Microarrayed human bone marrow organoids for modeling blood stem cell dynamics

Area of Science:

• Biomedical Engineering
• Hematology
• Stem Cell Biology

Background:

• Leukemia patient prognosis is often poor due to chemotherapy-resistant leukemic stem cells (LSCs) or inefficient hematopoietic stem/progenitor cell (HSPC) engraftment.
• Existing in vitro models do not fully recapitulate the complex microenvironment of native bone marrow (BM).

Purpose of the Study:

• To develop a scalable 3D in vitro bone marrow organoid (BMO) model.
• To assess the BMO's ability to mimic native BM structure and function, including cell behavior relevant to leukemia and stem cell transplantation.

Main Methods:

• Fabrication of BMOs through high-throughput aggregation of endothelial and mesenchymal cells within hydrogel microwells.
• Characterization of mesenchymal stem cell self-renewal and multilineage potential within the organoids.
• Analysis of endothelial cell self-organization into vascular networks and subsequent HSPC recruitment via chemokine signaling.
• Modeling of leukemic stem cell (LSC) migration and engraftment within the BMO system.

Main Results:

• BMOs successfully recapitulated key structural and cellular components of native BM.
• Mesenchymal cells maintained partial self-renewal and multilineage potential.
• Endothelial cells formed functional vessel-like networks that facilitated chemokine-dependent HSPC recruitment.
• The model allowed for the observation of LSC migration and nesting, similar to in vivo behavior.

Conclusions:

• The developed 3D BMO system provides a robust and scalable in vitro platform for studying leukemia and stem cell engraftment.
• This model system holds significant potential for preclinical drug screening and patient-specific assays in hematological malignancies.
• The BMO facilitates understanding of HSPC homing mechanisms and LSC behavior within a biomimetic environment.