Abstract
We previously reported a new approach for culturing difficult-to-preserve primary patient-derived multiple myeloma cells (MMC) using an osteoblast (OSB)-derived 3D tissue scaffold constructed in a perfused microfluidic environment and a culture medium supplemented with patient plasma. In the current study, we used this biomimetic model to show, for the first time, that the long-term survival of OSB is the most critical factor in maintaining the ex vivo viability and proliferative capacity of MMC. We found that the adhesion and retention of MMC to the tissue scaffold was meditated by osteoblastic N-cadherin, as one of potential mechanisms that regulate MMC-OSB interactions. However, in the presence of MMC and patient plasma, the viability and osteogenic activity of OSB became gradually compromised, and consequently MMC could not remain viable over 3 weeks. We demonstrated that the long-term survival of both OSB and MMC could be enhanced by: (1) optimizing perfusion flow rate and patient-derived plasma composition in the culture medium and (2) replenishing OSB during culture as a practical means of prolonging MMC’s viability beyond several weeks. These findings were obtained using a high-throughput well plate-based perfusion device from the perspective of optimizing the ex vivo preservation of patient-derived MM biospecimens for downstream use in biological studies and chemosensitivity analyses.
Highlights
Multiple myeloma (MM), an incurable B-cell malignancy, is the second most common blood cancer in the U.S with a typical survival of 5 to 7 years.[1,2] MM represents a paradigm for the intricate role played by the tumor microenvironment in the progression and development of drug resistant cancers
[17] MM cells (MMC)-OSB cell-cell interactions are mediated in part by N-cadherin homophilc interactions. [22, 29] Likewise, OSB support MMC growth by secreting a number of soluble factors. [18, 19] In this study, we showed that: (1) N-cadherin expression by OSB can mediate adhesion between MMC and OSB, (2) optimized perfusion flow and patient-derived plasma concentration are critical for the viability of both OSB and MMC, and (3) replenishing OSB during culture can be used a practical means of prolonging MMC viability and expansion. doi:10.1371/journal.pone.0125995.g008
We found that N-cadherin expressed by OSB contributes to the homing and/or retention of MMC to the OSB scaffolding
Summary
Multiple myeloma (MM), an incurable B-cell malignancy, is the second most common blood cancer in the U.S with a typical survival of 5 to 7 years.[1,2] MM represents a paradigm for the intricate role played by the tumor microenvironment in the progression and development of drug resistant cancers. Primary human MM cells (MMC) rarely metastasize to murine and other animal bones due to species-related issues, resulting in the use of complicated, inconsistent, time-consuming, and costly patient derived models.[3,4] Of note, Lawson et al, [5] recently developed a new xenograft model where NOD/SCID-GAMMA (NSG) mice were injected via the tail vein with MM cell lines or with MMC from one patient sample. This simple approach proved beneficial for the assessment of various drug treatments. Ex vivo maintenance and expansion of primary human MMC have been problematic[10] due to the lack of an in vitro technology capable of reproducing the complex bone marrow microenvironment
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