Assistant Professor Cornell University Ithaca, New York, United States
Introduction:: The lymphatic vascular system, a network of lymphatic vessels (LVs), plays a role in human health and disease. LVs maintain fluid homeostasis in tissues by draining excess interstitial fluid leaked from blood capillaries and returning the fluid back to blood circulation. Since the interstitial fluid contains immune cells, LVs modulate host immunity. In addition, the intestinal LVs (lacteals) absorb dietary fat in the GI tract and the meningeal LVs transport metabolic wastes in the brain. Therefore, impaired lymphatic function in different organs contributes to numerous human diseases, such as lymphedema (fluid), immune dysfunction (immune cells), metabolic disease (dietary fat), and neurodegenerative disease (brain waste). In cancer, LVs transport tumor cells to lymph nodes triggering metastasis; are also known to impact tumor immune microenvironments. The aforementioned human diseases are directly or indirectly linked to lymphatic drainage, a function unique to LVs involving the transport of interstitial fluid into LVs. Despite the significance of lymphatic drainage, the homeostasis and dysregulation of this function have not been well understood.
Materials and Methods:: Animal models have been widely used in the field for decades, however as it is often difficult to isolate the relative contributions of biological and biophysical factors in these in vivo models, they have not been as helpful in identifying mechanisms of multifactorial human lymphatic disease. By contrast, traditional cell cultures in two-dimensional dishes or transwells are easy to control, but they do not recapitulate the three-dimensional (3D) in vivo organization of lymphatics. So, there has been a clear, unmet need for a 3D culture that reconstitutes human lymphatics to permit controlled experiments investigating bona fide lymphatic structure and function. Here we generate bioengineered 3D in vitro systems that recapitulate the native structure and function of LVs.
Results, Conclusions, and Discussions:: Using the system, we decipher the mechanisms and targets of lymphatic dysfunction. For example, we understand skin lymphatic dysfunction in inflammation to understand mechanisms of secondary lymphedema by focusing on lymphatic endothelial cell-cell junction formation, interstitial fluid drainage and lymph transport, lymphatic primary valve function, and secondary lymphatic valve function.
Acknowledgements (Optional): : This work was supported by NIH grants (CA279560, AI168886, HL165135, and AI166772).
