Kitlo hematopoietic stem cells exhibit distinct lymphoid-primed chromatin landscapes that enhance thymic reconstitution Journal Article
| Authors: | Elias, H. K.; Mitra, S.; da Silva, M. B.; Rajagopalan, A.; Gipson, B.; Lee, N.; Kousa, A. I.; Ali, M. A. E.; 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. M. |
| Article Title: | Kitlo hematopoietic stem cells exhibit distinct lymphoid-primed chromatin landscapes that enhance thymic reconstitution |
| 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. © The Author(s) 2025. |
| Keywords: | transplantation, homologous; genetics; nonhuman; t lymphocyte; t-lymphocytes; mouse; animal; cytology; metabolism; animals; mice; stem cell factor receptor; proto-oncogene proteins c-kit; bone marrow; animal experiment; protein; hematopoietic stem cell transplantation; mice, inbred c57bl; c57bl mouse; immunology; engraftment; immune response; thymus; thymus gland; chromatin; bone; hematopoietic stem cells; rodent; hematopoietic stem cell; lymphopoiesis; allotransplantation; experimental study; cell; lymphoid cell; infectious disease; article |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-07-04 |
| Start Page: | 6170 |
| Language: | English |
| DOI: | 10.1038/s41467-025-61125-1 |
| PUBMED: | 40615375 |
| PROVIDER: | scopus |
| PMCID: | PMC12227609 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK authors are Harold K. Elias and Michael G. Kharas -- Source: Scopus |
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