Recent research has highlighted the remarkable heterogeneity of the vascular system, composed of both the blood and lymphatic vasculatures. These systems vary significantly across organs, with differences in morphology, function, and developmental origin. In particular, the lymphatic system has emerged as an important organ-specific regulator of tissue homeostasis, extending beyond its traditional role in fluid drainage to active shaping local immune responses through modulation of adaptive immunity. Moreover, lymphatic endothelial cells (LECs) produce paracrine (lymphangiocrine) factors that regulate organ growth and regeneration. The growing recognition of the diverse functions of the lymphatic system in important physiological processes and disease conditions, such as autoimmune disease and atherosclerosis, highlights the need for a better understanding of the underlying mechanisms.
We have discovered an unexpected organ-specific mechanism of lymphatic morphogenesis, which we termed lymphvasculogenesis, and identified novel lymphatic vessel origins in certain tissues (see:
When vascular development goes awry, it can result in vascular anomalies such as vascular malformations and lymphedema. These disorders are often cause by genetic mutations that disrupt normal vessel growth mechanisms, manifesting in organ- and vessel type-specific manner. In collaboration with geneticists and clinicians, we have identified and functionally characterized gene mutations responsible for some of these anomalies. By developing advanced mouse models, we are investigating the underlying mechanisms of these diseases and exploring potential therapeutic strategies (see:
Endothelial cells in adult tissues are largely quiescent, yet they must continually maintain essential vascular functions. For example, a key challenge for lymphatic capillaries is to remain highly permeable for efficient fluid uptake while also withstanding rapid changes in tissue volume, such as during swelling, without losing structural integrity. Using advanced imaging techniques, we found that the endothelial cells lining these vessels are highly dynamic, continuously extending broad protrusions that overlap with neighboring cells. This behavior gives rise to their characteristic oak leaf–like shape, which plays a crucial role in reinforcing the mechanical stability of the monolayer while maintaining flexibility and permeability (See:
Future questions we seek to address are how lymphatic vessels adapt and respond to physiological and pathological stresses such as upon wounding, inflammation and oedema.
Lymphatic vessels are present in nearly all tissues, where they likely play largely underexplored roles in maintaining tissue homeostasis and function. Recently, we identified a novel subtype of lymphatic endothelial cells (iLECs) residing at lymphatic capillary terminals, characterized by the expression of genes linked to immunomodulatory functions. Notably, we found that the iLEC population selectively expands and drives disease pathology in a genetic mouse model of lymphatic malformation (LM), a condition characterized by uncontrolled oncogene-driven vessel growth (See:
Our ongoing research aims to further investigate the role of iLECs in human physiology and their potential involvement in immune-related conditions, including psoriasis, wound healing, cancer, and vascular malformations.
To gain groundbreaking insights into vascular biology, we strive to overcome observational limitations by developing and utilizing cutting-edge genetic and imaging research tools. For example, we have generated and employed genetic mouse strains for targeted gene manipulation in LECs and their subpopulations, as well as disease models of lymphatic and venous malformations. We have employed advanced genetic models developed by Rui Benedito (CNIC, Madrid) for high-fidelity conditional gene targeting and genetic mosaics. Combined with longitudinal two-photon (2P) intravital imaging, these tools have allowed us to visualize endothelial cell behavior, therapy responses, cell shape and actin dynamics in vivo with unprecedented resolution (see:
In parallel with in vivo technologies, we characterise the molecular using single-cell transcriptomics (see: