Microfluidic device engineered to study the trafficking of multiple myeloma cancer cells through the sinusoidal niche of bone marrow

Chao Sui,Jenny Zilberberg,Woo Lee

doi:10.1038/s41598-022-05520-4

Abstract

Multiple myeloma (MM) is an incurable B cell malignancy characterized by the accumulation of monoclonal abnormal plasma cells in the bone marrow (BM). It has been a significant challenge to study the spatiotemporal interactions of MM cancer cells with the embedded microenvironments of BM. Here we report a microfluidic device which was designed to mimic several physiological features of the BM niche: (1) sinusoidal circulation, (2) sinusoidal endothelium, and (3) stroma. The endothelial and stromal compartments were constructed and used to demonstrate the device’s utility by spatiotemporally characterizing the CXCL12-mediated egression of MM cells from the BM stroma and its effects on the barrier function of endothelial cells (ECs). We found that the egression of MM cells resulted in less organized and loosely connected ECs, the widening of EC junction pores, and increased permeability through ECs, but without significantly affecting the number density of viable ECs. The results suggest that the device can be used to study the physical and secreted factors determining the trafficking of cancer cells through BM. The sinusoidal flow feature of the device provides an integral element for further creating systemic models of cancers that reside or metastasize to the BM niche.

Highlights

Multiple myeloma (MM) is an incurable B cell malignancy characterized by the accumulation of monoclonal abnormal plasma cells in the bone marrow (BM)
These results indicate that an endothelial lumen structure could be formed in the sinusoid chamber within 12 h while BM stromal cells (BMSCs) being uniformly dispersed in collagen and co-cultured in the stroma chamber
No close contacts between MM.1S cells and BMSCs were detected. These results suggested that MM.1S cells migrated through the endothelium in response to CXCL12 while BMSCs did not

Summary

Introduction

Multiple myeloma (MM) is an incurable B cell malignancy characterized by the accumulation of monoclonal abnormal plasma cells in the bone marrow (BM). Significant progress has been made with developing microfabricated cell culture devices to recapitulate in vitro the physiological functions of organs (“organs on a chip”) and model the pathophysiological developments of human diseases[1]. The lumen of sinusoidal microvessels is composed of a porous and leaky layer of endothelial cells (ECs), allowing the trafficking of leukocytes and hematopoietic stem and progenitor c ells[21,22]. This leakiness allows the trafficking of immune cells. Intravital microscopy s tudies[20,24] have shown that the average velocity of blood through sinusoidal microvessels (~ 20 μm in diameter) is on the order of ~ 0.2 mm/s with the corresponding shear stress (τw) of ~ 0.1 Pa exerted on ECs

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