Endothelial-specific depletion of TGF-β signaling affects lymphatic function

Abstract Background Transforming growth factor (TGF)-β is a multifunctional cytokine involved in cell differentiation, cell proliferation, and tissue homeostasis. Although TGF-β signaling is essential for maintaining blood vessel functions, little is known about the role of TGF-β in lymphatic homeos...

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Autores principales:	Kunpei Fukasawa, Kako Hanada, Kei Ichikawa, Masanori Hirashima, Takahiro Takagi, Susumu Itoh, Testuro Watabe, Fumiko Itoh
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	TGF-β Lymphatic vessel Endothelial cell Prox1 Tumor metastasis Pathology RB1-214
Acceso en línea:	https://doaj.org/article/f1dce799d34944ca932abddf07f07cd3
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spelling	oai:doaj.org-article:f1dce799d34944ca932abddf07f07cd32021-12-05T12:18:54ZEndothelial-specific depletion of TGF-β signaling affects lymphatic function10.1186/s41232-021-00185-41880-8190https://doaj.org/article/f1dce799d34944ca932abddf07f07cd32021-12-01T00:00:00Zhttps://doi.org/10.1186/s41232-021-00185-4https://doaj.org/toc/1880-8190Abstract Background Transforming growth factor (TGF)-β is a multifunctional cytokine involved in cell differentiation, cell proliferation, and tissue homeostasis. Although TGF-β signaling is essential for maintaining blood vessel functions, little is known about the role of TGF-β in lymphatic homeostasis. Methods To delineate the role of TGF-β signaling in lymphatic vessels, TβRIIfl/fl mice were crossed with Prox1-CreERT2 mice to generate TβRIIfl/fl; Prox1-CreERT2 mice. The TβRII gene in the lymphatic endothelial cells (LECs) of the conditional knockout TβRIIiΔLEC mice was selectively deleted using tamoxifen. The effects of TβRII gene deletion on embryonic lymphangiogenesis, postnatal lymphatic structure and drainage function, tumor lymphangiogenesis, and lymphatic tumor metastasis were investigated. Results Deficiency of LEC-specific TGF-β signaling in embryos, where lymphangiogenesis is active, caused dorsal edema with dilated lymphatic vessels at E13.5. Postnatal mice in which lymphatic vessels had already been formed displayed dilation and increased bifurcator of lymphatic vessels after tamoxifen administration. Similar dilation was also observed in tumor lymphatic vessels. The drainage of FITC-dextran, which was subcutaneously injected into the soles of the feet of the mice, was reduced in TβRIIiΔLEC mice. Furthermore, Lewis lung carcinoma cells constitutively expressing GFP (LLC-GFP) transplanted into the footpads of the mice showed reduced patellar lymph node metastasis. Conclusion These data suggest that TGF-β signaling in LECs maintains the structure of lymphatic vessels and lymphatic homeostasis, in addition to promoting tumor lymphatic metastasis. Therefore, suppression of TGF-β signaling in LECs might be effective in inhibiting cancer metastasis.Kunpei FukasawaKako HanadaKei IchikawaMasanori HirashimaTakahiro TakagiSusumu ItohTesturo WatabeFumiko ItohBMCarticleTGF-βLymphatic vesselEndothelial cellProx1Tumor metastasisPathologyRB1-214ENInflammation and Regeneration, Vol 41, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TGF-β Lymphatic vessel Endothelial cell Prox1 Tumor metastasis Pathology RB1-214
spellingShingle	TGF-β Lymphatic vessel Endothelial cell Prox1 Tumor metastasis Pathology RB1-214 Kunpei Fukasawa Kako Hanada Kei Ichikawa Masanori Hirashima Takahiro Takagi Susumu Itoh Testuro Watabe Fumiko Itoh Endothelial-specific depletion of TGF-β signaling affects lymphatic function
description	Abstract Background Transforming growth factor (TGF)-β is a multifunctional cytokine involved in cell differentiation, cell proliferation, and tissue homeostasis. Although TGF-β signaling is essential for maintaining blood vessel functions, little is known about the role of TGF-β in lymphatic homeostasis. Methods To delineate the role of TGF-β signaling in lymphatic vessels, TβRIIfl/fl mice were crossed with Prox1-CreERT2 mice to generate TβRIIfl/fl; Prox1-CreERT2 mice. The TβRII gene in the lymphatic endothelial cells (LECs) of the conditional knockout TβRIIiΔLEC mice was selectively deleted using tamoxifen. The effects of TβRII gene deletion on embryonic lymphangiogenesis, postnatal lymphatic structure and drainage function, tumor lymphangiogenesis, and lymphatic tumor metastasis were investigated. Results Deficiency of LEC-specific TGF-β signaling in embryos, where lymphangiogenesis is active, caused dorsal edema with dilated lymphatic vessels at E13.5. Postnatal mice in which lymphatic vessels had already been formed displayed dilation and increased bifurcator of lymphatic vessels after tamoxifen administration. Similar dilation was also observed in tumor lymphatic vessels. The drainage of FITC-dextran, which was subcutaneously injected into the soles of the feet of the mice, was reduced in TβRIIiΔLEC mice. Furthermore, Lewis lung carcinoma cells constitutively expressing GFP (LLC-GFP) transplanted into the footpads of the mice showed reduced patellar lymph node metastasis. Conclusion These data suggest that TGF-β signaling in LECs maintains the structure of lymphatic vessels and lymphatic homeostasis, in addition to promoting tumor lymphatic metastasis. Therefore, suppression of TGF-β signaling in LECs might be effective in inhibiting cancer metastasis.
format	article
author	Kunpei Fukasawa Kako Hanada Kei Ichikawa Masanori Hirashima Takahiro Takagi Susumu Itoh Testuro Watabe Fumiko Itoh
author_facet	Kunpei Fukasawa Kako Hanada Kei Ichikawa Masanori Hirashima Takahiro Takagi Susumu Itoh Testuro Watabe Fumiko Itoh
author_sort	Kunpei Fukasawa
title	Endothelial-specific depletion of TGF-β signaling affects lymphatic function
title_short	Endothelial-specific depletion of TGF-β signaling affects lymphatic function
title_full	Endothelial-specific depletion of TGF-β signaling affects lymphatic function
title_fullStr	Endothelial-specific depletion of TGF-β signaling affects lymphatic function
title_full_unstemmed	Endothelial-specific depletion of TGF-β signaling affects lymphatic function
title_sort	endothelial-specific depletion of tgf-β signaling affects lymphatic function
publisher	BMC
publishDate	2021
url	https://doaj.org/article/f1dce799d34944ca932abddf07f07cd3
work_keys_str_mv	AT kunpeifukasawa endothelialspecificdepletionoftgfbsignalingaffectslymphaticfunction AT kakohanada endothelialspecificdepletionoftgfbsignalingaffectslymphaticfunction AT keiichikawa endothelialspecificdepletionoftgfbsignalingaffectslymphaticfunction AT masanorihirashima endothelialspecificdepletionoftgfbsignalingaffectslymphaticfunction AT takahirotakagi endothelialspecificdepletionoftgfbsignalingaffectslymphaticfunction AT susumuitoh endothelialspecificdepletionoftgfbsignalingaffectslymphaticfunction AT testurowatabe endothelialspecificdepletionoftgfbsignalingaffectslymphaticfunction AT fumikoitoh endothelialspecificdepletionoftgfbsignalingaffectslymphaticfunction
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Endothelial-specific depletion of TGF-β signaling affects lymphatic function

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