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

Harold K. Elias (), Sneha Mitra, Marina B. Silva, Adhithi Rajagopalan, Brianna Gipson, Nicole Lee, Anastasia I. Kousa, Mohamed A. E. Ali, Simon Grassmann, Rhoshini Raghuraman, Xiaoqun C. Zhang, Susan DeWolf, Melody Smith, Hana Andrlova, Kimon V. Argyropoulos, Roshan Sharma, Teng Fei, Joseph C. Sun, Cynthia E. Dunbar, Christopher Y. Park, Christina S. Leslie, Avinash Bhandoola, Michael G. Kharas () and Marcel R. M. Brink ()
Additional contact information
Harold K. Elias: Memorial Sloan Kettering Cancer Center
Sneha Mitra: Memorial Sloan Kettering Cancer Center
Marina B. Silva: Memorial Sloan Kettering Cancer Center
Adhithi Rajagopalan: Memorial Sloan Kettering Cancer Center
Brianna Gipson: Memorial Sloan Kettering Cancer Center
Nicole Lee: Memorial Sloan Kettering Cancer Center
Anastasia I. Kousa: Memorial Sloan Kettering Cancer Center
Mohamed A. E. Ali: New York University Grossman School of Medicine
Simon Grassmann: Memorial Sloan Kettering Cancer Center
Rhoshini Raghuraman: Memorial Sloan Kettering Cancer Center
Xiaoqun C. Zhang: Memorial Sloan Kettering Cancer Center
Susan DeWolf: Memorial Sloan Kettering Cancer Center
Melody Smith: Stanford University School of Medicine
Hana Andrlova: Memorial Sloan Kettering Cancer Center
Kimon V. Argyropoulos: Memorial Sloan Kettering Cancer Center
Roshan Sharma: Memorial Sloan Kettering Cancer Center
Teng Fei: Memorial Sloan Kettering Cancer Center
Joseph C. Sun: Memorial Sloan Kettering Cancer Center
Cynthia E. Dunbar: NIH
Christopher Y. Park: New York University Grossman School of Medicine
Christina S. Leslie: Memorial Sloan Kettering Cancer Center
Avinash Bhandoola: NIH
Michael G. Kharas: Memorial Sloan Kettering Cancer Center
Marcel R. M. Brink: City of Hope National Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61125-1

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