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Strategies for Thymic Regeneration: Recent Advances Towards Clinical Therapy

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Synthetic Immunology

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Abstract

The thymus plays a critical role in maintaining immune well-being, but paradoxically undergoes progressive age-related atrophy. Many efforts have been made to deepen our understanding of its biology, with future therapies aimed at re-establishing T cell production in immunocompromised patients. This includes the elderly, and patients undergoing cytoablative treatments or chronically infected with immunotropic viruses. Here we discuss major pre-clinical approaches to thymic regeneration, as a representation of the strategies potentially able to be utilised therapeutically. We outline thymic physiology and development to assist in understanding the rationale behind each regenerative strategy – broadly, reactivation of endogenous thymic epithelial progenitor cells, de novo generation of thymic epithelium, and the facilitating effects on these of bioengineering. Continued advancement in these approaches may lead to their clinical translation for the recovery of immune competence in the aged or immune deficient, and tolerance applications in the developing field of stem cell therapeutics.

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Abbreviations

allo-HSCT:

Allogeneic HSCT

ADE:

Anterior definitive endoderm

Aire:

Autoimmune regulator

Bcl2:

B cell lymphoma 2

biomaterials:

Biomimetic materials

BM:

Bone marrow

BMT:

Bone marrow transplantation

Bmp4:

Bone morphogenetic protein 4

CCL21:

Chemokine (C-C motif) ligand 21

CCR7:

Chemokine (C-C motif) receptor 7

CXCL12:

Chemokine (C-X-C motif) ligand 12

CLP:

Common lymphoid progenitor

cTEC:

Cortical

CMJ:

Cortico-medullary junction

CMJ:

Cortico-medullary junction

K8:

Cytokeratin-8

Dll:

Delta-like ligands

DC:

Dendritic cell

DGCR8:

DiGeorge syndrome chromosomal region 8

DP:

Double positive

(E)11.5:

Embryonic day

ESCs:

Embryonic stem cells

EAE:

Experimental autoimmune encephalomyelitis

ECM:

Extracellular matrix

Fgfr2IIIb:

Fgf receptor 2 variant IIIb

Fgf8:

Fibroblast growth factor 8

Foxn1:

Forkhead box-containing gene n1

Foxa2:

Forkhead-box gene a2

GPCRs:

G protein-coupled receptors

GRL:

Ghrelin

Gcm2:

Glial cell missing homologue 2

GvHD:

Graft versus host disease

GH:

Growth hormone

GHRH:

Growth hormone releasing hormone

HSCT:

Hematopoietic stem cell transplantation

Hox:

Homeobox

HIV:

Human immunodeficiency virus

HIF-1α:

Hypoxia inducible factor-1 alpha

iPSCs:

Induced pluripotent stem cells

iTECs:

Induced TECs

Igf1:

Insulin-like growth factor 1

IFNα:

Interferon alpha

IL-7:

Interleukin-7

Jag:

Jagged

KGF:

Keratinocyte growth factor

KO:

Knock-out

Klf4:

Kruppel-like factor 4

LRCs:

Label retaining cells

LHRH:

Luteinising hormone releasing hormone

LTi:

Lymphoid tissue inducer

MHC:

Major histocompatibility complex

mTEC:

Medullary

ME-ADE-PE:

Mesendoderm to anterior definitive endoderm to pharyngeal endoderm

miRNAs:

MicroRNAs

MEFs:

Mouse embryonic fibroblasts

MTS24:

Mouse thymic stroma 24

mTEChi:

mTECs characterised by high MHCII expression

mTEClo:

mTECs characterised by low MHCII expression

MafB:

Musculoaponeurotic fibrosarcoma oncogene homologue B

MOG:

Myelin oligodendrocyte glycoprotein

NC:

Neural crest

OKSM:

Oct4 Klf4, Sox2 and c-Myc

Oct4:

Octamer-binding transcription factor 4

Pax:

Paired box gene

Eya:

Pax-Eyes absent homologue

Plet-1:

Placenta-expressed transcript-1

PSGL1:

Platelet (P)-selectin glycoprotein ligand 1

Pdgfrα:

Platelet-derived growth factor receptor alpha

PEG:

Polyethylene glycol

ROS:

Reactive oxygen species

RA:

Retinoic acid

RNAi:

RNA interference

Sox2:

Sex determining region Y-box 2

SSA:

Sex steroid ablation

Six:

Sine oculis-related homeobox homologue

SP:

Single positive

SMC:

Smooth muscle cell

SDS:

Sodium dodecyl sulfate

SST:

Somatostatin

Shh:

Sonic hedgehog

Spry:

Sprouty

SCF:

Stem cell factor

SL-TBI:

Sub-lethal total body irradiation

Tbx-1:

T box gene

TCR:

T cell receptors

Treg:

T regulatory

pp3:

Third pharyngeal pouch

3D:

Three-dimensional

TECs:

Thymic epithelial cells

TEPC:

Thymic epithelial progenitor cell

TSC:

Thymic stromal cells

TRAs:

Tissue-restricted self-antigens

TGF-β:

Transforming growth factor-β

TA:

Transit amplifying

TN:

Triple negative

TNF:

Tumour necrosis factor

p63:

Tumour protein 63

UEA-1:

Ulex europaeus agglutinin-1

Vegf:

Vascular-endothelial growth factor

c-Myc:

v-myc avian myelocytomatosis viral oncogene homolog

WT:

Wild-type

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  1. Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia

    Marco Barsanti, Michael Hun, Richard Boyd & Ann Chidgey

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  1. Marco Barsanti
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  2. Michael Hun
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Correspondence to Ann Chidgey .

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  1. Kitano Hospital, Kita-ku, Osaka, Japan

    Takeshi Watanabe

  2. Division of Experimental Immunology, University of Tokushima, Tokushima, Japan

    Yousuke Takahama

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Barsanti, M., Hun, M., Boyd, R., Chidgey, A. (2016). Strategies for Thymic Regeneration: Recent Advances Towards Clinical Therapy. In: Watanabe, T., Takahama, Y. (eds) Synthetic Immunology. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56027-2_3

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