development of hematological diseases. Disclosures: No relevant conflicts of interest to declare.

C-Myb Controls Hematopoietic Stem Cell Quiescence and Differentiation Via Regulation of p57Kip2

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3878-3878
Author(s):  
Michael P Cooke ◽  
Susan E Sutton ◽  
Albert E Parker
Keyword(s):  
Cell Cycle ◽  
Fold Increase ◽  
Short Term ◽  
Hematopoietic Stem ◽  
Cell Cycle Genes ◽  
Stem Cell Quiescence ◽  
Cell Quiescence ◽  
Factor C ◽  
Mediated Reduction

Abstract Abstract 3878 A seminal feature of long-term hematopoietic stem cells (HSC) is quiescence. We recently described a mutation of the transcription factor c-Myb, M303V that leads to thrombocytosis and a ten-fold increase HSC number. Here we report that increased HSC number in c-MybM303V mice results from increased cycling of long-term and short-term HSC. Analysis of cell cycle genes revealed a decrease in the cell cycle inhibitor p57kip2 (Cdkn1c), a gene expressed in long-term but not short-term HSC. Mechanistic studies reveal that c-Myb binds and activates the p57 promoter and this capacity is diminished by the c-MybM303V mutation. Restoration of p57 in c-MybM303V HSC prevents thrombocytosis and shRNA mediated reduction of p57 in HSC followed by transplantation leads to enhanced numbers of HSC. These data highlight c-Myb and p57 as key regulators of HSC quiescence and differentiation. Disclosures: Cooke: Novartis: Employment. Sutton:Novartis: Employment. Parker:Novartis: Employment.

scholarly journals Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection

2020 ◽  
Author(s):  
Fan Tang ◽  
Yan Tie ◽  
Weiqi Hong ◽  
Yuquan Wei ◽  
Chongqi Tu ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Low Dose ◽  
Surgical Stress ◽  
Suppressor Cells ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Myeloid Derived Suppressor Cells ◽  
Term Survival ◽  
Premetastatic Niche

AbstractSurgical resection is a common therapeutic option for primary solid tumors. However, high cancer recurrence and metastatic rates after resection are the main cause of cancer related mortalities. This implies the existence of a “fertile soil” following surgery that facilitates colonization by circulating cancer cells. Myeloid-derived suppressor cells (MDSCs) are essential for premetastatic niche formation, and may persist in distant organs for up to 2 weeks after surgery. These postsurgical persistent lung MDSCs exhibit stronger immunosuppression compared with presurgical MDSCs, suggesting that surgery enhances MDSC function. Surgical stress and trauma trigger the secretion of systemic inflammatory cytokines, which enhance MDSC mobilization and proliferation. Additionally, damage associated molecular patterns (DAMPs) directly activate MDSCs through pattern recognition receptor-mediated signals. Surgery also increases vascular permeability, induces an increase in lysyl oxidase and extracellular matrix remodeling in lungs, that enhances MDSC mobilization. Postsurgical therapies that inhibit the induction of premetastatic niches by MDSCs promote the long-term survival of patients. Cyclooxygenase-2 inhibitors and β-blockade, or their combination, may minimize the impact of surgical stress on MDSCs. Anti-DAMPs and associated inflammatory signaling inhibitors also are potential therapies. Existing therapies under tumor-bearing conditions, such as MDSCs depletion with low-dose chemotherapy or tyrosine kinase inhibitors, MDSCs differentiation using all-trans retinoic acid, and STAT3 inhibition merit clinical evaluation during the perioperative period. In addition, combining low-dose epigenetic drugs with chemokine receptors, reversing immunosuppression through the Enhanced Recovery After Surgery protocol, repairing vascular leakage, or inhibiting extracellular matrix remodeling also may enhance the long-term survival of curative resection patients.

scholarly journals Induction of Extracellular Matrix-Remodeling Genes by the Senescence-Associated Protein APA-1

2002 ◽  
Vol 22 (21) ◽  
pp. 7385-7397 ◽  
Author(s):  
Jennifer A. Benanti ◽  
Dawnnica K. Williams ◽  
Kristin L. Robinson ◽  
Harvey L. Ozer ◽  
Denise A. Galloway
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Zinc Finger Protein ◽  
Kinase Inhibitor ◽  
Human Fibroblasts ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Telomere Attrition ◽  
Cyclin Dependent Kinase Inhibitor ◽  
The Matrix

ABSTRACT Human fibroblasts undergo cellular senescence after a finite number of divisions, in response to the erosion of telomeres. In addition to being terminally arrested in the cell cycle, senescent fibroblasts express genes that are normally induced upon wounding, including genes that remodel the extracellular matrix. We have identified the novel zinc finger protein APA-1, whose expression increased in senescent human fibroblasts independent of telomere shortening. Extended passage, telomerase-immortalized fibroblasts had increased levels of APA-1 as well as the cyclin-dependent kinase inhibitor p16. In fibroblasts, APA-1 was modified by the ubiquitin-like protein SUMO-1, which increased APA-1 half-life, possibly by blocking ubiquitin-mediated degradation. Overexpression of APA-1 did not cause cell cycle arrest; but, it induced transcription of the extracellular matrix-remodeling genes MMP1 and PAI2, which are associated with fibroblast senescence. MMP1 and PAI2 transcript levels also increased in telomerase-immortalized fibroblasts that had high levels of APA-1, demonstrating that the matrix-remodeling phenotype of senescent fibroblasts was not induced by telomere attrition alone. APA-1 was able to transactivate and bind to the MMP1 promoter, suggesting that APA-1 is a transcription factor that regulates expression of matrix-remodeling genes during fibroblast senescence.

Long-term effects for acute phase myocardial infarct VEGF165gene transfer cardiac extracellular matrix remodeling

2009 ◽  
Vol 27 (1) ◽  
pp. 22-31 ◽  
Author(s):  
Fabio D'Aguiar Mataveli ◽  
Sang Won Han ◽  
Helena Bonciani Nader ◽  
Aline Mendes ◽  
Rose Kanishiro ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Acute Phase ◽  
Myocardial Infarct ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Long Term Effects

scholarly journals Unraveling the Big Sleep: Molecular Aspects of Stem Cell Dormancy and Hibernation

2021 ◽  
Vol 12 ◽  
Author(s):  
Itamar B. Dias ◽  
Hjalmar R. Bouma ◽  
Robert H. Henning
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Future Perspective ◽  
Acid Oxidation ◽  
Hematopoietic Stem ◽  
Dormant State ◽  
Stem Cell Quiescence ◽  
Cell Quiescence ◽  
Molecular Aspects

Tissue-resident stem cells may enter a dormant state, also known as quiescence, which allows them to withstand metabolic stress and unfavorable conditions. Similarly, hibernating mammals can also enter a state of dormancy used to evade hostile circumstances, such as food shortage and low ambient temperatures. In hibernation, the dormant state of the individual and its cells is commonly known as torpor, and is characterized by metabolic suppression in individual cells. Given that both conditions represent cell survival strategies, we here compare the molecular aspects of cellular quiescence, particularly of well-studied hematopoietic stem cells, and torpor at the cellular level. Critical processes of dormancy are reviewed, including the suppression of the cell cycle, changes in metabolic characteristics, and cellular mechanisms of dealing with damage. Key factors shared by hematopoietic stem cell quiescence and torpor include a reversible activation of factors inhibiting the cell cycle, a shift in metabolism from glucose to fatty acid oxidation, downregulation of mitochondrial activity, key changes in hypoxia-inducible factor one alpha (HIF-1α), mTOR, reversible protein phosphorylation and autophagy, and increased radiation resistance. This similarity is remarkable in view of the difference in cell populations, as stem cell quiescence regards proliferating cells, while torpor mainly involves terminally differentiated cells. A future perspective is provided how to advance our understanding of the crucial pathways that allow stem cells and hibernating animals to engage in their ‘great slumbers.’

Deletion of Puma and p21Waf1 In Mice Deactivates p53-Induced Cell Death and Cell Cycle Arrest, but Protects Mice From Irradiation-Induced Lymphomagenesis by a Mechanism Involving Hemopoietic Stem Cell Quiescence

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 90-90
Author(s):  
Josefina Pinon Hofbauer ◽  
Claudia Holler ◽  
Ursula Denk ◽  
Daniela Asslaber ◽  
Gerd Fastner ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Death ◽  
Stem Cell ◽  
Tumor Suppression ◽  
Hemopoietic Stem Cell ◽  
Cycle Arrest ◽  
Stem Cell Quiescence ◽  
Cell Quiescence

Abstract Abstract 90 Introduction: The p53 gene is non-functional in >50% of human tumors. In mice deletion of p53 leads to a high incidence of tumors and to a significant acceleration of tumorigenesis induced by repeated gamma-irradiation. While a large number of effects have been described for p53, current concepts of p53-mediated tumor suppression discuss the roles of p53 in regulation of cell cycle and apoptosis as being essential. Two main targets have been identified in this respect: p21Waf1 as an essential regulator of cell cycle arrest downstream of p53 and Puma as the largest single contribution towards p53 induced cell death. Methods: We have generated p21Waf1/Puma doubly deficient (i.e. double-knockout – DKO) mice on a pure C57BL/6 background to investigate the effects on tumorigenesis. Results: In ex vivo irradiation studies DKO thymocytes expectedly showed reduced cell death and loss of a G1/S arrest upon irradiation. When following a cohort of mice for spontaneous tumor development, the DKO mice did not differ from wild-type (WT) controls. Since this may be explained by additional p53 down-stream effectors essential for tumor suppression, we set out to challenge the mice with an established repeated irradiation protocol (4 × 1.75 Gy over 4 weeks) in order to increase the likelihood of uncovering a defect in tumor suppression not apparent in unchallenged mice. While irradiated WT mice developed thymic lymphomas at an expected rate and p53 deficiency accelerated the lymphoma formation as published, irradiated DKO mice did not develop any thymic lymphoma at all. During the irradiation protocol WT mice followed a series of depletion and regrowth cycles in thymic cellularity with a high rate of cell death early post irradiations in TUNEL assays and a surge of proliferation on day 5 after irradiations detected by in vivo BrdU labeling. By contrast in DKO mice thymic cellularity dropped only slightly during the first irradiation cycle. This was followed by a slow and steady decline in cellularity over the following 3 cycles of irradiation. No late apoptotic wave or loss of proliferative capacity of remaining thymocytes could explain the loss of cellularity, nor could senescence of thymocytes be detected by SA-β-Gal staining in situ, suggesting that thymic influx was defective. It had previously been reported for the repeat-irradiation lymphomagenesis model, that the irradiation of hemopoietic precursor cells was essential for tumorigenesis. In contrast to thymic cellularity, DKO LSK numbers stayed relatively stable over the course of the 4 irradiations. By comparison WT LSK numbers dropped to about 50% by the time 4 irradiations were completed. Indeed, short-term repopulating (ST) cells dropped significantly, while long-term repopulating (LT) and multipotent progenitor (MPP) cell populations stayed more stable. In DKO marrows the relative content of LT, ST and MPP cells proved very stable across the irradiation schedule. In vivo BrdU labelling showed that WT LSK had a higher fraction of labelled cells at baseline and a >100% increase in the proliferative fraction during irradiation, while in DKO LSK the proliferation index was lower and stayed stably low over time, compatible with the replenishment defect observed in the thymus. DKO stem cells were only slightly more efficient (1.6-fold) than WT in bone marrow reconstitution experiments without challenge. However, when mixed chimeras were then subjected to the irradiation protocol with 4 × 1.75 Gy a clear advantage of the DKO cells became apparent (28-fold). Moreover, when reconstituting lethally irradiated mice with a mixture of WT and DKO marrow taken from repeatedly irradiated donors the efficacy ratio was 1:152. Conclusion: Our data contrast observations made in cell lines, where loss of Puma and p21Waf1 led to a p53-resistant outgrowth of cells. We present in an animal model that loss of Puma and p21Waf1 is not tumorigenic and in fact protects mice from irradiation carcinogenesis. Together with our recently published findings in irradiated Puma singly-deficient mice (Labi G&D 2010), our data suggest that tumorigenesis in irradiated DKO mice is inhibited by effects on hemopoietic stem cell reactivity to DNA damage. A combination of lack of generation of free niche space through protection of hemopoietic stem cells from cell death and a stem cell quiescence state retained in DKO stem cells after irradiation seems responsible for the phenotype. Disclosures: No relevant conflicts of interest to declare.

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