Abstract
So far, thymus involution in adults is believed to be irreversible, and endogenous innovation for thymus‐related immunodeficiency remains to be an intractable puzzle. With the expectation of addressing this dilemma, human ovarian surface epithelium (OSE) has been reengineered as epithelial‐mesenchymal transition (EMT)‐tridimensional‐spheroid biologics (ETSB) using a dynamic EMT‐3D‐floating system along with 160 Gy X‐ray‐amelioration, which inoculates subcutaneously into aging rhesus and athymic Balb/cnu/nu mice. Herein, it is bioinformatically validated that ETSB can reset Clock/Arntl‐Per3/Tim molecule rhythm dynamics to re‐prime thymus residual (parathyroid or fatty‐like invalid vesicles yet no thymic architecture) to evolutionary transcription with overall cortex‐medulla endogenized by TECs undergoing MET/EMT reversion. Rhythm dynamics immediately resettles the bHLH‐LTβR‐NFκB‐RelA/B loop as a cascade to provoke the core immune microenvironment for multifunctional innovation of dynamic TCR orchestration, with harmonious naïve T‐subsets and TRECs renewals (P < 0.005). Subsequently, peripheral biological burden and tumor metastasis dynamics are addressed by innovative TCR‐defense/attack dynamics quickly (P < 0.005 vs Control), yet without autoimmune indication to hosts. Moreover, a functional blockade of core‐rhythm dynamics deeply impedes the endogenous innovation of invalid thymus residual. Thus this study may help pioneer a prospective strategy to innovate panoramic central‐peripheral immune microenvironments and defense dynamics for immune‐deficient/aging victims.
Highlights
3D-ETSB are derived from human ovarian surface epithelium (OSE) undergoing epithelial-mesenchymal transition (EMT)/MET reversion (Figure 1A)
For the expression patterns of active genes, it is found that ETSB has expressed transcriptional factors and functional genes associated with clock modulation and sequent EMT development, but losing epithelium differentiation (Figure 1F)
Transcriptome waveform distribution illustrates that ETSB/EMT-3D-spheroids have clustered higher expression density over 2D-CB or Control (Figure S1F, Supporting Information, density refers to the ratio of the number of genes under the expression to total number of genes based on whole transcriptome RNAseq)
Summary
With the expectation of addressing this dilemma, human ovarian surface epithelium (OSE) has been reengineered as epithelial-mesenchymal transition (EMT)-tridimensional-spheroid biologics (ETSB) using a dynamic EMT-3D-floating system along with 160 Gy X-ray-amelioration, which inoculates subcutaneously into aging rhesus and athymic Balb/cnu/nu mice. It is status and thymus-related immune dysfunction plays a crucial role responsible for many immune-deficient/aging disorders; where thymus-related tissues/cells transplantation, despite having somewhat of an expectation to correct immune deficiency bioinformatically validated that ETSB can reset Clock/Arntl-Per3/Tim molecule rhythm dynamics to re-prime thymus residual (parathyroid or fatty-like invalid vesicles yet no thymic architecture) to evolutionary transcription with overall cortex-medulla endogenized by TECs undergoing MET/EMT reversion. Thymic involution” results in decreased output and functional capacity of T-cell reservoir, and severely impairs the immune response to newly encountered antigens and increases incident of infection or tumor-dependent morbidity and mortality, making thymic involution a major cause of the age-related immune decline.[8,9] Thymus recession impairs the capacity to recover adaptive immunity following immune depletion in patients.[10,11] investigation to restore thymus function for aging hosts and, especially, the strategies aimed at dead-end thymic rhythm renewal for immune deficient victims, would be beneficial in a wide variety of practical clinical settings
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