A previously under-recognized role of CXCL12 in endogenous thymic regeneration

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Presentation Time: 10:45 AM - 11:00 AM
Abstract ID: 4796 - B

Presenting Author:
Maria K Lagou , Postdoctoral Research Fellow at Albert Einstein Col. of Med.

Abstract:

The thymus is a primary lymphoid organ for T cell development. Sensitive to stress, it undergoes acute involution in response to cytotoxic stimuli, e.g., cytoablative chemotherapy. Thus, establishing regeneration strategies to restore thymic function is vital for pediatric cancer and transplantation patients receiving such treatments. However, lack of insight for detailed mechanisms of thymic repair has impeded progress towards supporting thymic function in these patients. We developed a mouse model of cyclophosphamide-induced thymic involution, with detailed regeneration kinetics at cell population (flow cytometry) and microanatomical (digital pathology) levels. We found consistent defects of early thymocyte progenitor (ETP) seeding and trafficking during endogenous thymic repair. Single cell ATACseq analysis revealed perturbations in chromatin accessibility of the thymocyte-homing chemokine CXCL12 in various stromal cell subsets, including early developmental stages of cortical thymic epithelial cells (cTEC^lo) and endothelial cells, suggesting structural adaptations to accommodate ETP trafficking during thymic repair. We currently employ CXCL12 conditional ablation in cTEC^lo and pharmacological suppression using specific CXCR4 antagonists, to highlight the unreported role of CXCL12/CXCR4 axis in endogenous thymic repair. Together, our efforts shed novel mechanistic insights on the structural and functional adaptations of thymic stromal cells after cytotoxic chemotherapy.