Human iPSC-derived bone marrow organoids with integrated hematopoietic and T cell-supportive niches.

BACKGROUND: The anatomical separation of bone marrow and thymus limits the efficient generation of human immune cells in vitro and constrains experimental platforms for modeling integrated hematopoiesis. We investigated whether a synthetic human bone marrow could be engineered to support both hematopoietic and T-lineage-associated functions. METHODS: We generated human induced pluripotent stem cell-derived bone marrow organoids (iBMOs) that self-organize into stromal, vascular, and hematopoietic compartments and provide microenvironmental cues supportive of T cell differentiation. RESULTS: iBMOs produced hematopoietic progenitors and yielded stable stromal stem cell lines (iBOSS) that expressed Notch-associated molecules and supported the differentiation of iPSC-derived hematopoietic progenitors toward T-lineage and dendritic cell-associated populations in vitro. Following transplantation into immunodeficient mice, iBMOs sustained human erythropoiesis and underwent bone formation, demonstrating autonomous niche activity in vivo. CONCLUSION: This integrated bone marrow organoid platform provides a physiologically relevant system for studying human hematopoietic development and immune cell differentiation and offers a scalable foundation for regenerative medicine and immunotherapy applications.