Sophie Rosenberger,
"A microfluidic and Transwell model of en-dothelial barriers to investigate DLBCL cell-intrinsic and -extrinsic conditions for transmigration"
, 2025
Original Titel:
A microfluidic and Transwell model of en-dothelial barriers to investigate DLBCL cell-intrinsic and -extrinsic conditions for transmigration
Sprache des Titels:
Englisch
Original Kurzfassung:
Lymphoma is a heterogeneous group of lymphoproliferative diseases characterized by the abnormal growth of lymphocytes, which can lead to the presence of malignant cells in the lymphatic system, bone marrow or extranodal sites. It comprises numerous distinct subtypes involving B-, T- or Natural Killer (NK) cells, all of which are integral components of the immune system. When these cells undergo malignant transformation, they can disrupt normal immune function, leading to impaired immune surveillance, and increased susceptibility to infections, particularly in the advanced stages of the disease. Lymphoma is broadly categorized into two major subtypes: Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL). Among NHL subtypes, Diffuse Large B-cell Lymphoma (DLBCL) is the most common and aggressive form. The current standard therapy for DLBCL involves multi-agent chemotherapy, such as the CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) regimen. However, unfortunately a considerable number of patients experience relapse or develop refractory disease, which can involve the central nervous system (CNS). Although CNS involvement is relatively rare, it is associated with a more aggressive clinical course and presents unique treatment challenges. The blood-brain barrier (BBB) limits the delivery of most therapeutic agents, complicating treatment strategies. Therefore, clinical outcomes remain poor, highlighting the need for novel therapeutic approaches. Improving the understanding of lymphoma extravasation, particularly its interactions with the vascular endothelial barrier and the BBB, is crucial. This knowledge could enable the development of targeted interventions to disrupt the extravasation cascade or provide support for the barrier, ultimately improving outcomes for patients with CNS involvement. In this study, a Transwell system and a single-channel microfluidic system were established and tested to model the endothelial barrier. Endothelial cells (ECs) were seeded to simulate the barrier, and migration assays with lymphoma cells were performed. The results demonstrated that the integrity of the endothelial barrier depends on the functional status of the ECs. Healthy, viable ECs formed a robust and tight barrier, characterized by well-defined tight junctions. In contrast, senescent ECs failed to establish a functional barrier, thereby exhibiting reduced cell-cell contacts and resulting in numerous gaps, which facilitated the passing of both ADR-treated and non-senescent lymphoma cells through the Transwell pores.
Forschungs-