Modeling Structural Elements and Functional Responses to Lymphatic‐Delivered Cues in a Murine Lymph Node on a Chip

Abstract

Lymph nodes (LNs) are organs of the immune system, critical for maintenance of homeostasis and initiation of immune responses, yet there are few models that accurately recapitulate LN functions in vitro. To tackle this issue, an engineered murine LN (eLN) was developed, replicating key cellular components of the mouse LN; incorporating primary murine lymphocytes, fibroblastic reticular cells (FRCs), and lymphatic endothelial cells (LECs). T and B cells compartments are incorporated within the eLN that mimic LN cortex and paracortex architectures. When challenged, the eLN elicits both robust inflammatory responses and antigen‐specific immune activation, showing that the system can differentiate between non‐specific and antigen‐specific responses and can be monitored in real‐time. Beyond immune responses, this model also enables interrogation of changes in stromal cells, thus permitting investigations of all LN cellular components in homeostasis and different disease settings, such as cancer. Here, we present how LN behavior can be influenced by murine melanoma‐derived factors. In conclusion, the eLN model presents a promising platform for in vitro study of LN biology that will enhance understanding of stromal and immune responses in the murine LN, and in doing so will enable development of novel therapeutic strategies to improve LN responses in disease.This article is protected by copyright. All rights reserved

Ex vivo model of breast cancer cell invasion in live lymph node tissue

“…22,23 For these reasons, a variety of 3D cell culture systems have been developed to recapitulate features of LN architecture and signaling cues in the context of cancer metastasis. These systems have mimicked the microenvironment or fluid dynamics of specific anatomical regions of TDLNs; 24,25 recreated molecular communication between immune and tumor compartments; 26 and allowed for the testing of the effects of microenvironmental cues and immunotherapies on tumor cell survival. [27][28][29] While these systems potentially enable precise control of the microenvironment and allow time-course analysis, to date no model has captured the dynamic events of cancer cell invasion and spread in the spatially organized LN, nor replicated the role of chemokine signaling in cancer cell invasion of the LN parenchyma.…”