scholarly journals Molecular responses to therapeutic proteasome inhibitors in multiple myeloma patients are donor-, cell type- and drug-dependent

Oncotarget ◽  
2018 ◽  
Vol 9 (25) ◽  
pp. 17797-17809 ◽  
Author(s):  
Eleni-Dimitra Papanagnou ◽  
Evangelos Terpos ◽  
Efstathios Kastritis ◽  
Issidora S. Papassideri ◽  
Ourania E. Tsitsilonis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Donor Cell ◽  
Cell Type ◽  
Molecular Responses ◽  
Drug Dependent ◽  
Donor Cell Type

scholarly journals Rabbit somatic cell cloning: effects of donor cell type, histone acetylation status and chimeric embryo complementation

Reproduction ◽  
2007 ◽  
Vol 133 (1) ◽  
pp. 219-230 ◽  
Author(s):  
Feikun Yang ◽  
Ru Hao ◽  
Barbara Kessler ◽  
Gottfried Brem ◽  
Eckhard Wolf ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Nuclear Transfer ◽  
Donor Cell ◽  
Epigenetic Mark ◽  
Cell Type ◽  
Developmental Potential ◽  
Acetylation Status ◽  
Donor Cells ◽  
Donor Cell Type

The epigenetic status of a donor nucleus has an important effect on the developmental potential of embryos produced by somatic cell nuclear transfer (SCNT). In this study, we transferred cultured rabbit cumulus cells (RCC) and fetal fibroblasts (RFF) from genetically marked rabbits (Alicia/Basilea) into metaphase II oocytes and analyzed the levels of histone H3-lysine 9-lysine 14 acetylation (acH3K9/14) in donor cells and cloned embryos. We also assessed the correlation between the histone acetylation status of donor cells and cloned embryos and their developmental potential. To test whether alteration of the histone acetylation status affects development of cloned embryos, we treated donor cells with sodium butyrate (NaBu), a histone deacetylase inhibitor. Further, we tried to improve cloning efficiency by chimeric complementation of cloned embryos with blastomeres fromin vivofertilized or parthenogenetic embryos. The levels of acH3K9/14 were higher in RCCs than in RFFs (P<0.05). Although the type of donor cells did not affect development to blastocyst, after transfer into recipients, RCC cloned embryos induced a higher initial pregnancy rate as compared to RFF cloned embryos (40 vs 20%). However, almost all pregnancies with either type of cloned embryos were lost by the middle of gestation and only one fully developed, live RCC-derived rabbit was obtained. Treatment of RFFs with NaBu significantly increased the level of acH3K9/14 and the proportion of nuclear transfer embryos developing to blastocyst (49 vs 33% with non-treated RFF,P<0.05). The distribution of acH3K9/14 in either group of cloned embryos did not resemble that inin vivofertilized embryos suggesting that reprogramming of this epigenetic mark is aberrant in cloned rabbit embryos and cannot be corrected by treatment of donor cells with NaBu. Aggregation of embryos cloned from NaBu-treated RFFs with blastomeres fromin vivoderived embryos improved development to blastocyst, but no cloned offspring were obtained. Two live cloned rabbits were produced from this donor cell type only after aggregation of cloned embryos with a parthenogenetic blastomere. Our study demonstrates that the levels of histone acetylation in donor cells and cloned embryos correlate with their developmental potential and may be a useful epigenetic mark to predict efficiency of SCNT in rabbits.

Abstract P404: Membrane Composition Of Cardiac-derived Extracellular Vesicles Changes With Vesicle Origin And Determines Uptake

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Sruti Bheri ◽  
Jessica R Hoffman ◽  
Hyun-Ji Park ◽  
Michael E Davis
Keyword(s):  
Extracellular Vesicles ◽  
Lipid Membrane ◽  
Recipient Cell ◽  
Donor Cell ◽  
Membrane Lipid ◽  
Least Squares Regression ◽  
Membrane Composition ◽  
Cell Type ◽  
Uptake Mechanism ◽  
Donor Cell Type

Introduction: Myocardial infarction (MI) is a leading cause of mortality worldwide. The potency of cell-based therapies for MI is increasingly attributed to the release of extracellular vesicles (EVs) which consist of a lipid/protein membrane and encapsulate RNA cargo. Specifically, EVs from ckit+ progenitor cells (CPCs) and mesenchymal stromal cells (MSCs) are shown to be pro-reparative, with clinical trials ongoing. Despite copious research into EV cargo, the role of donor cell type on EV membrane composition and its effects on EV uptake mechanism by recipient cells remain unclear. This is crucial for designing EV-based therapeutics as uptake mechanism dictates the functionality of the cargo. Thus, we hypothesized that (1) EV membrane composition varies by donor cell type and (2) this variation covaries with the mechanism of uptake. Methods: EVs were isolated using differential ultracentrifugation from four cardiac cell types: CPCs, MSCs, cardiac endothelial cells (CECs) and rat cardiac fibroblasts (RCFs) grown in normoxia (18% O 2 ) or hypoxia (1% O 2 ) to mimic ischemic conditions. EVs were characterized for size and concentration. EV lipid membrane profile was assessed through LC/MS/MS. Donor cell’s role on EV uptake mechanism was determined by inhibiting known uptake pathways (clathrin, dynamin, macropinocytosis and caveolae/lipid raft) with small molecules and quantifying CEC/RCF endocytosis of EVs with flow cytometry. Finally, partial least squares regression was used to determine the most important lipids involved in EV uptake mechanism. Results: EVs were successfully isolated and characterized. The EV membrane lipid profiles clustered by donor cell type. Uptake mechanism of EVs varied based on both donor and recipient cell type with dynamin mediated endocytosis being the most common. Further, the uptake mechanism was independent of normoxic/hypoxic conditioning. Finally, supervised learning methods revealed specific lipid classes (sphingolipids and glycerophospholipids) covaried with EV uptake mechanism. Conclusion: This work highlights the importance of the understudied EV membrane and its role in delivering therapeutic cargo. Active donor cell selection for efficient EV uptake will allow for more potent EV-based MI therapies.

Donor cell-type specific paracrine effects of cell transplantation for post-infarction heart failure

2009 ◽  
Vol 47 (2) ◽  
pp. 288-295 ◽  
Author(s):  
Yasunori Shintani ◽  
Satsuki Fukushima ◽  
Anabel Varela-Carver ◽  
Joon Lee ◽  
Steven R. Coppen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Transplantation ◽  
Donor Cell ◽  
Cell Type ◽  
Paracrine Effects ◽  
Cell Type Specific ◽  
Infarction Heart ◽  
Donor Cell Type

Red blood cell generation from human induced pluripotent stem cells of different donor cell type origin

2013 ◽  
Vol 41 (8) ◽  
pp. S27
Author(s):  
Isabel Dorn ◽  
Katharina Klich ◽  
Martina Radstaak ◽  
Katherina Psathaki ◽  
Marcos Arauzo-Bravo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Blood Cell ◽  
Induced Pluripotent Stem Cells ◽  
Red Blood Cell ◽  
Pluripotent Stem Cells ◽  
Donor Cell ◽  
Cell Generation ◽  
Cell Type ◽  
Induced Pluripotent ◽  
Donor Cell Type

Coordination between donor cell type and cell cycle stage improves nuclear cloning efficiency in cattle

2003 ◽  
Vol 59 (1) ◽  
pp. 45-59 ◽  
Author(s):  
D.N Wells ◽  
G Laible ◽  
F.C Tucker ◽  
A.L Miller ◽  
J.E Oliver ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Donor Cell ◽  
Cloning Efficiency ◽  
Cell Type ◽  
Cell Cycle Stage ◽  
Donor Cell Type

scholarly journals Analysis of Molecular-Cellular Responses to Proteasome Inhibitors in Multiple Myeloma Patients; A Translational Approach of Proteasome Inhibitors In Vivo Effects from the Drosophila Experimental Model to Humans

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3250-3250
Author(s):  
Eleni-Dimitra Papanagnou ◽  
Tina Bagratuni ◽  
Efstathios Kastritis ◽  
Issidora Papassideri ◽  
Evangelos Terpos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Cell Types ◽  
Cell Type ◽  
Regulatory Circuit ◽  
Healthy Donors ◽  
Somatic Tissues

Abstract Organisms require efficient surveillance of proteome functionality to prevent disruption of proteostasis. Central to the proteostasis ensuring network is the proteasome, which degrades both normal short-lived ubiquitinated proteins and damaged or mutated proteins. Over-activation of the proteasome seems to represent a hallmark of advanced tumors and thus, its selective inhibition provides a strategy for the development of novel anti-tumor therapies. This approach is applied in multiple myeloma (MM) that represents the second most common hematological malignancy. Specifically, proteasome inhibitors have demonstrated clinical efficacy in the treatment of MM and mantle cell lymphoma and are evaluated for the treatment of other malignancies. Nevertheless, the impact of proteasome dysfunction in normal human tissues (which relates to side effects in the clinic) remains poorly understood. By using the fruit fly Drosophila melanogaster as an in vivo experimental platform to study proteasome physiology we found that proteasome functionality is sex-, tissue- and age-dependent. Oral administration of proteasome inhibitors (e.g. Bortezomib or Carfilzomib) in young flies suppressed proteasome activities in the somatic tissues; reduced motor function (recapitulating peripheral neuropathy of Bortezomib treatment in the clinic) and caused premature aging. It also increased oxidative stress and activated an Nrf2-dependent feedback regulatory circuit that upregulated proteasome genes in order to restore normal proteasome functionality. Moreover, in line with observations in the clinic, Carfilzomib was found to cause milder (as compared to Bortezomib) neuromusculatory toxicity and reduction of flies' lifespan. To address the question whether these findings can be translated in humans we started characterizing proteasome physiology in both healthy donors, as well as in MM patients treated with therapeutic proteasome inhibitors. For our studies we used isolated red blood cells (RBCs; represent an anucleate relatively "long-lived" proteome) and peripheral blood mononucleated cells (PBMCs; represent cell lineages with active genomic responses). Our analyses in healthy donors of different ages revealed significant variability of basal proteasome peptidase activities in both cell types. PBMCs expressed (as compared to RBCs) higher basal proteasome activities and RBCs from females had higher chymotrypsin-like activity as compared to RBCs from males of similar age. Furthermore, as in the flies' somatic tissues, proteasome activities were found (independently of sex and cell type) to decline during aging. Studies in RBCs and PBMCs isolated from MM patients treated with Bortezomib revealed donor-, cell type- and drug-specific readouts. In most (but not all) cases proteasome activities were suppressed in both cell types at 24-hrs post-drug administration. RBCs were particularly sensitive to the inhibitor and their proteasome activities remained low during the entire course of treatment. On the contrary, PBMCs were characterized by phases of rebound proteasome activities during the periods of no drug administration; these phases correlated with upregulation of proteasome genes expression, indicating that the feedback regulatory circuit which functions to restore proteasome activities in flies is also operational in humans. Additional gene expression analyses in PBMCs showed that proteasome inhibition also triggers the induction of genes involved in chaperon, autophagy, unfolded protein- and antioxidant-responses pathways; while, as in the fly model, the intensity of genes induction seems to decline during aging. Interestingly, in those patients who (despite treatment) showed no reduction of proteasome activities we found marginal gene expression alterations, suggesting that the observed gene induction largely depends on proteasome loss of function. Importantly, at the clinical level we observed a positive correlation between the degree of proteasome inhibition (in PBMCs or RBCS) and the depth of disease responses. The similarities between the Drosophila pharmacological model and the MM patients indicate that the molecular responses to proteasome malfunction are largely conserved in higher metazoans. We foresee that our ongoing studies will support a more personalized clinical therapeutic approach in hematological malignancies. Disclosures Terpos: Amgen: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Novartis: Honoraria; Celgene: Honoraria, Other: Travel expenses. Dimopoulos:Celgene: Honoraria; Onyx: Honoraria; Novartis: Honoraria; Genesis: Honoraria; Janssen-Cilag: Honoraria; Janssen: Honoraria; Amgen: Honoraria.

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