The human bone marrow is a complex organ that is crucial for the self-renewal and differentiation of hematopoietic progenitor cells into various blood cell lines. Disorders in this hematopoietic system can cause numerous diseases.

Natural killer cells (NK cells) are large granular lymphocytes (white blood cells) that can trigger programmed cell death (apoptosis) in virus-infected cells as well as cancer cells. They are part of the first defense line of the innate immune system against a variety of pathogens and developing tumor cells. NK cells develop from lymphoid progenitor cells in the bone marrow.

The research team, led by Dr. Moran Grossman, Deputy Director of Teva Pharmaceutical Industries Ltd. in Netanya, Israel, in cooperation with TissUse GmbH Berlin, reconstructed human bone marrow by culturing human hematopoietic stem cells along with lymphoid progenitor cells and mesenchymal stromal cells in a microfluidic chip. The differentiation of NK cells was triggered by a specific cultivation medium.

Using their model, the research team was able to trace the differentiation of all developmental stages of NK cells within 28 days of culture. In addition to NK cells, granulocytes, monocytes and dendritic cells also developed. The differentiated NK cells could be activated after stimulation of cytokine production with the stimulant reagent phorbol 12-myristate 13-acetate (PMA) and ionomycin, a substance that triggers a rapid and controlled increase in intracellular calcium, indicating the functionality of the cells. A week-long treatment with an anti-IL-15 antibody resulted in a dose-dependent reduction in circulating NK cells. This effect was partially reversible after treatment was stopped.

The researchers are convinced that the model presented replicates human NK cell development in the bone marrow. It could serve as a basis for studying related diseases and drug effects.

Original publication:
Koenig L, Ben-Eliezer I, Tao TP, Winter A & Grossman M (2025) Modeling human natural killer cell development and drug response in a microfluidic bone marrow model. Front. Immunol. 16:1499397. doi: 10.3389/fimmu.2025.1499397