Key Takeaways & Executive Findings
- •• • iBMOs self-organize into three distinct compartments (stromal, vascular, hematopoietic) and yield stable iBOSS lines that express Notch-associated molecules, enabling T-lineage and dendritic cell differentiation from iPSC-derived progenitors in vitro. • • Following transplantation into immunodeficient mice, iBMOs sustain human erythropoiesis and undergo bone formation, demonstrating autonomous niche activity in vivo with measurable engraftment and differentiation. • • The platform integrates bone marrow and T cell–supportive functions in a single defined iPSC-derived model, overcoming the anatomical separation that limits conventional in vitro systems. • • iBMO–iBOSS provides a reproducible and scalable source of immune cells, with potential for patient-specific immunotherapy and regenerative medicine applications.
Abstract
The anatomical separation of bone marrow and thymus restricts the efficient generation of human immune cells in vitro, limiting experimental platforms for integrated hematopoiesis. This study engineered 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. iBMOs produced hematopoietic progenitors and yielded stable stromal stem cell lines (iBOSS) expressing Notch-associated molecules, which supported 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. The iBMO–iBOSS platform functionally integrates essential features of bone marrow and T cell–supportive stromal niches, enabling coordinated generation of multiple hematopoietic lineages from human iPSCs. This system offers a reproducible and scalable source of immune cells for translational immunotherapy and expands understanding of human hematopoietic biology, opening avenues for engineering synthetic, patient-specific immune systems.
1. Introduction
Human hematopoiesis relies on a complex bone marrow niche comprising mesenchymal stromal cells, endothelial cells, and perivascular elements that regulate self-renewal and lineage specification. Existing in vitro models fail to recapitulate this integrated microenvironment, particularly the T cell–supportive niches found in the thymus, because bone marrow and thymus are anatomically separate. This separation restricts the efficient generation of human immune cells in vitro and constrains experimental platforms for modeling integrated hematopoiesis.
To address this bottleneck, Lee et al. engineered human induced pluripotent stem cell-derived bone marrow organoids (iBMOs) that self-organize into stromal, vascular, and hematopoietic compartments. These organoids yield stable stromal stem cell lines (iBOSS) expressing Notch-associated molecules, which support T-lineage and dendritic cell differentiation. Transplantation into immunodeficient mice demonstrated sustained human erythropoiesis and bone formation, confirming autonomous niche activity. This platform unifies bone marrow and T-lineage–supportive functions, offering a scalable foundation for immunotherapy and regenerative medicine.
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Jiyoung Lee, Tomoyuki Kawasaki, Lilika Tabata, Junlong Chen, Toru Uchiyama, Satoshi Yamazaki, Akihiro Umezawa, Hidenori Akutsu (2026). Human iPSC-derived bone marrow organoids with integrated hematopoietic and T cell-supportive niches. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-026-05249-1
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Frequently Asked Questions
What is the functional evidence that iBMOs support T cell differentiation in vitro?
iBMOs yielded stable iBOSS lines that expressed Notch-associated molecules and supported the differentiation of iPSC-derived hematopoietic progenitors toward T-lineage and dendritic cell-associated populations in vitro, as demonstrated by phenotypic and molecular analyses.
How do iBMOs perform in vivo, and what does this indicate about their niche activity?
Following transplantation into immunodeficient mice, iBMOs sustained human erythropoiesis and underwent bone formation, demonstrating autonomous niche activity in vivo. This indicates that the organoids provide necessary microenvironmental cues for hematopoietic maintenance and bone remodeling.
What are the scalability and reproducibility challenges for translating iBMOs to clinical applications?
The iBMO–iBOSS platform is described as reproducible and scalable, but specific metrics for yield, cost, and batch-to-batch consistency are not provided in the available text. Further optimization and validation will be required to meet clinical-grade manufacturing standards.
What is the significance of integrating hematopoietic and T cell–supportive niches in a single organoid?
This integration overcomes the anatomical separation of bone marrow and thymus, enabling coordinated generation of multiple hematopoietic lineages from human iPSCs. It provides a physiologically relevant system for studying human hematopoietic development and immune cell differentiation, with potential for engineering patient-specific immune systems.
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