Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.

Vascular abnormalities contribute to many diseases such as cancer and diabetic retinopathy. In angiogenesis new blood vessels, headed by a migrating tip cell, sprout from pre-existing vessels in response to signals, e.g., vascular endothelial growth factor (VEGF). Tip cells meet and fuse (anastomosi...

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Autores principales:	Katie Bentley, Giovanni Mariggi, Holger Gerhardt, Paul A Bates
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/37fb55b7fb9c437a91a2d39d5ef78b8d
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spelling	oai:doaj.org-article:37fb55b7fb9c437a91a2d39d5ef78b8d2021-11-25T05:42:52ZTipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.1553-734X1553-735810.1371/journal.pcbi.1000549https://doaj.org/article/37fb55b7fb9c437a91a2d39d5ef78b8d2009-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19876379/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Vascular abnormalities contribute to many diseases such as cancer and diabetic retinopathy. In angiogenesis new blood vessels, headed by a migrating tip cell, sprout from pre-existing vessels in response to signals, e.g., vascular endothelial growth factor (VEGF). Tip cells meet and fuse (anastomosis) to form blood-flow supporting loops. Tip cell selection is achieved by Dll4-Notch mediated lateral inhibition resulting, under normal conditions, in an interleaved arrangement of tip and non-migrating stalk cells. Previously, we showed that the increased VEGF levels found in many diseases can cause the delayed negative feedback of lateral inhibition to produce abnormal oscillations of tip/stalk cell fates. Here we describe the development and implementation of a novel physics-based hierarchical agent model, tightly coupled to in vivo data, to explore the system dynamics as perpetual lateral inhibition combines with tip cell migration and fusion. We explore the tipping point between normal and abnormal sprouting as VEGF increases. A novel filopodia-adhesion driven migration mechanism is presented and validated against in vivo data. Due to the unique feature of ongoing lateral inhibition, 'stabilised' tip/stalk cell patterns show sensitivity to the formation of new cell-cell junctions during fusion: we predict cell fates can reverse. The fusing tip cells become inhibited and neighbouring stalk cells flip fate, recursively providing new tip cells. Junction size emerges as a key factor in establishing a stable tip/stalk pattern. Cell-cell junctions elongate as tip cells migrate, which is shown to provide positive feedback to lateral inhibition, causing it to be more susceptible to pathological oscillations. Importantly, down-regulation of the migratory pathway alone is shown to be sufficient to rescue the sprouting system from oscillation and restore stability. Thus we suggest the use of migration inhibitors as therapeutic agents for vascular normalisation in cancer.Katie BentleyGiovanni MariggiHolger GerhardtHolger GerhardtPaul A BatesPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 5, Iss 10, p e1000549 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Katie Bentley Giovanni Mariggi Holger Gerhardt Holger Gerhardt Paul A Bates Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.
description	Vascular abnormalities contribute to many diseases such as cancer and diabetic retinopathy. In angiogenesis new blood vessels, headed by a migrating tip cell, sprout from pre-existing vessels in response to signals, e.g., vascular endothelial growth factor (VEGF). Tip cells meet and fuse (anastomosis) to form blood-flow supporting loops. Tip cell selection is achieved by Dll4-Notch mediated lateral inhibition resulting, under normal conditions, in an interleaved arrangement of tip and non-migrating stalk cells. Previously, we showed that the increased VEGF levels found in many diseases can cause the delayed negative feedback of lateral inhibition to produce abnormal oscillations of tip/stalk cell fates. Here we describe the development and implementation of a novel physics-based hierarchical agent model, tightly coupled to in vivo data, to explore the system dynamics as perpetual lateral inhibition combines with tip cell migration and fusion. We explore the tipping point between normal and abnormal sprouting as VEGF increases. A novel filopodia-adhesion driven migration mechanism is presented and validated against in vivo data. Due to the unique feature of ongoing lateral inhibition, 'stabilised' tip/stalk cell patterns show sensitivity to the formation of new cell-cell junctions during fusion: we predict cell fates can reverse. The fusing tip cells become inhibited and neighbouring stalk cells flip fate, recursively providing new tip cells. Junction size emerges as a key factor in establishing a stable tip/stalk pattern. Cell-cell junctions elongate as tip cells migrate, which is shown to provide positive feedback to lateral inhibition, causing it to be more susceptible to pathological oscillations. Importantly, down-regulation of the migratory pathway alone is shown to be sufficient to rescue the sprouting system from oscillation and restore stability. Thus we suggest the use of migration inhibitors as therapeutic agents for vascular normalisation in cancer.
format	article
author	Katie Bentley Giovanni Mariggi Holger Gerhardt Holger Gerhardt Paul A Bates
author_facet	Katie Bentley Giovanni Mariggi Holger Gerhardt Holger Gerhardt Paul A Bates
author_sort	Katie Bentley
title	Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.
title_short	Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.
title_full	Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.
title_fullStr	Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.
title_full_unstemmed	Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.
title_sort	tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/37fb55b7fb9c437a91a2d39d5ef78b8d
work_keys_str_mv	AT katiebentley tippingthebalancerobustnessoftipcellselectionmigrationandfusioninangiogenesis AT giovannimariggi tippingthebalancerobustnessoftipcellselectionmigrationandfusioninangiogenesis AT holgergerhardt tippingthebalancerobustnessoftipcellselectionmigrationandfusioninangiogenesis AT holgergerhardt tippingthebalancerobustnessoftipcellselectionmigrationandfusioninangiogenesis AT paulabates tippingthebalancerobustnessoftipcellselectionmigrationandfusioninangiogenesis
_version_	1718414452334788608

Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.

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