Bone marrow organoids: Decoding the three-dimensional code of hematopoietic niches

Abstract

The bone marrow serves not only as a “factory” for hematopoiesis but also as a dynamic ecological “repository” regulating immune responses, metabolic processes, and disease progression. Its complexity stems from the three-dimensional interplay of vascular networks, mesenchymal stromal cells, hematopoietic stem cells, and immune cells -a spatial dynamism poorly captured by traditional models. Recently, the first functional human bone marrow organoids were constructed in vitro through multilineage differentiation and self-organization of induced pluripotent stem cells. This model accurately captures the key functional and structural characteristics of the human bone marrow hematopoietic niche, marking a significant milestone in advancing research on hematopoietic development and bone marrow diseases.

Keywords

Bone marrow organoids / Human induced pluripotent stem cells / Hematopoietic microenvironment

References

[1] Khan AO, RodriguezRomera A, Reyat JS, et al. Human bone marrow organoids for disease modeling, discovery, and validation of therapeutic targets in hematologic malignancies. Cancer Discov. 2023; 13(2):364-385. doi: 10.1158/2159-8290.CD-22-0199

[2] Pinho S, Frenette PS. Haematopoietic stem cell activity and interactions with the niche. Nat Rev Mol Cell Biol. 2019; 20(5):303-320. doi: 10.1038/s41580-019-0103-9

[3] Frenz-Wiessner S, Fairley SD, Buser M, et al. Generation of complex bone marrow organoids from human induced pluripotent stem cells. Nat Methods. 2024; 21(5):868-881. doi: 10.1038/s41592-024-02172-2

[4] Frey L, Natalia Z, Łyszkiewicz M, et al. Mammalian VPS45 orchestrates trafficking through the endosomal system. Blood. 2021; 137(14):1932-1944. doi: 10.1182/blood.2020006871

[5] Fan Y, Murgia M, Linder MI, et al. HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation. J Clin Invest. 2022; 132(9):e153153. doi: 10.1172/JCI153153

[6] Baccin C, Al-Sabah J, Velten L, et al. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat Cell Biol. 2020; 22(1):38-48. doi: 10.1038/s41556-019-0439-6

[7] Fan YX, Mizoguchi Y, Tatematsu M, et al. Analyzing mitochondrial respiration of human induced pluripotent stem cell-derived myeloid progenitors using seahorse technology. STAR Protoc. 2023; 4(1):102073. doi: 10.1016/j.xpro.2023.102073

[8] Hirakawa H, Gao L, Tavakol DN, Vunjak-Novakovic G, Ding L. Cellular plasticity of the bone marrow niche promotes hematopoietic stem cell regeneration. Nat Genet. 2023; 55(11):1941-1952. doi: 10.1038/s41588-023-01528-2

[9] Koh BI, Mohanakrishnan V, Jeong HW, et al. Adult skull bone marrow is an expanding and resilient haematopoietic reservoir. Nature. 2024; 636(8041):172-181. doi: 10.1038/s41586-024-08163-9

[10] Luff SA, Creamer JP, Valsoni S, et al. Identification of a retinoic acid-dependent haemogenic endothelial progenitor from human pluripotent stem cells. Nat Cell Biol. 2022; 24(5): 616-624. doi: 10.1038/s41556-022-00898-9

[11] De Janon A, Thapa A, Zhou F, et al. Self-supporting human acute myeloid leukemia (AML) bone marrow organoids established from patient-derived xenografts mimic the human AML microenvironment, with distinct cytokine kinetics correlating with dynamic cell proliferation and metabolic shifts. Blood. 2023; 142(1):1337-1338. doi: 10.1182/blood-2023-189230

[12] Wang J, Wu Y, Li G, et al. Engineering large-scale self-mineralizing bone organoids with bone matrix-inspired hydroxyapatite hybrid bioinks. Adv Mater. 2024;36:e2309875. doi: 10.1002/adma.202309875