HSPCs and T_reg cells cooperate to preserve extramedullary hematopoiesis under chronic inflammation

Hematopoietic stem and progenitor cells (HSPCs) are localized within specialized niches of the bone marrow (BM). However, during hematological disorders or infections, the functionality of these cells in the BM is compromised, leading to extramedullary hematopoiesis (EMH). Chronic inflammation drives EMH, yet its impact on HSPCs outside the BM is poorly understood. Using a mouse model of chronic autoinflammatory disease, we demonstrated the presence of extramedullary HSPCs in blood, spleen, and inflamed tails and paws. Single-cell transcriptomics revealed a unique expression profile in extramedullary HSCs, with significant up-regulation of Cd53, MHCII-associated, and immunosuppressive genes. We further demonstrated that extramedullary CD53⁺ HSPCs act as antigen-presenting cells, promoting the development of regulatory T cells (T_reg cells) to control chronic inflammation at extramedullary sites. Conversely, T_reg cells exert a protective role on extramedullary HSPCs. Together, our findings revealed a mutually supportive relationship between a unique subset of HSPCs and T cells in inflamed tissues during chronic inflammation.