Notch hyper-activation drives trans-differentiation of hESC-derived endothelium
During development, endothelial cells (EC) display tissue-specific attributes that are unique to each vascular bed, as well as generic signaling mechanisms that are broadly applied to create a patent circulatory system. We have previously utilized human embryonic stem cells (hESC) to generate tissue...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-09-01
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| Series: | Stem Cell Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1873506116301209 |
| _version_ | 1818369270108651520 |
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| author | David Reichman Limor Man Laura Park Raphael Lis Jeannine Gerhardt Zev Rosenwaks Daylon James |
| author_facet | David Reichman Limor Man Laura Park Raphael Lis Jeannine Gerhardt Zev Rosenwaks Daylon James |
| author_sort | David Reichman |
| collection | DOAJ |
| description | During development, endothelial cells (EC) display tissue-specific attributes that are unique to each vascular bed, as well as generic signaling mechanisms that are broadly applied to create a patent circulatory system. We have previously utilized human embryonic stem cells (hESC) to generate tissue-specific EC sub-types (Rafii et al., 2013) and identify pathways that govern growth and trans-differentiation potential of hESC-derived ECs (James et al., 2010). Here, we elucidate a novel Notch-dependent mechanism that induces endothelial to mesenchymal transition (EndMT) in confluent monolayer cultures of hESC-derived ECs. We demonstrate density-dependent induction of EndMT that can be rescued by the Notch signaling inhibitor DAPT and identify a positive feedback signaling mechanism in hESC-ECs whereby trans-activation of Notch by DLL4 ligand induces elevated expression and surface presentation of DLL4. Increased Notch activation in confluent hESC-EC monolayer cultures induces areas of EndMT containing transitional cells that are marked by increased Jagged1 expression and reduced Notch signal integration. Jagged1 loss of function in monolayer hESC-ECs induces accelerated feedback stimulation of Notch signaling, increased expression of cell-autonomous, cis-inhibitory DLL4, and EndMT. These data elucidate a novel interplay of Notch ligands in modulating pathway activation during both expansion and EndMT of hESC-derived ECs. |
| first_indexed | 2024-12-13T23:21:10Z |
| format | Article |
| id | doaj.art-64bb1fbe3e42417395b4468bbf1fa3da |
| institution | Directory Open Access Journal |
| issn | 1873-5061 1876-7753 |
| language | English |
| last_indexed | 2024-12-13T23:21:10Z |
| publishDate | 2016-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Research |
| spelling | doaj.art-64bb1fbe3e42417395b4468bbf1fa3da2022-12-21T23:27:46ZengElsevierStem Cell Research1873-50611876-77532016-09-0117239140010.1016/j.scr.2016.09.005Notch hyper-activation drives trans-differentiation of hESC-derived endotheliumDavid Reichman0Limor Man1Laura Park2Raphael Lis3Jeannine Gerhardt4Zev Rosenwaks5Daylon James6Center for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10065, United StatesCenter for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10065, United StatesCenter for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10065, United StatesTri-Institutional Stem Cell Derivation Laboratory, Weill Cornell Medical College, New York, NY 10065, United StatesCenter for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10065, United StatesCenter for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10065, United StatesCenter for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10065, United StatesDuring development, endothelial cells (EC) display tissue-specific attributes that are unique to each vascular bed, as well as generic signaling mechanisms that are broadly applied to create a patent circulatory system. We have previously utilized human embryonic stem cells (hESC) to generate tissue-specific EC sub-types (Rafii et al., 2013) and identify pathways that govern growth and trans-differentiation potential of hESC-derived ECs (James et al., 2010). Here, we elucidate a novel Notch-dependent mechanism that induces endothelial to mesenchymal transition (EndMT) in confluent monolayer cultures of hESC-derived ECs. We demonstrate density-dependent induction of EndMT that can be rescued by the Notch signaling inhibitor DAPT and identify a positive feedback signaling mechanism in hESC-ECs whereby trans-activation of Notch by DLL4 ligand induces elevated expression and surface presentation of DLL4. Increased Notch activation in confluent hESC-EC monolayer cultures induces areas of EndMT containing transitional cells that are marked by increased Jagged1 expression and reduced Notch signal integration. Jagged1 loss of function in monolayer hESC-ECs induces accelerated feedback stimulation of Notch signaling, increased expression of cell-autonomous, cis-inhibitory DLL4, and EndMT. These data elucidate a novel interplay of Notch ligands in modulating pathway activation during both expansion and EndMT of hESC-derived ECs.http://www.sciencedirect.com/science/article/pii/S1873506116301209 |
| spellingShingle | David Reichman Limor Man Laura Park Raphael Lis Jeannine Gerhardt Zev Rosenwaks Daylon James Notch hyper-activation drives trans-differentiation of hESC-derived endothelium Stem Cell Research |
| title | Notch hyper-activation drives trans-differentiation of hESC-derived endothelium |
| title_full | Notch hyper-activation drives trans-differentiation of hESC-derived endothelium |
| title_fullStr | Notch hyper-activation drives trans-differentiation of hESC-derived endothelium |
| title_full_unstemmed | Notch hyper-activation drives trans-differentiation of hESC-derived endothelium |
| title_short | Notch hyper-activation drives trans-differentiation of hESC-derived endothelium |
| title_sort | notch hyper activation drives trans differentiation of hesc derived endothelium |
| url | http://www.sciencedirect.com/science/article/pii/S1873506116301209 |
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