Modeling human natural killer cell development and drug response in a microfluidic bone marrow model

Area of Science:

• Hematology
• Immunology
• Biotechnology

Background:

• The human bone marrow is vital for blood cell development, but studying it is complex.
• Human cell-based microfluidic models offer a promising avenue for investigating bone marrow biology.
• Understanding hematopoietic stem and progenitor cell differentiation is crucial for disease research and drug development.

Purpose of the Study:

• To develop and validate a microfluidic bone marrow model for studying human hematopoietic stem and progenitor cell differentiation.
• To investigate the kinetics and functionality of natural killer (NK) cell development in vitro.
• To assess the impact of anti-interleukin-15 (IL-15) therapy on NK cell subtypes within the model.

Main Methods:

• Human hematopoietic stem and progenitor cells were co-cultured with mesenchymal stromal cells on a ceramic scaffold within a microfluidic device.
• NK cell differentiation was induced using a lymphoid cultivation medium supplemented with IL-15.
• Cell differentiation, kinetics, and functionality were analyzed using flow cytometry, EdU staining, and stimulation assays.

Main Results:

• The model achieved differentiation into all developmental stages of NK cells within 28 days, alongside myeloid cell development.
• Differentiated NK cells exhibited functionality upon stimulation, and treatment with an anti-IL-15 antibody reduced late-stage NK cell proliferation.
• A dose-dependent reduction in circulating NK cells was observed, with partial reversibility after treatment cessation.

Conclusions:

• The developed microfluidic bone marrow model effectively recapitulates human NK cell development.
• This model serves as a valuable platform for studying bone marrow-related diseases and evaluating drug responses.
• The findings highlight the potential of targeting IL-15 for modulating NK cell populations in therapeutic strategies.