PUBLICATION

Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration

Authors

Gancz, D., Raftrey, B.C., Perlmoter, G., Marín-Juez, R., Semo, J., Matsuoka, R.L., Karra, R., Raviv, H., Moshe, N., Addadi, Y., Golani, O., Poss, K.D., Red-Horse, K., Stainier, D.Y., Yaniv, K.

ID

ZDB-PUB-191110-11

Date

2019

Source

eLIFE 8: (Journal)

Registered Authors

Karra, Ravi, Marín-Juez, Rubén, Matsuoka, Ryota, Poss, Kenneth D., Semo, Jonathan, Stainier, Didier, Yaniv, Karina

Keywords

developmental biology, mouse, regenerative medicine, stem cells, zebrafish

MeSH Terms

Animals
Animals, Genetically Modified
Heart/embryology
Heart/growth & development
Heart/physiology*
Lymphangiogenesis/genetics
Lymphangiogenesis/physiology*
Lymphatic System/cytology
Lymphatic System/metabolism
Lymphatic System/physiology
Lymphatic Vessels/metabolism
Lymphatic Vessels/physiology*
Mice, Knockout
Mice, Transgenic
Mutation
Myocardial Infarction/physiopathology
Myocardium/metabolism*
Regeneration/genetics
Regeneration/physiology*
Signal Transduction/genetics
Signal Transduction/physiology*
Zebrafish

(all 22)

PubMed

31702554 Full text @ Elife

Abstract

In recent years there has been increasing interest in the role of lymphatics in organ repair and regeneration, due to their importance in immune surveillance and fluid homeostasis. Experimental approaches aimed at boosting lymphangiogenesis following myocardial infarction in mice, were shown to promote healing of the heart. Yet, the mechanisms governing cardiac lymphatic growth remain unclear. Here we identify two distinct lymphatic populations in the hearts of zebrafish and mouse, one that forms through sprouting lymphangiogenesis, and the other by coalescence of isolated lymphatic cells. By tracing the development of each subset, we reveal diverse cellular origins and differential response to signaling cues. Finally, we show that lymphatic vessels are required for cardiac regeneration in zebrafish as mutants lacking lymphatics display severely impaired regeneration capabilities. Overall, our results provide novel insight into the mechanisms underlying lymphatic formation during development and regeneration, opening new avenues for interventions targeting specific lymphatic populations.

Genes / Markers

Marker	Marker Type	Name
cxcl12a	GENE	chemokine (C-X-C motif) ligand 12a (stromal cell-derived factor 1)
cxcl12b	GENE	chemokine (C-X-C motif) ligand 12b (stromal cell-derived factor 1)
cxcr4a	GENE	chemokine (C-X-C motif) receptor 4a
flt4	GENE	fms related receptor tyrosine kinase 4
vegfaa	GENE	vascular endothelial growth factor Aa
vegfc	GENE	vascular endothelial growth factor c
vegfd	GENE	vascular endothelial growth factor D

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Figures

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Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
Citrine	hu7135Tg; nim5Tg	standard conditions	Adult		bulbus arteriosus heart lymph vessel	IFL	Figure 1
Citrine	hu7135Tg; nim5Tg	standard conditions	Adult		cardiac lymphatic endothelial cluster	IFL	Figure 1
DsRed	nz101Tg; y251Tg	standard conditions	Adult	Not Detected	heart blood vessel	IFL	Figure 1
DsRed	nz101Tg; y251Tg	standard conditions	Adult		heart lymph vessel	IFL	Figure 1
EGFP	nz101Tg; y251Tg	standard conditions	Adult		cardiac lymphatic endothelial cluster	IFL	Figure 1
GFP	nim5Tg; t007Tg	standard conditions	Days 45-89		heart lymph vessel endothelial tip cell	IFL	Figure 1
TagBFP	hu7135Tg; nim5Tg	standard conditions	Adult		bulbus arteriosus heart lymph vessel	IFL	Figure 1
TagBFP	hu7135Tg; nim5Tg	standard conditions	Adult		cardiac lymphatic endothelial cluster	IFL	Figure 1
TagBFP	hu7135Tg; nim5Tg	standard conditions	Adult		heart lymph vessel	IFL	Figure 1
TagRFP	nim5Tg; t007Tg	standard conditions	Days 45-89		bulbus arteriosus heart lymph vessel	IFL	Figure 1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
cxcl12b^mu100/mu100; nz101Tg	standard conditions	Adult	bulbus arteriosus lymph vessel spatial pattern, normal	Figure 2
cxcr4a^um20/um20; nz101Tg	standard conditions	Adult	bulbus arteriosus lymph vessel spatial pattern, abnormal	Figure 2
cxcr4a^um20/um20; nz101Tg	standard conditions	Adult	bulbus arteriosus lymphangiogenic sprout decreased amount, abnormal	Figure 2
cxcr4a^um20/um20; nz101Tg	standard conditions	Adult	bulbus arteriosus lymphangiogenic sprout variability of count, abnormal	Figure 2
cxcr4a^um20/um20; nz101Tg; wz2Tg	standard conditions	Adult	cardiac lymphatic endothelial cluster normal amount, normal	Figure 4
cxcr4a^um20/um20; nz101Tg; wz2Tg	standard conditions	Adult	cardiac ventricle lymph vessel absent, abnormal	Figure 3
cxcr4a^um20/um20; nz101Tg; wz2Tg	standard conditions	Adult	cardiac ventricle lymph vessel agenesis, abnormal	Figure 3
cxcr4a^um20/um20; nz101Tg; wz2Tg	cryoablation: cardiac ventricle	Adult	cardiac ventricle has extra parts of type regenerating tissue Collagen, abnormal	Figure 7
cxcr4a^um20/um20; nz101Tg; wz2Tg	cryoablation: cardiac ventricle	Adult	cardiac ventricle regenerating tissue has extra parts of type cardiac ventricle lymph vessel, abnormal	Figure 7
flt4^um203/um203; nz101Tg	standard conditions	Days 21-29	medial facial lymph vessel decreased length, abnormal	Figure 2 supplement 2.

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
bns257		Insertion	vegfd
hu7135Tg	TgBAC(flt4:Citrine)	Transgenic Insertion
mu100		Indel	cxcl12b
nim5Tg	TgBAC(prox1a:KALTA4,4xUAS-E1B:TagRFP)	Transgenic Insertion
nz101Tg	Tg(-5.2lyve1b:DsRed)	Transgenic Insertion
pd262Tg	Tg(actb2:LOXP-TagBFP-LOXP-vegfaa)	Transgenic Insertion
s843Tg	Tg(kdrl:EGFP)	Transgenic Insertion
sd2Tg	Tg(gata1a:DsRed)	Transgenic Insertion
t007Tg	Tg(sox10:Cre-ERT2,myl7:GFP)	Transgenic Insertion
um18		Point Mutation	vegfc

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
myocardial infarction	flt4^um203/um203; nz101Tg; y1Tg	cryoablation: cardiac ventricle	TAS
myocardial infarction	vegfc^um18/+; nz101Tg; y1Tg	cryoablation: cardiac ventricle	TAS

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Sequence Targeting Reagents

Target	Reagent	Reagent Type
vegfd	CRISPR1-vegfd	CRISPR

Fish

Fish
cxcl12b^mu100/mu100; nz101Tg
cxcl12b^mu100/mu100; nz101Tg; wz2Tg
cxcr4a^um20; nz101Tg; wz2Tg
cxcr4a^um20/um20; nz101Tg
cxcr4a^um20/um20; nz101Tg; wz2Tg
flt4^um203/um203; nz101Tg
flt4^um203/um203; nz101Tg; wz2Tg
flt4^um203/um203; nz101Tg; y1Tg
hu7135Tg; nim5Tg
nim5Tg; t007Tg

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Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-lyve1	monoclonal		IgG1	Rat
Ab2-erg	monoclonal		IgG	Rabbit
Ab4-prox1	polyclonal	prox1a	IgG	Goat
Ab7-cdh5	monoclonal		IgG2a	Rat
Ab10-prox1	polyclonal		IgG	Rabbit

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Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
Citrine	EFG	Citrine
Cre	EFG	Cre
DsRed	EFG	DsRed
EGFP	EFG	EGFP
GFP	EFG	GFP
KALTA4	EFG	KALTA4
mCherry	EFG	mCherry
TagBFP	EFG	TagBFP
TagRFP	EFG	TagRFP

Mapping

Gancz et al., 2019 ZDB-PUB-191110-11 PMID:31702554

Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration

Gancz et al., 2019

ZDB-PUB-191110-11
PMID:31702554