Radioresistant intrathymic stem cells: retrospective analysis and concept of the role in thymic oncogenesis and post-irradiation regeneration

Radioresistant thymic cells encompass minor subsets of lymphoid precursors of T cells (TLPs), innate lymphoid cells (ILCs), as well as stromal-epithelial and endothelial populations. This review focuses on radioresistant TLPs and their regenerative and functional roles in thymic regeneration following damaging influences, particularly irradiation, as well as their secretory product, referred to as thymocyte growth factor (THGF). Retrospective analysis of experimental data assumes that THGF-producing and THGF-responsive cells correspond to the earliest stage of thymocyte precursors, double-negative (DN) TLPs, of CD117^-Thy-1⁺Sca-1⁺CD44⁺CD25^-CD4^-CD8^- phenotype, and may be a target for thymic oncogenesis, when they are in the activated DN1→DN2 stage. Unique features of THGF-driven proliferation of these cells include a colchicine-resistant DNA synthesis and, presumably, the formation of a "daughter" cell pool within "mother" cell-like structures, as well as the formation of colony-cluster-like structures, which are presumably composed mainly of single activated mother DN1 and surrounding daughter TLPs progressing from DN2 to DN4 stage. This atypical proliferation mode may represent an evolutionarily conserved mechanism of "defended mitosis" and/or amitotic or endomitotic pathways division, protecting against radiation-induced injury and thus allowing the cell expansion. THGF, which is induced by γ-irradiation and appears essential for autocrine expansion of radioresistant TLPs, initiates a cascade that enables subsequent responsiveness to IL-7, SCF, IL-2, and additional cytokines. The presented analysis proposes the concept of intrathymic dormant stem cells, which become activated under extreme conditions, and insights into parallels between THGF-responsive cells and other radioresistant thymic populations, suggesting an integrated network of stromal and lymphoid elements that orchestrate thymic regeneration. Together, this review proposes a model in which THGF acts as a critical regulator of dormant intrathymic stem cells, enabling their activation, protected proliferation, and differentiation, and thereby contributing crucially to the lymphoid lineage of thymic regeneration after irradiation, in addition to the concept of the IL-22-dependent pathway of stromal-epithelial regeneration of intrathymic niches microenvironment.