Engineering the Stem Cell Microenvironment for Lymphatic Regeneration

摘要

ABSTRACT The lymphatic system is an integral part of the circulatory system, where extracellular fluid flows from vascular capillaries into the lymphatic vessels and is returned to the vascular system via the thoracic duct. Additionally, lymphatic vessels regulate homeostasis of tissue fluid, absorption of dietary fat, and trafficking of immune cells. Consequently, dysfunction in lymphatic vessels is associated with development of many diseases, including obesity and metabolic disease, aging and Alzheimer’s disease, chronic wound and cancer, as well as inflammation and cardiovascular diseases. Therefore, controlling lymphatic vascular formation and augmenting its function is postulated as a promising therapeutic target for preventing and treating these debilitating diseases. Unfortunately, therapeutic lymphangiogenesis has not been widely explored partly due to the unavailability of a clinically-relevant cell source and controllable matrix environment. The overall goal of the research program is to derive lymphatic endothelial cells (LECs) and lymphatic muscle cells (LMCs) from human pluripotent stem cells (hPSCs) that can be used as a clinically-relevant cell source for modeling lymphatic function and physiology, as well as therapeutic lymphangiogenesis in a synthetic and controllable matrix environment. To this end, our lab is at the forefront of developing multi-disciplinary approaches to utilize stem cells and synthetic biomaterials for basic understanding of stem cell differentiation and lymphatic vessel morphogenesis, as well as approaches in therapeutic lymphangiogenesis. We have recently established xeno-free, well-defined and controllable differentiation protocols to direct hPSCs differentiation to clinically-relevant vascular progenitor cells with high reproducibility and efficiency, as well as wide clinical applicability. Furthermore, synthetic matrices can be used to provide spatial and temporal control for these progenitor cells to undergo lymphatic vascular morphogenesis, useful for basic understanding of lymphatic vascular biology and a range of therapeutic applications. These results establish a fundamental link between vascular and lymphatic morphogenesis within synthetic matrices. We are currently focused on bridging the large knowledge gap between molecular understanding of vascular and lymphatic differentiation and morphogenesis in a developmental context. Furthermore, we are also testing the impact of lymphatic vasculature to attenuate inflammatory response, prevent edema, and eventually promote tissue regeneration in a wound healing model. Cumulatively, we are combining approaches in stem cell and bioengineering, biomaterials and microfluidics, as well as lymphatic and systems biology to develop the necessary component in therapeutic lymphangiogenesis: reliable human cell sources from hPSCs within a biologically rational synthetic and controllable matrix environment. Collectively, this research has the potential to not only advance our basic understanding of lymphatic vasculatures in health and disease, but also to revolutionize the way we manage and treat a myriad of diseases that will benefit from innovative therapeutic lymphangiogenesis.