Cellular trans-differentiation and morphogenesis toward the lymphatic lineage in regenerative medicine

Lymphedema is a medically irresolvable condition. The lack of therapies addressing lymphatic vessel dysfunction suggests that improved understanding of lymphatic cell differentiation and vessel maturation processes is key to the development of novel, regenerative medicine, and tissue engineering approaches. In this review we provide an overview of lymphatic characterization markers and morphology in development. Further, we describe multiple differentiation processes of the lymphatic system during embryonic, postnatal, and pathogenic development. Using the example of pathogenic Kaposi's sarcoma-associated herpes infection, we illustrate the involvement of the Notch and PI3K pathways for lymphatic transdifferentiation. We also discuss the plasticity of certain cell types and biofactors that enable transdifferentiation toward the lymphatic lineage. Here we argue the importance of pathway-associated induction factors for lymphatic transdifferentiation, including growth factors such as vascular endothelial growth factor receptor-C and interleukins, and the involvement of extracellular matrix characteristics and dynamics for morphological functionality.