Endocrine pancreatic β cells require endothelial signals for normal function
Endocrine pancreatic β cells do not form a basement membrane (BM). Instead, the β cells require endothelial signals for their differentiation and for normal function (Lammert et al. 2003, Yoshitomi & Zaret 2004). During late embryonic development, β cells express high levels of VEGF-A that attract endothelial cells that, in turn, form the vasculature of the islets (Lammert et al. 2003, Nikolova et al., 2006). β cells in VEGF-A deficient mice have shown to have reduced insulin gene expression compared to fully vascularized control islets (Nikolova et al., 2006).
The vascular basement membrane formed next to the β cells contains alpha-4 and alpha-5 laminin isoforms (Sixt et al., 2001). Immunostaining of fetal human pancreas suggests that laminin-411 is expressed (Petajaniemi et al. 2002), however, adult human islets have been suggested to be surrounded by a double BM containing both laminin-511 and laminin-411 but where the BM facing the human endocrine islet only contain laminin-511/521 (Virtanen et al. 2008). A study by Kantengwa et al. demonstrates the presence of the laminin receptor integrin a3β1 on primary and transformed rat islet cells, and an important role of β1 integrins in islet cell attachment and spreading in vitro (Kantengwa et al., 1997).
Laminin-411 and -511 stimulate proliferation and insulin production in vitro
By using pancreas-specific laminins in cell culture, the biological environment of the pancreas can be mimicked, making pancreatic islet cells thrive. In a study by Dr. Doug Melton et al. they investigated which endothelial signals that promote β cell proliferation and function. They show that laminin isoforms -411 and -511 stimulate β1 integrin signaling–dependent insulin production in vitro (Nikolova et al., 2006). The authors suggest that treating islets with these biologically relevant laminin isoforms prior to transplantation could help maintain insulin production until new capillaries are formed in transplanted islets (Nikolova et al., 2006).
Laminin-411 is a potent differentiation inducer of insulin-producing cells
In a publication by Qu et al. they show that laminin-411 act as a potent differentiation inducer of UC-MSC into insulin producing cells (Qu et al., 2014). In the article, they show that laminin-411 induces the expression of pancreatic precursor markers and markedly up-regulate insulin expression, both at mRNA and protein level. More importantly, administration of laminin 411-induced insulin producing cells rapidly and significantly down-regulated fasting blood glucose levels, significantly reduced the HbA1c concentration and markedly improved the symptoms and survival of type-1 diabetic rats (Qu et al., 2014).
Laminin cultured pancreatic islets expand and maintain function ex vivo
Watch this lecture by Dr. Anna Domogatskaya from Karolinska Institutet where she presents her unpublished results showing the effects alpha-4 and alpha-5 laminin isoforms has on mouse pancreatic islets in culture. The main results can be summarized as:
- The pancreatic islets spread out into flattened adherent clusters
- All endocrine cells types (alpha, beta, delta, PP-cells) of the islet start to proliferate
- All the endocrine cell types maintain marker specific expression
- The cultured islets maintain functional ability for glucose-dependent insulin release
- Role of VEGF-A in vascularization of pancreatic islets. Lammert et al. Curr Biol., 2003
- Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Yoshitomi & Zaret. Development, 2004
- Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. Sixt et al. J Cell Biol., 2001
- Identification and characterization of alpha 3 beta 1 integrin on primary and transformed rat islet cells. Kantengwa et al. Exp Cell Res. 1997
- Blood vessels of human islets of Langerhans are surrounded by a double basement membrane. Virtanen et al. Diabetologia, 2008
- Localization of laminin α4-chain in developing and adult human tissues. Petajaniemi et al. J Histochem Cytochem., 2002
- The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation. Nikolova et al. Dev Cell., 2006
- Laminin 411 acts as a potent inducer of umbilical cord mesenchymal stem cell differentiation into insulin-producing cells. Qu et al. J Transl Med., 2014