Scholarlink

<p>Hematopoietic stem cells (HSC) with multilineage potential are critical for T cell reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). The Kit<sup>lo</sup> 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 Kit<sup>lo</sup> HSCs provide superior thymic recovery and T cell reconstitution, resulting in improved immune responses to post-transplant infection. Kit<sup>lo</sup> 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 Kit<sup>lo</sup> HSCs exhibiting higher activity of lymphoid-specifying transcription factors, such as, ZBTB1. <i>Zbtb1</i> deletion diminishes HSC engraftment and T cell potential; by contrast, reinstating <i>Zbtb1</i> in megakaryocytic-biased Kit<sup>hi</sup> HSCs rescues hematopoietic engraftment and T cell potential in vitro and in vivo. Furthermore, age-associated decline in Kit<sup>lo</sup> HSCs is associated with diminished T lymphopoietic potential in aged BM precursors; meanwhile,&#xa0;Kit<sup>lo</sup> HSCs in aged mice maintain enhanced lymphoid potential, but their per-cell capacity is diminished. Lastly, we observe an analogous human BM KIT<sup>lo</sup> HSC subset with enhanced lymphoid potential. Our results thus uncover an age-related epigenetic regulation of lymphoid-competent Kit<sup>lo</sup> HSCs for T cell reconstitution.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月4日

查看全文
  • Harold K. Elias,
  • Sneha Mitra,
  • Marina B. da 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,
  • Marcel R. M. van den Brink

摘要

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.