02573nas a2200337   4500000000100000000000100001008004100002260001500043653001100058653002200069653003100091653002700122653001400149100001800163700001600181700001300197700001400210700001500224700001300239700001400252700001300266700001200279700001700291700001400308700001500322245010800337856009300445490000700538520167600545022001402221       2024                            d  c2024-01-2210aIGFBP510aThymus involution10asingle-cell RNA sequencing10athymic epithelial cell10athymocyte1 aXiaojing Yang1 aXichan Chen1 aWei Wang1 aSiming Qu1 aBinbin Lai1 aJi Zhang1 aJian Chen1 aChao Han1 aYi Tian1 aYingbin Xiao1 aWeiwu Gao1 aYuzhang Wu00aTranscriptional profile of human thymus reveals IGFBP5 is correlated with age-related thymic involution  uhttps://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1322214/full0 v153 a<p>Thymus is the main immune organ which is responsible for the production of self-tolerant and functional T cells, but it shrinks rapidly with age after birth. Although studies have researched thymus development and involution in mouse, the critical regulators that arise with age in human thymus remain unclear. We collected public human single-cell transcriptomic sequencing (scRNA-seq) datasets containing 350,678 cells from 36 samples, integrated them as a cell atlas of human thymus. Clinical samples were collected and experiments were performed for validation. We found early thymocyte-specific signaling and regulons which played roles in thymocyte migration, proliferation, apoptosis and differentiation. Nevertheless, signaling patterns including number, strength and path completely changed during aging, Transcription factors (FOXC1, MXI1, KLF9, NFIL3) and their target gene, IGFBP5, were resolved and up-regulated in aging thymus and involved in promoting epithelial-mesenchymal transition (EMT), responding to steroid and adipogenesis process of thymic epithelial cell (TECs). Furthermore, we validated that IGFBP5 protein increased at TECs and Hassall’s corpuscle in both human and mouse aging thymus and knockdown of IGFBP5 significantly increased the expression of proliferation-related genes in thymocytes. Collectively, we systematically explored cell-cell communications and regulons of early thymocytes as well as age-related differences in human thymus by using both bioinformatic and experimental verification, indicating IGFBP5 as a functional marker of thymic involution and providing new insights into the mechanisms of thymus involution.</p>  a1664-3224