scholarly journals Variant cell cycles regulated by Notch signaling control cell size and ensure a functional blood-brain barrier

Development ◽  
2018 ◽  
Vol 145 (3) ◽  
pp. dev157115 ◽  
Author(s):  
Jessica R. Von Stetina ◽  
Laura E. Frawley ◽  
Yingdee Unhavaithaya ◽  
Terry L. Orr-Weaver
Keyword(s):  
Notch Signaling ◽  
Cell Size ◽  
Blood Brain Barrier ◽  
Control Cell ◽  
Brain Barrier ◽  
Cell Cycles ◽  
Blood Brain ◽  
Variant Cell

Inhibition of Notch and tumor regression

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14623-e14623
Author(s):  
A. A. Epenetos ◽  
C. Kousparou ◽  
S. Stylianou
Keyword(s):  
Stem Cells ◽  
Fusion Protein ◽  
Notch Signaling ◽  
Blood Brain Barrier ◽  
Tumor Regression ◽  
The Self ◽  
Brain Barrier ◽  
Self Renewal ◽  
Blood Brain ◽  
Repeat Administration

e14623 Background: Notch signaling is an evolutionary-conserved pathway in vertebrates and invertebrates which is involved many developmental processes, including cell fate decisions, apoptosis, proliferation, and stem-cell self renewal. There is increasing evidence that the same molecular pathways regulating the self renewal of stem cells are also being employed in cancer progression. The Notch signal transduction pathway has been implicated in the self-renewal of stem cells in hematopoietic, skin, neural, germ and breast tissue. Increasing evidence suggests that the Notch signaling pathway is frequently up regulated in many forms of cancer including acute T-cell lymphoblastic leukemia, cervical, prostate, lung, breast and others. Thus,inhibition of the pathway could provide a novel treatment of cancer and cancer stem cells. Methods: We have genetically engineered a fusion protein, consisting of the Drosophila transcription factor Antennapedia (ANTP) and with the truncated version of Mastermind-like (MAML) that behaves in a dominant negative (DN) fashion and inhibits Notch activation (ANTP/DN MAML, TR4). This novel fusion protein has been tested for its ability to target tumor cells in vitro and in vivo. Results: Our data show that ANTP/DN MAML fusion protein, TR4 contains signals for proper cell targeting, internalization and nuclear transport. Furthermore, TR4 inhibits human mammary and colon xenograft tumor growth and metastases in immuno deficient mice.TR4 presence and activity was also detected in the brains of treated animals demonstrating that TR4 can cross the blood-brain barrier and potentially eliminate brain tumors and metastases, unlike other anticancer drugs and biological such as monoclonal antibodies that cannot cross the blood brain barrier. TR4 was found to be non- immunogenic following repeat administration in healthy animals. At very high doses (>10x therapeutic dose) it caused anorexia and weight loss in mice. Conclusions: The TR4 protein, a Notch inhibitor, can induce tumor regression and resolution of breast and colon cancer xenografts. It is non- immunogenic following repeat administration and has acceptable toxicity profile. No significant financial relationships to disclose.

scholarly journals RETRACTED: In Vitro Modeling of Blood-Brain Barrier with Human iPSC-Derived Endothelial Cells, Pericytes, Neurons, and Astrocytes via Notch Signaling

2017 ◽  
Vol 8 (3) ◽  
pp. 634-647 ◽  
Author(s):  
Kohei Yamamizu ◽  
Mio Iwasaki ◽  
Hitomi Takakubo ◽  
Takumi Sakamoto ◽  
Takeshi Ikuno ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Notch Signaling ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
In Vitro Modeling ◽  
Blood Brain ◽  
Human Ipsc

scholarly journals The blood-brain barrier studied in vitro across species

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0236770
Author(s):  
Maj Schneider Thomsen ◽  
Nanna Humle ◽  
Eva Hede ◽  
Torben Moos ◽  
Annette Burkhart ◽  
...  
Keyword(s):  
Tight Junction ◽  
Cell Size ◽  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Brain Barrier ◽  
Tight Junction Proteins ◽  
Apparent Permeability ◽  
Blood Brain ◽  
Junction Proteins

The blood-brain barrier (BBB) is formed by brain capillary endothelial cells (BECs) supported by pericytes and astrocytes. The BBB maintains homeostasis and protects the brain against toxic substances circulating in the blood, meaning that only a few drugs can pass the BBB. Thus, for drug screening, understanding cell interactions, and pathology, in vitro BBB models have been developed using BECs from various animal sources. When comparing models of different species, differences exist especially in regards to the transendothelial electrical resistance (TEER). Thus, we compared primary mice, rat, and porcine BECs (mBECs, rBECs, and pBECs) cultured in mono- and co-culture with astrocytes, to identify species-dependent differences that could explain the variations in TEER and aid to the selection of models for future BBB studies. The BBB models based on primary mBECs, rBECs, and pBECs were evaluated and compared in regards to major BBB characteristics. The barrier integrity was evaluated by the expression of tight junction proteins and measurements of TEER and apparent permeability (Papp). Additionally, the cell size, the functionality of the P-glycoprotein (P-gp) efflux transporter, and the expression of the transferrin receptor were evaluated and compared. Expression and organization of tight junction proteins were in all three species influenced by co-culturing, supporting the findings, that TEER increases after co-culturing with astrocytes. All models had functional polarised P-gp efflux transporters and expressed the transferrin receptor. The most interesting discovery was that even though the pBECs had higher TEER than rBECs and mBECs, the Papp did not show the same variation between species, which could be explained by a significantly larger cell size of pBECs. In conclusion, our results imply that the choice of species for a given BBB study should be defined from its purpose, instead of aiming to reach the highest TEER, as the models studied here revealed similar BBB properties.

scholarly journals The blood-brain barrier studied in vitro across species

2020 ◽  
Author(s):  
Maj Schneider Thomsen ◽  
Nanna Humle ◽  
Eva Hede ◽  
Torben Moos ◽  
Annette Burkhart ◽  
...  
Keyword(s):  
Tight Junction ◽  
Cell Size ◽  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Brain Barrier ◽  
Tight Junction Proteins ◽  
Apparent Permeability ◽  
Blood Brain ◽  
Junction Proteins

AbstractThe blood-brain barrier (BBB) is formed by brain capillary endothelial cells (BECs) supported by pericytes and astrocytes. The BBB maintains homeostasis and protects the brain against toxic substances circulating in the blood, which consequently means that only a few drugs can pass the BBB. Thus for drug screening, understanding cell interactions, and pathology, in vitro BBB models have been developed using BECs from various animal sources. When comparing models of different species, differences exist especially in regards to the transendothelial electrical resistance (TEER). Thus, in the present study, we compared primary mice, rat, and porcine BECs (mBECs, rBECs, and pBECs) cultured in mono- and co-culture with astrocytes, to identify potential species-dependent differences that could explain the variations in TEER and aid to the selection of models for future in vitro BBB studies.The in vitro BBB models based on primary mBECs, rBECs, and pBECs were evaluated and compared in regards to major BBB characteristics. The barrier integrity was evaluated by the expression of tight junction proteins and measurements of TEER and apparent permeability (Papp). Furthermore, the cell size, the functionality of the P-glycoprotein (P-gp) efflux transporter, and the expression of the transferrin receptor were evaluated and compared.pBECs exhibit the highest TEER followed by rBECs and mBECs, but surprisingly the Papp was not that different, which might be explained by a significantly larger cell size of pBECs than rBECs and mBECs. The expression and organization of many tight junction proteins were in all three species influenced by co-culturing, which supports the findings that the TEER increases after co-culturing with astrocytes. Furthermore, all models had functional polarised P-gp efflux transporters and expressed the transferrin receptor. In conclusion, the choice of species for in vitro BBB modeling should be based on the purpose of the study.

Conformationally Constrained Peptide Drugs Targeted at the Blood-Brain Barrier

1995 ◽  
Author(s):  
Thomas P. Davis ◽  
Thomas J. Abbruscato ◽  
Elizabeth Brownson ◽  
Victor J. Hruby
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Peptide Drugs ◽  
Conformationally Constrained ◽  
Blood Brain
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