[First published online] 2010-11-22 / 名古屋大学博士学位論文 学位の種類 : 博士(医学)(課程) 学位授与年月日:平成23年3月25日 澤井晶穂氏の博士論文として提出された

Thesis (Ph.D)--Biomedical Engineering, Georgia Institute of Technology, 2008. / Committee Chair: Elliot Chaikof; Committee Member: Marc Levenston; Committee Member: Robert Nerem; Committee Member: Vincent Conticello; Committee Member: Yadong Wang. Part of the SMARTech Electronic Thesis and Dissertation Collection.

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Thesis (Ph. D.)--Mechanical Engineering, Georgia Institute of Technology, 2008. / Committee Chair: Nerem, Robert; Committee Member: Chaikof, Elliot; Committee Member: Taylor, W. Robert; Committee Member: Vito, Raymond; Committee Member: Wight, Thomas.

Thesis (M.S.)--California Polytechnic State University, 2009. / Mode of access: Internet. Title from PDF title page; viewed on September 23, 2009. Major professor: Kristen O'Halloran Cardinal, Ph.D. "Presented to the faculty of the California Polytechnic State University, San Luis Obispo." "In partial fulfillment of the requirements for the degree [of] Master of Science in General Engineering with specialization in Biomedical Engineering." "June 2009." Includes bibliographical references (p. 110-122).

Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2009. / Committee Chair: Wang, Yadong; Committee Member: Dudley, Samuel; Committee Member: Garcia, Andres; Committee Member: McDevitt, Todd; Committee Member: Rosen, David.

Thesis (M. S.)--Mechanical Engineering, Georgia Institute of Technology, 2009. / Committee Chair: Nerem, Robert M.; Committee Member: Gleason, Rudolf L.; Committee Member: Taylor, W. Robert; Committee Member: Vito, Raymond P.; Committee Member: Wang, Yadong.

Thesis (M.S.)--California Polytechnic State University, 2009. / Mode of access: Internet. Title from PDF title page; viewed on November 19, 2009. Major professor: Dr. Kristen O'Halloran Cardinal. "Presented to the faculty of California Polytechnic State University, San Luis Obispo." "In partial fulfillment of the requirements for the degree [of] Master of Science in Biomedical Engineering." "August 2009." Includes bibliographical references (p. 143-158).

Angiogenesis is the process of new blood vessel sprouting from pre-existing vessels and is responsible for generating the majority of nascent vessels during development, tissue regeneration and disease. During angiogenesis, sprouting endothelial cells (ECs) are organised into leading 'tip' cells (TCs) and trailing 'stalk' cells (SCs). This hierarchal organisation of TCs and SCs is essential for the coordinated collective migration of ECs during sprouting. However, the precise mechanisms that define TC verses SC behaviour and identity remains uncertain. Transcriptomic analysis of sprouting vessels in zebrafish embryos led to the identification of a novel TC-associated gene, transmembrane 4 L six family member 1 (tm4sf1). We find that tm4sf1 expression is tightly spatiotemporally restricted to migrating TCs during intersegmental vessel (ISV) sprouting in zebrafish. Furthermore, TC tm4sf1 expression is controlled by the vascular endothelial growth factor receptor (Vegfr) - Notch signalling axis. Morpholino oligonucleotide (MO)-mediated knockdown of tm4sf1 reveals a subtle delay in ISV sprouting upon loss of tm4sf1 expression. Moreover, using multiplexed, real-time imaging approaches and in-depth analysis of TC and SC behaviours at single cell resolution, we reveal that the delay in ISV sprouting is specifically due to reduced TC motility. Furthermore, we find that tm4sf1 functions to induce TC motility in the leading daughter cell following TC mitosis, to rapidly re-establish post-mitotic TC behaviour. Generation of tm4sf1 mutant zebrafish lines using both transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR) confirms that Tm4sf1 modulates TC behaviour. Additionally, mechanistic studies in human ECs reveal that tm4sf1 regulates VEGFR-mediated signalling upon VEGF-stimulation, which subsequently controls cell migration and expression of the TC determinants, DLL4 and VEGFR2. Hence, our results suggest that tm4sf1 is a novel modulator of the TC-SC hierarchy and collective EC migration during ISV sprouting. Overall, these findings have potential therapeutic implications since tm4sf1 may be a promising target for the manipulation of pathological angiogenesis in disease.