- Bone marrow on-a-chip for one-step recruitment and expansion of leukaemic stem cells
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Abstract:
- Leukemic Stem Cells (LSC), which show intimate interactions with the bone marrow (BM) niche, are known to be responsible for drug resistance and relapse. To date, however, there is a lack of adequate markers to identify bona fide LSC. This raises the importance to study these LSC in more detail to develop more effective disease models and therapies. Here, we propose the use of a microfluidic device to artificially engineer bone marrow environment to chemoattract true LSC populations. Polydimethylsiloxane is used to fabricate these devices using soft lithography techniques. The device comprises of two side channels, housing leukemic cells and BMSC respectively, separated by a collagen matrix capture channel. Bone marrow stromal cells (BMSC) are used to mimic the BM niche while THP-1 cells are used to model acute myeloid leukemia. THP-1 will migrate towards the BM niche in the co-culture system, which can then be quantified and extracted for further analysis. Our findings demonstrate that the device supports co-culture of BMSC and THP-1 with over 90% viable cells at 72h post-seeding. BM was able to recruit a sub-population of THP-1, resulting in an increase number of cells captured. 129±29 cells migrated towards the BM niche as compared to 0 cells in control setup at 72h while the distance migrated was 61.7±51.4μm in BM niche compared to 0 μm in control setup at 72h. The addition of AMD3100 CXCR4 antagonist attenuated these effects in a dose dependent fashion, mirroring clinical observations that the leukemic migration to bone marrow is induced by CXCR4-SDF1 axis. Fluid flow was subsequently introduced to represent in vivo flow and shear stress conditions in order to achieve a more physiologically relevant model. These studies provide a proof-of-concept for using this device to study the LSC subpopulations in greater detail.
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