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Kitlo hematopoietic stem cells exhibit distinct lymphoid-primed chromatin landscapes that enhance thymic reconstitution.

Kitlo hematopoietic stem cells exhibit distinct lymphoid-primed chromatin landscapes that enhance thymic reconstitution. Nature communications Elias, H. K., Mitra, S., da Silva, M. B., Rajagopalan, A., Gipson, B., Lee, N., Kousa, A. I., Ali, M. A., Grassmann, S., Raghuraman, R., Zhang, X. C., DeWolf, S., Smith, M., Andrlova, H., Argyropoulos, K. V., Sharma, R., Fei, T., Sun, J. C., Dunbar, C. E., Park, C. Y., Leslie, C. S., Bhandoola, A., Kharas, M. G., van den Brink, M. R. 2025; 16 (1): 6170

Abstract

Hematopoietic stem cells (HSC) with multilineage potential are critical for T cell reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). The Kitlo HSC subset is enriched for multipotential precursors, but their T cell potential remains poorly characterized. Using a preclinical allo-HCT mouse model, we demonstrate that Kitlo HSCs provide superior thymic recovery and T cell reconstitution, resulting in improved immune responses to post-transplant infection. Kitlo HSCs with augmented bone marrow (BM) lymphopoiesis mitigate age-associated thymic alterations and enhance T cell recovery in middle-aged mice. Mechanistically, chromatin profiling reveals Kitlo HSCs exhibiting higher activity of lymphoid-specifying transcription factors, such as, ZBTB1. Zbtb1 deletion diminishes HSC engraftment and T cell potential; by contrast, reinstating Zbtb1 in megakaryocytic-biased Kithi HSCs rescues hematopoietic engraftment and T cell potential in vitro and in vivo. Furthermore, age-associated decline in Kitlo HSCs is associated with diminished T lymphopoietic potential in aged BM precursors; meanwhile, Kitlo HSCs in aged mice maintain enhanced lymphoid potential, but their per-cell capacity is diminished. Lastly, we observe an analogous human BM KITlo HSC subset with enhanced lymphoid potential. Our results thus uncover an age-related epigenetic regulation of lymphoid-competent Kitlo HSCs for T cell reconstitution.

View details for DOI 10.1038/s41467-025-61125-1

View details for PubMedID 40615375