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locus notch homolog protein 1 ], suggesting experiments in drug development, with a strategic shift
+
endothelial-to-hematopoietic transition), and mesenchymal toward “new approach methodologies,” such as artificial
populations (pericytes [angiopoietin 1 ], vascular smooth intelligence-based predictive models and organoid toxicity
+
muscle cells [actin alpha 2 ], and osteochondral precursors testing. Organoids, as a core technology in this transition,
+
[paired related homeobox 1 ]). This high-resolution exhibit distinct advantages in precision, efficiency, and
+
molecular map provides a foundation for analyzing cellular ethical compliance, with demonstrated applications across
interactions within the niche (Figure 1B). multiple research and development scenarios. The high-
throughput potential of BMOs (e.g., 96-well plate culture)
2. Paradigm shift: From static models to supports diverse toxicity assessment studies, including
dynamic simulation hematotoxicity screening, evaluation of synergistic

Unlike previous organoids modeling yolk sac damaging effects of chemotherapeutic agents on HSCs
hematopoiesis, the more recently developed BMOs and stromal cells, and validation of targeted therapies (e.g.,
8
replicated key features of the aorta-gonad-mesonephros testing the therapeutic efficacy of Janus kinase inhibitors in
region via arterial endothelial differentiation. scRNA-seq myelofibrosis-modeled organoids).
showed HSCs expressing fetal liver-stage markers (e.g., By integrating gene editing with organoid technology,
selectin L, Musashi RNA binding protein 2), indicating their BMOs enable HSC expansion optimization through
transitional state toward mature HSCs. This discovery offers supplementation with retinoic acid or Hedgehog pathway
insights into human HSC development and differentiation agonists, thereby enhancing transplantation efficiency.
trajectories. Furthermore, constructing mutation-specific organoids
Upon lipopolysaccharide stimulation, BMOs secreted based on individual genetic profiles allows screening of
interleukin (IL)-6/IL-8 within 4 h, with pre-neural personalized therapeutic regimens, making patient-specific
populations expanding 2.5-fold by 24 h. This rapid response treatments feasible. 12
mirrors in vivo “emergency hematopoiesis” and demonstrates
niche-autonomous regulation of granulocyte differentiation 4. Conclusion
without exogenous granulocyte colony-stimulating factor. The in vitro reconstruction of the bone marrow niche
This model enables dynamic studies of post-infection or represents not only a technical achievement but also a
chemotherapy-induced bone marrow regeneration. paradigm shift from “reductionism” to “systems biology.”

Clustered regularly interspaced short palindromic Integrating spatial transcriptomics and live-cell imaging,
repeats-engineered BMOs with VPS45 mutations exhibited BMOs may decode spatiotemporal cellular crosstalk
increased reticulin fiber deposition, expansion of alpha- within niches, bridging molecular mechanisms to clinical
smooth muscle actin myofibroblasts, and collagen translation. Future BMOs could serve as “ex vivo testbeds”
+
accumulation, leading to hematopoietic defects and for personalized medicine, offering novel strategies for the
elevated apoptosis of mature neutrophils, consistent with design of drug screening models, in vivo regeneration, and
bone marrow biopsy phenotypes in VPS45-deficient precision therapies.
patients (Figure 1C). Such “genotype-phenotype linkage Acknowledgments
models” may offer biopsy-free solutions for studying rare
hematologic disorders. 9-11 None.

3. Expansion of applications: From basic Funding
research to clinical translation This work was supported by Natural Science Foundation of

Leukemia cells rely on the bone marrow microenvironment Shandong Province (grant no.: ZR2023MC125) and Marine
to acquire drug resistance. By integrating patient-derived Aquaculture Innovation and Entrepreneurship Consortium
induced pluripotent stem cells, BMOs can be engineered Project of Shandong Province (grant no.: YZ2024007).
into “leukemia niche organoids” to investigate stroma-
mediated drug resistance mechanisms (e.g., the role of Conflict of interest
the C-X-C motif chemokine ligand 12-C-X-C chemokine The authors declare they have no competing interests.
receptor type 4 axis in minimal residual disease) and
evaluate immune cell interactions (e.g., infiltration and Author contributions
cytotoxic efficacy of chimeric antigen receptor T-cell Conceptualization: Liangyu Guo, Panpan Pan
therapy cells within organoids). Formal analysis: Yifan Xia
On April 10, 2025, the United States Food and Drug Investigation: All authors
Administration announced a phased elimination of animal Methodology: Liangyu Guo, Yifan Xia

Volume 1 Issue 2 (2025) 3 doi: 10.36922/OR025110011