Recent Advancements in Regenerative Approaches for Thymus Rejuvenation

Abstract

The thymus plays a key role in adaptive immunity by generating a diverse population of T cells that defend the body against pathogens. Various factors from disease and toxic insults contribute to the degeneration of the thymus resulting in a fewer output of T cells. Consequently, the body is prone to a wide host of diseases and infections. In this review, first, the relevance of the thymus is discussed, followed by thymic embryological organogenesis and anatomy as well as the development and functionality of T cells. Attempts to regenerate the thymus include in vitro methods, such as forming thymic organoids aided by biofabrication techniques that are transplantable. Ex vivo methods that have shown promise in enhancing thymic regeneration are also discussed. Current regenerative technologies have not yet matched the complexity and functionality of the thymus. Therefore, emerging techniques that have shown promise and the challenges that lie ahead are explored.

Key Factors for Thymic Function and Development

“…Considering these restrictions, combining different approaches instead of a single may better unlock the thymic regenerative potential and be more suitable for translating to the clinic. More detailed analyses of current thymic regenerative strategies are provided in the recent reviews ( 15 , 177 , 178 ).…”

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“…In TECs proliferation and immunophenotype differentiation, several transcription factors and signaling pathways are involved, many produced by the fetal mesenchymal cells, during the thymus development process: the forkhead family transcription factor [forkhead box N1 (FOXN1)], the earliest involved and the master regulator of TECs, the sonic hedgehog (Shh), the fibroblast growth factor (FGF) [61,63], the bone morphogenetic protein (BMP), the Wnt (combined name from wingless and Int-1), that mediates the expression of FOXN1 and intervenes in T-cell development; the Wnt/β-catenin, which fine tuning is critical for embryonic organogenesis and which establish different TECs subpopulations [64,65]. Some other transcriptional regulatory pathways of thymus and TECs development involve factors, such as paired box (PAX) 1 and PAX9, HOXA3 homeobox protein, and T-box transcription factor 1 (TBX1), but many more studies are needed to completely elucidate how these factors can be employed to restore or boost the thymic function [66].…”

“…The dynamic of epithelial progenitors in the thymus cortex is controlled by permanent interactions with developing thymocytes [67]. Different expressions for markers of the TECs progenitor cells were identified, such as CD24 and stem cells antigen-1 (Sca-1) (stem cell markers), CD205, 𝛽5T proteasome subunit, and IL7YFP [63,67,68]. There are rare identical subsets of progenitors for two types of TECs, such as placenta-expressed transcript 1 (PLET1)(+) Ly-51(+) [progenitor able to generate cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs)] and CD45(-) epithelial cell adhesion molecule (EpCAM)(+) (proved to be capable of selfrenewal) [63].…”

“…Different expressions for markers of the TECs progenitor cells were identified, such as CD24 and stem cells antigen-1 (Sca-1) (stem cell markers), CD205, 𝛽5T proteasome subunit, and IL7YFP [63,67,68]. There are rare identical subsets of progenitors for two types of TECs, such as placenta-expressed transcript 1 (PLET1)(+) Ly-51(+) [progenitor able to generate cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs)] and CD45(-) epithelial cell adhesion molecule (EpCAM)(+) (proved to be capable of selfrenewal) [63]. Also, unipotent progenitors for cTECs [expressing EpCAM(+) CD205(+) and CD40(-)] and mTECs (expressing claudin-3 and -4) were described [63].…”

Editorial: Thymus function and aging: A focus on thymic epithelial cells

“…In this Research Topic are collected the efforts of many research groups in trying to overcome the thymus aging/injury problem by applying different regenerative or thymus replacement strategies. The basis of these is the epithelial compartment, in particular, the thymic epithelial stem cells (TESCs) as the target cells to stimulate thymus recovery in vivo or for growing thymus-replacing organoids in vitro ( 3 , 4 ). Several research groups have described TESCs in the embryonal ( 5 ) and adult ( 6 – 8 ) mouse thymus, which were identified as the bipotent TEC progenitors differentiating into cortical (c) and medullary (m) TEC lineages ( 5 – 8 ).…”