PUBLICATION

Zebrafish Regulatory T Cells Mediate Organ-Specific Regenerative Programs

Authors

Hui, S.P., Sheng, D.Z., Sugimoto, K., Gonzalez-Rajal, A., Nakagawa, S., Hesselson, D., Kikuchi, K.

ID

ZDB-PUB-171220-5

Date

2017

Source

Developmental Cell 43: 659-672.e5 (Journal)

Registered Authors

Hesselson, Daniel, Hui, Subhra Prakash, Kikuchi, Kazu, Sheng, Delicia

Keywords

cardiomyocyte, heart, neural stem cell, regeneration, regulatory T cell, retina, spinal cord, zebrafish

MeSH Terms

Animals
Cell Differentiation/physiology
Cell Proliferation/physiology
Forkhead Transcription Factors/physiology
Heart/physiology
Models, Animal
Nerve Regeneration/physiology
Organogenesis/immunology
Organogenesis/physiology
Regeneration/physiology*
Retina/physiology
Spinal Cord/physiology
T-Lymphocytes, Regulatory/physiology*
Zebrafish/physiology*
Zebrafish Proteins/physiology

(all 15)

PubMed

29257949 Full text @ Dev. Cell

Abstract

The attenuation of ancestral pro-regenerative pathways may explain why humans do not efficiently regenerate damaged organs. Vertebrate lineages that exhibit robust regeneration, including the teleost zebrafish, provide insights into the maintenance of adult regenerative capacity. Using established models of spinal cord, heart, and retina regeneration, we discovered that zebrafish T_reg-like (zT_reg) cells rapidly homed to damaged organs. Conditional ablation of zT_reg cells blocked organ regeneration by impairing precursor cell proliferation. In addition to modulating inflammation, infiltrating zT_reg cells stimulated regeneration through interleukin-10-independent secretion of organ-specific regenerative factors (Ntf3: spinal cord; Nrg1: heart; Igf1: retina). Recombinant regeneration factors rescued the regeneration defects associated with zT_reg cell depletion, whereas Foxp3a-deficient zT_reg cells infiltrated damaged organs but failed to express regenerative factors. Our data delineate organ-specific roles for T_reg cells in maintaining pro-regenerative capacity that could potentially be harnessed for diverse regenerative therapies.

Genes / Markers

Marker	Marker Type	Name
actb2	GENE	actin, beta 2
aldh1a2	GENE	aldehyde dehydrogenase 1 family, member A2
areg	GENE	amphiregulin
bcl2a	GENE	BCL2 apoptosis regulator a
bcl2l1	GENE	BCL2 like 1
bcl2l10	GENE	BCL2 like 10
bcl6aa	GENE	BCL6A transcription repressor a
bcl6ab	GENE	BCL6A transcription repressor b
bcl6b	GENE	BCL6B transcription repressor
bdnf	GENE	brain-derived neurotrophic factor

1 - 10 of 72

Show

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
areg	foxp3a^vcc6/vcc6; vcc3Tg/+	cold damage: heart	Adult	regenerating tissue T cell	RTPCR	Fig. 7
areg	foxp3a^vcc6/vcc6; vcc3Tg/+	transection: spinal cord	Adult	regenerating tissue T cell	RTPCR	Fig. 7
areg	foxp3a^vcc6/vcc6; vcc3Tg/+	perforation: retina	Adult	regenerating tissue T cell	RTPCR	Fig. 7
areg	vcc3Tg/+	perforation: retina	Adult	regenerating tissue T cell	RTPCR	Fig. 6
areg	vcc3Tg/+	transection: spinal cord	Adult	regenerating tissue T cell	RTPCR	Fig. 6
areg	vcc3Tg/+	cold damage: heart	Adult	regenerating tissue T cell	RTPCR	Fig. 6
bcl6ab	WT	cold damage: heart	Adult	heart	RTPCR	Fig. 1
bcl6ab	WT	cold damage: heart	Adult	regenerating tissue heart	RTPCR	Fig. 1
bcl6b	WT	transection: spinal cord	Adult	regenerating tissue spinal cord	RTPCR	Fig. 1
bcl6b	WT	transection: spinal cord	Adult	spinal cord	RTPCR	Fig. 1

1 - 10 of 109

Show

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	cold damage: heart	Adult	heart bcl6ab expression increased amount, abnormal	Fig. 1
WT	cold damage: heart	Adult	heart foxp3a expression increased amount, abnormal	Fig. 1
WT	perforation: retina	Adult	retina cd4-1 expression increased amount, abnormal	Fig. 1
WT	perforation: retina	Adult	retina foxp3a expression increased amount, abnormal	Fig. 1
WT	perforation: retina	Adult	retina gata3 expression increased amount, abnormal	Fig. 1
WT	transection: spinal cord	Adult	spinal cord bcl6b expression decreased amount, abnormal	Fig. 1
WT	transection: spinal cord	Adult	spinal cord cd4-1 expression increased amount, abnormal	Fig. 1
WT	transection: spinal cord	Adult	spinal cord foxp3a expression increased amount, abnormal	Fig. 1
WT	transection: spinal cord	Adult	spinal cord foxp3b expression decreased amount, abnormal	Fig. 1
WT	transection: spinal cord	Adult	spinal cord gata3 expression increased amount, abnormal	Fig. 1

1 - 10 of 75

Show

Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
f1Tg	Tg(myl7:GFP)	Transgenic Insertion
mi2001Tg	Tg(gfap:GFP)	Transgenic Insertion
sa1423		Point Mutation	il10
vcc3Tg	TgBAC(foxp3a:TagRFP,cryaa:EGFP)	Transgenic Insertion
vcc4Tg	TgBAC(lck:EGFP)	Transgenic Insertion
vcc5Tg	TgBAC(foxp3a:TagCFP-NTR)	Transgenic Insertion
vcc6		Small Deletion	foxp3a
vcc10Tg	TgBAC(foxp3a:EGFP)	Transgenic Insertion
vcc11Tg	TgBAC(lck:TagRFP)	Transgenic Insertion

1 - 9 of 9

Show

Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
foxp3a^vcc6/vcc6
foxp3a^vcc6/vcc6; mi2001Tg/+
foxp3a^vcc6/vcc6; vcc3Tg/+
mi2001Tg/+; vcc3Tg/+
mi2001Tg/+; vcc5Tg/+
vcc3Tg/+
vcc5Tg/+
vcc10Tg/+
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
TagCFP	EFG	TagCFP
EGFP	EFG	EGFP
GFP	EFG	GFP
NTR	EFG	NTR
TagRFP	EFG	TagRFP

Mapping

Hui et al., 2017 ZDB-PUB-171220-5 PMID:29257949

Zebrafish Regulatory T Cells Mediate Organ-Specific Regenerative Programs

Hui et al., 2017

ZDB-PUB-171220-5
PMID:29257949