Research

The Lymphedema Society of Singapore was founded in April 2020 with four main aims.

Why is lymphatic research important?

Millions of people around the globe suffer from a disorder or disease of the lymphatic system, and millions more are at risk as a result of surgery, injury, infection, or some other insult to their lymphatic system. Although the lymphatic system is vital for the preservation of our health and immunity, our understanding of this system is limited.

The mission of our Society is to fill this gap in knowledge by bringing together medical professionals, researchers and patients and by supporting lymphatic research. Scientific advancements hold the key to improve the diagnosis and treatments of lymphedema, and thus the quality of life of the patients.

What is the lymphatic system?

The lymphatic system consists of a network of vessels connecting lymphoid organs such as lymph nodes, tonsils, thymus and spleen. Lymph flow is unidirectional from the periphery to the heart: the lymph absorbs interstitial fluid from tissues, and returns it to the blood circulation at the thoracic duct after passing through the lymph nodes. In the peripheral tissue, lymph containing lipids, immune cells, macromolecules and fluid is first collected by blind-ending initial or capillary lymphatic vessels which in turn empty into larger lymphatic vessels, i.e the collecting vessels or collectors. Unlike the initial lymphatic vessels, the collecting lymphatics exhibit circumferential smooth muscle cell coverage (Figure 1) and luminal valves that propel and maintain unidirectional flow. Running parallel to the venous circulation, the primary function of the lymphatic system is to drain excess interstitial fluid leaking out from blood capillaries into the tissue spaces. Other functions of the lymphatic system include fat absorption from the intestine, immune surveillance and resolution of inflammation.

Figure 1: Microscopy image of a collecting lymphatic vessel (green) surrounded by smooth muscle cells (red).
Figure 2: The interplay and chronological sequence between triggering factors and lymphedema pathological changes are not well understood. It is evident in clinical and animal models of lymphedema that inflammation, adipose tissue remodelling, and fibrosis in skin and lymphatic vessels occur as lymphedema progresses. In particular, the chronological sequence of adipose tissue remodelling between lymphedema stages remains unexplored. Moreover, it is not known if adipose tissue remodelling (1) and inflammation are two separate or synchronised events, and whether adipose tissue remodelling in lymphedema can promote fibrosis (2) as observed in obesity.

Lymphedema and the missing piece of the puzzle

There are still unresolved questions regarding the disease mechanisms in lymphedema. Research in past decades has shown the factors causing lymphedema are not solely attributed to lymph and fluid accumulation in the soft tissue. We believe there is a chain of complex and progressive events affecting different tissue compartments. As a consequence of impaired lymphatic drainage, proteins and lipids accumulate in the interstitial space, causing the regional tissue to undergo extensive and progressive architectural changes, including fat tissue deposition and fibrosis. These changes are also associated with inflammation (Figure 2). Our current research aims to understand how these events develop, the relationship between these events, and their interplay during disease progression. This research will help us learn more on lymphedema and advance the prevention, diagnosis and treatments of this condition through the discovery of novel targets.

Publications

Azhar SH, Lim HY, Tan B-K and Angeli V (2020) The Unresolved Pathophysiology of Lymphedema. Front. Physiol. 11:137. doi: 10.3389/fphys.2020.00137

Tay MHD, Lim SYJ, Leong YFI, Thiam CH, Tan KW, Torta FT, Narayanaswamy P, Wenk M, Angeli V. Halted Lymphocyte Egress via Efferent Lymph Contributes to Lymph Node Hypertrophy During Hypercholesterolemia. Front Immunol. 2019 Mar 27;10:575. doi: 10.3389/fimmu.2019.00575.

Wang JK, Yeo KP, Chun YY, Tan TTY, Tan NS, Angeli V, Choong C Fish scale-derived collagen patch promotes growth of blood and lymphatic vessels in vivo. Acta Biomater. 2017 Sep 6. pii: S1742-7061(17)30564-0. doi: 10.1016/j.actbio.2017.09.001.

Yeo KP, Angeli V. Bidirectional Crosstalk between Lymphatic Endothelial Cell and T Cell and Its Implications in Tumor Immunity. Front Immunol. 2017 Feb 6;8:83. doi: 10.3389/fimmu.2017.00083.

Pin YK, Khoo K, Tham M, Karwai T, Hwee TC, Puaux AL, Phua ML, Kato M, Angeli V, Abastado JP. Lymphadenectomy promotes tumor growth and cancer cell dissemination in the spontaneous RET mouse model of human uveal melanoma. Oncotarget. 2015 Dec 29;6(42):44806-18. doi: 10.18632/oncotarget.6326.

Tan KW, Chong SZ, Angeli V. Inflammatory lymphangiogenesis: cellular mediators and functional implications. Angiogenesis. 2014 Apr;17(2):373-81. doi: 10.1007/s10456-014-9419-4.

Lim HY, Thiam CH, Yeo KP, Bisoendial R, Hii CS, McGrath KC, Tan KW, Heather A, Alexander JS, Angeli V.Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab. 2013 May 7;17(5):671-84. doi: 10.1016/j.cmet.2013.04.002.

Tan KW, Yeo KP, Wong FH, Lim HY, Khoo KL, Abastado JP, Angeli V. Expansion of cortical and medullary sinuses restrains lymph node hypertrophy during prolonged inflammation.

J Immunol. 2012 Apr 15;188(8):4065-80. doi: 10.4049/jimmunol.1101854.

Hypercholesterolemic mice exhibit lymphatic vessel dysfunction and degeneration.

Lim HY, Rutkowski JM, Helft J, Reddy ST, Swartz MA, Randolph GJ, Angeli V. Am J Pathol. 2009 Sep;175(3):1328-37. doi: 10.2353/ajpath.2009.080963

Messages from Members and Clinical Professionals

To make a difference for lymphedema patients, lymphatic research is key.




Dr Veronique Angeli
Dr Veronique Angeli Research Professor
Lymphatic research is vital to unravel new perspectives on the pathophysiology of lymphedema as such information will be pivotal in the development of novel diagnostics and therapeutics which are currently limited.
Lim Hwee Ying
Lim Hwee YingResearcher
Each medical breakthrough begins with discovery and development in a lab. To transform scientific knowledge to clinical studies, and to final commercialisation, contributions from all sectors are needed.
Yeo Kim Pin
Yeo Kim PinResearcher