Lymph sacs are a part of the development of the
lymphatic system
The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...
, known as
lymphangiogenesis
Lymphangiogenesis is the formation of lymphatic vessels from pre-existing lymphatic vessels in a method believed to be similar to angiogenesis (blood vessel development).
Lymphangiogenesis plays an important physiological role in homeostasis, meta ...
.
The lymph sacs are precursors of the
lymph vessel
The lymphatic vessels (or lymph vessels or lymphatics) are thin-walled vessels (tubes), structured like blood vessels, that carry lymph. As part of the lymphatic system, lymph vessels are complementary to the cardiovascular system. Lymph vessel ...
s.
These sacs develop through the processes of
vasculogenesis
Vasculogenesis is the process of blood vessel formation, occurring by a '' de novo'' production of endothelial cells. It is sometimes paired with angiogenesis, as the first stage of the formation of the vascular network, closely followed by angio ...
and
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
. However, there is evidence of both of these processes in different organisms. In mice, it is thought that the lymphatic components form through an angiogenic process. But, there is evidence from bird embryos that gives rise to the idea that lymphatic vessels arise in the embryos through a vasculogenesis-like process from the lymphangioblastic endothelial precursor cells.
The development of the lymphatic system has been a highly debated topic in developmental biology for a long time. Previously, it was debated whether the lymph sacs developed from the venous system, or if they came from spaces in the
mesenchyme
Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...
, which come together in a centripetal direction and secondarily opened into the veins.
However, more recent research has shown that the formation of the lymphatic system begins when a subset of endothelial cells from the previously formed
jugular vein
The jugular veins are veins that take deoxygenated blood from the head back to the heart via the superior vena cava. The internal jugular vein descends next to the internal carotid artery and continues posteriorly to the sternocleidomastoid ...
sprout off to form the lymphatic sacs.
Because lymph sacs form from the venous system, they typically contain red blood cells.
It is believed that the lymph sacs are directly connected to the venous system and that the venous components and lymphatic components communicate through a small hole.
Studies have shown that the development of lymph sacs occurs through swelling and outgrowth of pre-lymphatic clusters from the
cardinal vein, in a process termed ''ballooning''. Following ballooning, there is the process of pinching, which separates the lymph sacs from the venous system.
These processes begin forming the lymph sacs during the 5th week of fetal development. At this time, the jugular lymph sacs develop.
These are a pair of enlargements that function in collecting fluid from the lymphatics of the upper limbs, upper trunk, head, and neck. The
lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...
s eventually develop at the place of the jugular lymphatic sacs.
From the left jugular lymphatic sac, the cervical part of the thoracic duct forms. From the right jugular lymphatic sac, the right lymphatic duct and the jugular and the subclavicular lymphatic trunks form.
One week later, during the 6th week of fetal development, four more lymph sacs form. These are the retroperitoneal lymph sac, the cysterna chyli, and paired posterior lymph sacs.
The posterior lymph sacs are associated with the junctions of the external and internal iliac veins. These four new lymph sacs function in the collection of lymph from the trunk and lower extremities of the body. The
cysterna chyli
The cisterna chyli (or cysterna chyli, and etymologically more correct, receptaculum chyli) is a dilated sac at the lower end of the thoracic duct in most mammals into which lymph from the intestinal trunk and two lumbar lymphatic trunks flow. It ...
drains into a pair of thoracic lymphatic ducts initially.
These ducts drain into the venous junctions of the internal jugular and subclavian veins.
However, these ducts eventually become one thoracic duct that is derived from the caudal portion of the right duct, the cranial portion of the left duct, and median anastomosis.
There are many
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
s that regulate the development of the lymphatic system, particularly the lymph sacs, but in all of the migrating lymphatic endothelial cell precursors, there is one specific factor present, ''Prospero-related homeobox-1 (
PROX1
Prospero homeobox protein 1 is a protein that in humans is encoded by the ''PROX1'' gene. The Prox1 gene is critical for the development of multiple
tissues. Prox1 activity is necessary and sufficient to specify a lymphatic endothelial cell fate i ...
)''.
Homologs of this transcription factor have been found in humans, chicks, newts, frogs, Drosophila, and zebrafish.
When the development of the lymphatic system begins from the cardinal vein, all of the endothelial cells appear to have the potential to become lymphatic.
This potential is indicated by the presence of some known lymphatic markers such as ''Vascular endothelial growth factor receptor-3 (Vegfr3 or Flt4; a receptor for VegfC and VegfD)'', and also the presence of ''Lyve1'', which is a lymphatic specific hyluronan receptor.
However, regardless of the presence of these markers, it appears that only the subset of endothelial cells that begin to express ''Prox1'' form the undeveloped lymph sacs. Once these cells start to express ''Prox1'', they begin to express more specific lymphatic markers such as ''Nrp2'' and ''Podoplanin''.
Many experiments involving mice have proven the importance of the ''Prox1'' transcription factor in the development of primitive lymph sacs.
In experiments where ''Prox1'' was knocked out in mice, the embryos were unable to form any lymphatic system. However, even when the mice did not have any ''Prox1'', the endothelial cells still migrate similarly to the way they would when developing a lymphatic system, but as these cells migrate, they never develop the ability to express the more specific lymphatic markers.
Instead, they will begin to express markers that are specific to blood vessel endothelium. These markers include ''CD34'' and ''Laminin''.
This experiment proves that ''Prox1'' is necessary for lymphatic cells to specify. It is believed that ''Prox1'' is the single most important transcription factor that programs the fate of endothelial cells becoming lymphatic components. It has also been found that ectopic expression of ''Prox1'' in blood vascular epithelium can force vascular endothelial cells to convert into lymphatic cells.
References
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Lymphatic system
Embryology of cardiovascular system