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Lymphangiogenesis and angiogenesis during human fetal pancreas development.

Roost MS, van Iperen L, de Melo Bernardo A, Mummery CL, Carlotti F, de Koning EJ, Chuva de Sousa Lopes SM - (2014)

Bottom Line: Whilst lymphatic vessels did not directly intrude the islets of Langerhans, three-dimensional reconstruction revealed that they were present in the vicinity of islets of Langerhans between W17-W22.Our data suggest that the blood and lymphatic machinery in the human pancreas is in place to support endocrine function from W17-W22 onwards.Our study provides the first systematic assessment of the progression of lymphangiogenesis during human pancreatic development.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.

ABSTRACT

Background: The complex endocrine and exocrine functionality of the human pancreas depends on an efficient fluid transport through the blood and the lymphatic vascular systems. The lymphatic vasculature has key roles in the physiology of the pancreas and in regulating the immune response, both important for developing successful transplantation and cell-replacement therapies to treat diabetes. However, little is known about how the lymphatic and blood systems develop in humans. Here, we investigated the establishment of these two vascular systems in human pancreas organogenesis in order to understand neovascularization in the context of emerging regenerative therapies.

Methods: We examined angiogenesis and lymphangiogenesis during human pancreas development between 9 and 22 weeks of gestation (W9-W22) by immunohistochemistry.

Results: As early as W9, the peri-pancreatic mesenchyme was populated by CD31-expressing blood vessels as well as LYVE1- and PDPN-expressing lymphatic vessels. The appearance of smooth muscle cell-coated blood vessels in the intra-pancreatic mesenchyme occurred only several weeks later and from W14.5 onwards the islets of Langerhans also became heavily irrigated by blood vessels. In contrast to blood vessels, LYVE1- and PDPN-expressing lymphatic vessels were restricted to the peri-pancreatic mesenchyme until later in development (W14.5-W17), and some of these invading lymphatic vessels contained smooth muscle cells at W17. Interestingly, between W11-W22, most large caliber lymphatic vessels were lined with a characteristic, discontinuous, collagen type IV-rich basement membrane. Whilst lymphatic vessels did not directly intrude the islets of Langerhans, three-dimensional reconstruction revealed that they were present in the vicinity of islets of Langerhans between W17-W22.

Conclusion: Our data suggest that the blood and lymphatic machinery in the human pancreas is in place to support endocrine function from W17-W22 onwards. Our study provides the first systematic assessment of the progression of lymphangiogenesis during human pancreatic development.

No MeSH data available.


Related in: MedlinePlus

Blood vessels and their association with smooth muscle cells and basement membrane formation during human pancreatic development. (A) Pancreata at W9, W11, W12 and W19 immunostained for CD31 and smooth muscle actin (ACTA2). Smooth muscle cell association with blood vessels in the peri-pancreatic mesenchyme (PPM, top panels) and intra-pancreatic mesenchyme (IPM, bottom panels) is shown. (B) Pancreas at W9 immunostained for CD31 and collagen type IV (COL4A) illustrating blood vessels in the PPM (top panels) and IPM (bottom panels). White arrows point to CD31-positive blood vessels with a continuous basement membrane. Note that autofluorescent red blood cells, as yellow/orange dots, are present in in all images. Scale bars: 30 μm.
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Fig2: Blood vessels and their association with smooth muscle cells and basement membrane formation during human pancreatic development. (A) Pancreata at W9, W11, W12 and W19 immunostained for CD31 and smooth muscle actin (ACTA2). Smooth muscle cell association with blood vessels in the peri-pancreatic mesenchyme (PPM, top panels) and intra-pancreatic mesenchyme (IPM, bottom panels) is shown. (B) Pancreas at W9 immunostained for CD31 and collagen type IV (COL4A) illustrating blood vessels in the PPM (top panels) and IPM (bottom panels). White arrows point to CD31-positive blood vessels with a continuous basement membrane. Note that autofluorescent red blood cells, as yellow/orange dots, are present in in all images. Scale bars: 30 μm.

Mentions: A key step in the maturation of the endothelial tubes to form arteries during vascular development is the attraction of mural cells and their subsequent differentiation to smooth muscle cells through endothelial cell association [42, 43]. The association of smooth muscle cells, expressing alpha smooth muscle actin (ACTA2), with the blood vessels (arteries) was observed as early as W9 (Figure 2A, left panels), but only in the PPM (Figure 2A, left panels). However, from W12 onwards the CD31-positive blood vessels in the IPM also started to show association with ACTA2-positive smooth muscle cells (Figure 2A, middle panels). From W12-W22, the number of CD31-positive blood vessels associated with ACTA2-positive cells, presumably arteries, increased both in the IPM and PPM (Figure 2A, right panels), but some of the large caliber CD31-positive vessels, presumably veins, remained devoid of smooth muscle cells. Large caliber blood vessels (uncoated or coated with ACTA2-positive smooth muscle cells) were never observed in close association with islets of Langerhans. Concluding, the association of smooth muscle cells with blood vessels showed a clear spatial developmental delay of several weeks between the IPM and PPM. By contrast, at W9 blood vessels containing a collagen type IV (COL4A)-rich basement membrane, another key step in the vascular maturation, was already clearly visible in both PPM and IPM (Figure 2B).Figure 2


Lymphangiogenesis and angiogenesis during human fetal pancreas development.

Roost MS, van Iperen L, de Melo Bernardo A, Mummery CL, Carlotti F, de Koning EJ, Chuva de Sousa Lopes SM - (2014)

Blood vessels and their association with smooth muscle cells and basement membrane formation during human pancreatic development. (A) Pancreata at W9, W11, W12 and W19 immunostained for CD31 and smooth muscle actin (ACTA2). Smooth muscle cell association with blood vessels in the peri-pancreatic mesenchyme (PPM, top panels) and intra-pancreatic mesenchyme (IPM, bottom panels) is shown. (B) Pancreas at W9 immunostained for CD31 and collagen type IV (COL4A) illustrating blood vessels in the PPM (top panels) and IPM (bottom panels). White arrows point to CD31-positive blood vessels with a continuous basement membrane. Note that autofluorescent red blood cells, as yellow/orange dots, are present in in all images. Scale bars: 30 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4362646&req=5

Fig2: Blood vessels and their association with smooth muscle cells and basement membrane formation during human pancreatic development. (A) Pancreata at W9, W11, W12 and W19 immunostained for CD31 and smooth muscle actin (ACTA2). Smooth muscle cell association with blood vessels in the peri-pancreatic mesenchyme (PPM, top panels) and intra-pancreatic mesenchyme (IPM, bottom panels) is shown. (B) Pancreas at W9 immunostained for CD31 and collagen type IV (COL4A) illustrating blood vessels in the PPM (top panels) and IPM (bottom panels). White arrows point to CD31-positive blood vessels with a continuous basement membrane. Note that autofluorescent red blood cells, as yellow/orange dots, are present in in all images. Scale bars: 30 μm.
Mentions: A key step in the maturation of the endothelial tubes to form arteries during vascular development is the attraction of mural cells and their subsequent differentiation to smooth muscle cells through endothelial cell association [42, 43]. The association of smooth muscle cells, expressing alpha smooth muscle actin (ACTA2), with the blood vessels (arteries) was observed as early as W9 (Figure 2A, left panels), but only in the PPM (Figure 2A, left panels). However, from W12 onwards the CD31-positive blood vessels in the IPM also started to show association with ACTA2-positive smooth muscle cells (Figure 2A, middle panels). From W12-W22, the number of CD31-positive blood vessels associated with ACTA2-positive cells, presumably arteries, increased both in the IPM and PPM (Figure 2A, right panels), but some of the large caliber CD31-positive vessels, presumably veins, remained devoid of smooth muscle cells. Large caliber blood vessels (uncoated or coated with ACTA2-positive smooth muscle cells) were never observed in close association with islets of Langerhans. Concluding, the association of smooth muscle cells with blood vessels showed a clear spatial developmental delay of several weeks between the IPM and PPM. By contrast, at W9 blood vessels containing a collagen type IV (COL4A)-rich basement membrane, another key step in the vascular maturation, was already clearly visible in both PPM and IPM (Figure 2B).Figure 2

Bottom Line: Whilst lymphatic vessels did not directly intrude the islets of Langerhans, three-dimensional reconstruction revealed that they were present in the vicinity of islets of Langerhans between W17-W22.Our data suggest that the blood and lymphatic machinery in the human pancreas is in place to support endocrine function from W17-W22 onwards.Our study provides the first systematic assessment of the progression of lymphangiogenesis during human pancreatic development.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.

ABSTRACT

Background: The complex endocrine and exocrine functionality of the human pancreas depends on an efficient fluid transport through the blood and the lymphatic vascular systems. The lymphatic vasculature has key roles in the physiology of the pancreas and in regulating the immune response, both important for developing successful transplantation and cell-replacement therapies to treat diabetes. However, little is known about how the lymphatic and blood systems develop in humans. Here, we investigated the establishment of these two vascular systems in human pancreas organogenesis in order to understand neovascularization in the context of emerging regenerative therapies.

Methods: We examined angiogenesis and lymphangiogenesis during human pancreas development between 9 and 22 weeks of gestation (W9-W22) by immunohistochemistry.

Results: As early as W9, the peri-pancreatic mesenchyme was populated by CD31-expressing blood vessels as well as LYVE1- and PDPN-expressing lymphatic vessels. The appearance of smooth muscle cell-coated blood vessels in the intra-pancreatic mesenchyme occurred only several weeks later and from W14.5 onwards the islets of Langerhans also became heavily irrigated by blood vessels. In contrast to blood vessels, LYVE1- and PDPN-expressing lymphatic vessels were restricted to the peri-pancreatic mesenchyme until later in development (W14.5-W17), and some of these invading lymphatic vessels contained smooth muscle cells at W17. Interestingly, between W11-W22, most large caliber lymphatic vessels were lined with a characteristic, discontinuous, collagen type IV-rich basement membrane. Whilst lymphatic vessels did not directly intrude the islets of Langerhans, three-dimensional reconstruction revealed that they were present in the vicinity of islets of Langerhans between W17-W22.

Conclusion: Our data suggest that the blood and lymphatic machinery in the human pancreas is in place to support endocrine function from W17-W22 onwards. Our study provides the first systematic assessment of the progression of lymphangiogenesis during human pancreatic development.

No MeSH data available.


Related in: MedlinePlus