Biomaterials. 2025 Sep 29;327:123744. doi: 10.1016/j.biomaterials.2025.123744. Online ahead of print.
ABSTRACT
Hematopoietic acute radiation syndrome (H-ARS) is a serious clinical condition caused by exposure to high-dose ionizing radiation that leads to the depletion of hematopoietic stem and progenitor cells with the collapse of the function of bone marrow. Despite the clinical significance of H-ARS, there have been few advances in H-ARS research owing to the dearth of physiologically relevant human models that mimic the complex bone marrow microenvironment. In this study, we used a stage-specific mesodermal differentiation protocol to establish human bone marrow organoids (hBMOs) derived from hiPSCs. The resulting organoids exhibited stromal-vascular architecture, supported multilineage hematopoiesis, and contained CD34+ hematopoietic populations, as confirmed by scRNA-seq and flow cytometry. To investigate the impact on the hematopoietic cell population, hBMOs were exposed to γ-irradiation at doses of 3, 6, and 9 Gy. The organoids exhibited a marked depletion of hematopoietic cell populations and disruption of niche architecture, which are hallmarks of radiation-induced hematopoietic cell damage. To evaluate the therapeutic potential of hBMOs in H-ARS, hBMOs transplanted into lethally irradiated NSG mice significantly improved survival with successful engraftment of human hematopoietic cells within the host. These findings establish hBMOs as a robust and translational human model of radiation-induced hematopoietic cell damage.
PMID:41052483 | DOI:10.1016/j.biomaterials.2025.123744