3D-Models of Insulin-Producing β-Cells: from Primary Islet Cells to Stem Cell-Derived Islets

Abstract

There is a need for physiologically relevant assay platforms to provide functionally relevant models of diabetes, to accelerate the discovery of new treatment options and boost developments in drug discovery. In this review, we compare several 3D-strategies that have been used to increase the functional relevance of ex vivo human primary pancreatic islets and developments into the generation of stem cell derived pancreatic beta-cells (β-cells). Special attention will be given to recent approaches combining the use of extracellular matrix (ECM) scaffolds with pancreatic molecular memory, which can be used to improve yield and functionality of in vitro stem cell-derived pancreatic models. The ultimate goal is to develop scalable cell-based platforms for diabetes research and drug screening. This article will critically assess key aspects related to in vitro pancreatic 3D-ECM models and highlight the most promising approaches for future research.

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Abbreviations

DM:

Diabetes mellitus

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

Islets:

Islets of Langerhans

β-cells:

Beta-cells

INS:

Insulin

C-PEP:

C-Peptide

GSIS:

Glucose-stimulated INS secretion

ESCs:

Embryonic stem cell

iPSC:

Induced pluripotent stem cell

MSCs:

Mesenchymal stem cells

ECM:

Extracellular matrix

BM:

Basement membrane

COL:

Collagen

LN:

Laminin

3D:

3-dimensional

References

  1. 1.

    American Diabetes Association (2010). Diagnosis and classification of diabetes mellitus. Diabetes Care, 33 Suppl 1, S62–S69.

    Article  Google Scholar 

  2. 2.

    Tiwari, N. (2014). Therapeutic targets for diabetes mellitus: an update. Clinical Pharmacology & Biopharmaceutics, 3.

  3. 3.

    Daneman, D. (2006). Type 1 diabetes. The Lancet, 367, 847–58.

    CAS  Article  Google Scholar 

  4. 4.

    Nathan, D. M., Zinman, B., Cleary, P. A., et al. (2009). Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983–2005). Archives of Internal Medicine, 169, 1307–1316.

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Croon, A. C., Karlsson, R., Bergström, C., et al. (2003). Lack of donors limits the use of islet transplantation as treatment for diabetes. Transplantation Proceedings, 35, 764.

    PubMed  Article  Google Scholar 

  6. 6.

    Paraskevas, S., Maysinger, D., Wang, R., Duguid, T. P., Rosenberg, L. (2000). Cell loss in isolated human islets occurs by apoptosis. Pancreas, 20, 270–276.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Wajchenberg, B. L. (2007) β-cell failure in diabetes and preservation by clinical treatment < beta Cell Failure in Diabetes and Preservation by Clinical.pdf>. Endocrine Reviews, 28, 187–218.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    He, Z. X., Zhou, Z. W., Yang, Y., et al. (2015). Overview of clinically approved oral antidiabetic agents for the treatment of type 2 diabetes mellitus. Clinical and Experimental Pharmacology & Physiology, 42, 125 – 38.

    CAS  Article  Google Scholar 

  9. 9.

    World Health Organization W (2015). Global report on diabetes.

  10. 10.

    Rowley, W. R., & Bezold, C. (2012). Creating public awareness: state 2025 diabetes forecasts. Population Health Management, 15, 194–200.

    PubMed  Article  Google Scholar 

  11. 11.

    International Diabetes Foundation I (2015). Diabetes atlas, Seventh Edition.

  12. 12.

    Otonkoski, T., Banerjee, M., Korsgren, O., Thornell, L. E., & Virtanen, I. (2008). Unique basement membrane structure of human pancreatic islets: implications for beta-cell growth and differentiation. Diabetes, Obesity & Metabolism, 10 Suppl 4, 119 – 127.

    CAS  Article  Google Scholar 

  13. 13.

    Hu, W., Zhao, G., Wang, C., Zhang, J., & Fu, L. (2012). Nonlinear optical microscopy for histology of fresh normal and cancerous pancreatic tissues. PloS One, 7, e37962.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Rojas, A., Khoo, A., Tejedo, J. R., Bedoya, F. J., Soria, B., & Martin, F. (2010). Islet cell development. In: M. S. Islam (Ed.), The islets of Langerhans, advances in experimental medicine and biology. Springer Science + Business Media B.V., pp. 59–75.

  15. 15.

    Cabrera, O., Berman, D. M., Kenyon, N. S., Ricordi, C., Berggren, P. O., & Caicedo, A. (2006). The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proceedings of the National Academy of Sciences of the United States of America, 103, 2334–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Bonner-Weir, S., Sullivan, B. A., & Weir, G. C. (2015). Human islet morphology revisited: human and rodent islets are not so different after all. The Journal of Histochemistry and Cytochemistry, 63, 604 – 612.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Brissova, M., Fowler, M. J., Nicholson, W. E., et al. (2005). Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. The Journal of Histochemistry and Cytochemistry, 53, 1087–1097.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Schuit, F. C., In’t Veld, P. A., & Pipeleers, D. G. (1988). Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells. Proceedings of the National Academy of Sciences, 85, 3865–3869.

    CAS  Article  Google Scholar 

  19. 19.

    Suckale, J., & Solimena, M. (2010). The insulin secretory granule as a signaling hub. Trends in Endocrinology and Metabolism: TEM, 21, 599–609.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Rorsman, P., & Braun, M. (2013). Regulation of insulin secretion in human pancreatic islets. Annual Review of Physiology, 75, 155 – 79.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    MacDonald, P. E., Joseph, J. W., & Rorsman, P. (2005). Glucose-sensing mechanisms in pancreatic beta-cells. Philosophical Transactions of the Royal Society of London Series B, Biological Sciences, 360, 2211–2225.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Bosco, D., Armanet, M., Morel, P., et al. (2010). Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes, 59, 1202–1210.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Wang, R. N., & Rosenberg, L. (1999). Maintenance of beta-cell function and survival following islet isolation requires re-establishment of the islet-matrix relationship. The Journal of Endocrinology, 163, 181 – 190.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Negi, S., Jetha, A., Aikin, R., Hasilo, C., Sladek, R., Paraskevas, S. (2012). Analysis of beta-cell gene expression reveals inflammatory signaling and evidence of dedifferentiation following human islet isolation and culture. PloS One, 7, e30415.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Zuellig, R. A., Cavallari, G., Gerber, P., et al. (2017). Improved physiological properties of gravity-enforced reassembled rat and human pancreatic pseudo-islets. Journal of Tissue Engineering and Regenerative Medicine, 11, 109 – 120.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Jiang, F. X., Cram, D. S., DeAizpurua, H. J., Harrison, L. C. (1999). Laminin-1 promotes differentiation of fetal mouse pancreatic beta-cells. Diabetes, 48, 722 – 730.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Cirulli, V., Beattie, G. M., Klier, G., et al. (2000). Expression and function of alpha(v)beta(3) and alpha(v)beta(5) integrins in the developing pancreas: roles in the adhesion and migration of putative endocrine progenitor cells. The Journal of Cell Biology, 150, 1445–1460.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Jiang, F. X., Naselli, G., & Harrison, L. C. (2002). Distinct distribution of laminin and its integrin receptors in the pancreas. The Journal of Histochemistry and Cytochemistry, 50, 1625–1632.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Miner, J. H., & Li, C. P. B. (2004). Laminins alpha2 and alpha4 in pancreatic acinar basement membranes are required for basal receptor localization. The Journal of Histochemistry and Cytochemistry, 52, 153–156.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Nikolova, G., Jabs, N., Konstantinova, I., et al. (2006). The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation. Developmental Cell, 10, 397–405.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Shih, H. P., Panlasigui, D., Cirulli, V., & Sander, M. (2016). ECM signaling regulates collective cellular dynamics to control pancreas branching morphogenesis. Cell Reports, 14, 169 – 179.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Kaido, T., Yebra, M., Cirulli, V., Rhodes, C., Diaferia, G., & Montgomery, A. M. (2006). Impact of defined matrix interactions on insulin production by cultured human beta-cells: effect on insulin content, secretion, and gene transcription. Diabetes, 55, 2723–2729.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Kaido, T., Yebra, M., Cirulli, V., & Montgomery, A. M. (2004). Regulation of human beta-cell adhesion, motility, and insulin secretion by collagen IV and its receptor alpha1beta1. The Journal of Biological Chemistry, 279, 53762–53769.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Daoud, J., Petropavlovskaia, M., Rosenberg, L., & Tabrizian, M. (2010). The effect of extracellular matrix components on the preservation of human islet function in vitro. Biomaterials, 31, 1676–1682.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Ko, J. H., Kim, Y. H., Jeong, S. H., et al. (2015). Collagen esterification enhances the function and survival of pancreatic beta cells in 2D and 3D culture systems. Biochemical and Biophysical Research Communications, 463, 1084–1090.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Yamashita, S., Ohashi, K., Utoh, R., Okano, T., & Yamamoto, M. (2015). Human laminin isotype coating for creating islet cell sheets. Cell Medicine, 8, 39–46.

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Rackham, C. L., Dhadda, P. K., Chagastelles, P. C., et al. (2013). Pre-culturing islets with mesenchymal stromal cells using a direct contact configuration is beneficial for transplantation outcome in diabetic mice. Cytotherapy, 15, 449 – 459.

    PubMed  Article  Google Scholar 

  38. 38.

    Zhao, M., Song, C., Zhang, W., et al. (2010). The three-dimensional nanofiber scaffold culture condition improves viability and function of islets. Journal of Biomedical Materials Research. Part A, 94, 667 – 672.

    PubMed  Google Scholar 

  39. 39.

    Schneider, S., Feilen, P. J., Slotty, V., et al. (2001). Multilayer capsules: a promising microencapsulation system for transplantation of pancreatic islets. Biomaterials, 22, 1961–1970.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Llacua, A., de Haan, B. J., Smink, S. A., & de Vos, P. (2016). Extracellular matrix components supporting human islet function in alginate-based immunoprotective microcapsules for treatment of diabetes. Journal of Biomedical Materials Research Part A, 104, 1788–1796.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Gallego-Perez, D., Higuita-Castro, N., Reen, R. K., et al. (2012). Micro/nanoscale technologies for the development of hormone-expressing islet-like cell clusters. Biomedical Microdevices, 14, 779 – 789.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Shalaly, N. D., Ria, M., Johansson, U., Avall, K., Berggren, P. O., & Hedhammar, M. (2016). Silk matrices promote formation of insulin-secreting islet-like clusters. Biomaterials, 90, 50–61.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Lee, B. R., Hwang, J. W., Choi, Y. Y., et al. (2012). In situ formation and collagen-alginate composite encapsulation of pancreatic islet spheroids. Biomaterials, 33, 837 – 845.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Jun, Y., Kim, M. J., Hwang, Y. H., et al. (2013). Microfluidics-generated pancreatic islet microfibers for enhanced immunoprotection. Biomaterials, 34, 8122–8130.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Jun, Y., Kang, A. R., Lee, J. S., et al. (2013). 3D co-culturing model of primary pancreatic islets and hepatocytes in hybrid spheroid to overcome pancreatic cell shortage. Biomaterials, 34, 3784–3794.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Weber, L. M., & Anseth, K. S. (2008). Hydrogel encapsulation environments functionalized with extracellular matrix interactions increase islet insulin secretion. Matrix Biology: Journal of the International Society for Matrix Biology, 27, 667 – 673.

    CAS  Article  Google Scholar 

  47. 47.

    Davis, N. E., Beenken-Rothkopf, L. N., Mirsoian, A., et al. (2012). Enhanced function of pancreatic islets co-encapsulated with ECM proteins and mesenchymal stromal cells in a silk hydrogel. Biomaterials, 33, 6691–6697.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Daoud, J. T., Petropavlovskaia, M. S., Patapas, J. M., et al. (2011). Long-term in vitro human pancreatic islet culture using three-dimensional microfabricated scaffolds. Biomaterials, 32, 1536–1542.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Liu, J., Liu, S., Chen, Y., Zhao, X., Lu, Y., & Cheng, J. (2015). Functionalized self-assembling peptide improves INS-1 beta-cell function and proliferation via the integrin/FAK/ERK/cyclin pathway. International Journal of Nanomedicine, 10, 3519–3531.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Dominguez-Bendala, J., Lanzoni, G., Klein, D., Alvarez-Cubela, S., & Pastori, R. L. (2016). The human endocrine pancreas: new insights on replacement and regeneration. Trends in Endocrinology and Metabolism: TEM, 27, 153 – 62.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Abdelalim, E. M., & Emara, M. M. (2015). Advances and challenges in the differentiation of pluripotent stem cells into pancreatic beta cells. World Journal of Stem Cells, 7, 174 – 181.

    PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Pagliuca, F. W., & Melton, D. A. (2013). How to make a functional beta-cell. Development, 140, 2472–2483.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Pagliuca, F. W., Millman, J. R., Gurtler, M., et al. (2014). Generation of functional human pancreatic beta cells in vitro. Cell, 159, 428 – 439.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Agulnick, A. D., Ambruzs, D. M., Moorman, M. A., et al. (2015). Insulin-producing endocrine cells differentiated in vitro from human embryonic stem cells function in macroencapsulation devices in vivo. Stem Cells Translational Medicine, 4, 1214–1222.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Vegas, A. J., Veiseh, O., Gurtler, M., et al. (2016). Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nature Medicine.

  56. 56.

    D’Amour, K. A., Agulnick, A. D., Eliazer, S., Kelly, O. G., Kroon, E., & Baetge, E. E. (2005). Efficient differentiation of human embryonic stem cells to definitive endoderm. Nature Biotechnology, 23, 1534–1541.

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Cho, C. H., Hannan, N. R., Docherty, F. M., et al. (2012). Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells. Diabetologia, 55, 3284–3295.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Zhang, D., Jiang, W., Liu, M., et al. (2009). Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Research, 19, 429 – 438.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Johannesson, M., Stahlberg, A., Ameri, J., Sand, F. W., Norrman, K., & Semb, H. (2009). FGF4 and retinoic acid direct differentiation of hESCs into PDX1-expressing foregut endoderm in a time- and concentration-dependent manner. PloS One, 4, e4794.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. 60.

    Xu, X., Browning, V. L., Odorico, J. S.. Activin (2011). BMP and FGF pathways cooperate to promote endoderm and pancreatic lineage cell differentiation from human embryonic stem cells. Mechanisms of Development, 128, 412 – 427.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Toyoda, T., Mae, S., Tanaka, H., et al. (2015). Cell aggregation optimizes the differentiation of human ESCs and iPSCs into pancreatic bud-like progenitor cells. Stem Cell Research, 14, 185 – 197.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Lumelsky, N., Blondel, O., Laeng, P., Velasco, I., Ravin, R., & McKay, R. (2001). Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science, 292, 1389–1394.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    D’Amour, K. A., Bang, A. G., Eliazer, S., et al. (2006). Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nature Biotechnology, 24, 1392 – 1401.

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Jiang, J., Au, M., Lu, K., et al. (2007). Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells, 25, 1940–1953.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Schulz, T. C., Young, H. Y., Agulnick, A. D., et al. (2012). A scalable system for production of functional pancreatic progenitors from human embryonic stem cells. PloS One, 7, e37004.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Rezania, A., Bruin, J. E., Arora, P., et al. (2014). Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nature Biotechnology, 32, 1121–1133.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Rezania, A., Bruin, J. E., Riedel, M. J., et al. (2012). Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes, 61, 2016–2029.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Russ, H. A., Parent, A. V., Ringler, J. J., et al. (2015). Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. The EMBO Journal, 34, 1759–1772.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Mao, G. H., Chen, G. A., Bai, H. Y., Song, T. R., & Wang, Y. X. (2009). The reversal of hyperglycaemia in diabetic mice using PLGA scaffolds seeded with islet-like cells derived from human embryonic stem cells. Biomaterials, 30, 1706–1714.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Bhonde, R. R., Sheshadri, P., Sharma, S., & Kumar, A. (2014). Making surrogate beta-cells from mesenchymal stromal cells: perspectives and future endeavors. The International Journal of Biochemistry & Cell Biology, 46, 90–102.

    CAS  Article  Google Scholar 

  71. 71.

    Chandra, V., Swetha, G., Muthyala, S., et al. (2011). Islet-like cell aggregates generated from human adipose tissue derived stem cells ameliorate experimental diabetes in mice. PloS One, 6, e20615.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Chandra, V., Swetha, G., Phadnis, S., Nair, P. D., & Bhonde, R. R. (2009). Generation of pancreatic hormone-expressing islet-like cell aggregates from murine adipose tissue-derived stem cells. Stem Cells, 27, 1941–1953.

  73. 73.

    Chao, K. C., Chao, K. F., Fu, Y. S., & Liu, S. H. (2008). Islet-like clusters derived from mesenchymal stem cells in Wharton’s jelly of the human umbilical cord for transplantation to control type 1 diabetes. PloS One, 3, e1451.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Qu, H., Liu, X., Ni, Y., et al. (2014). Laminin 411 acts as a potent inducer of umbilical cord mesenchymal stem cell differentiation into insulin-producing cells. Journal of Translation Medicine, 12, 135.

    Article  CAS  Google Scholar 

  75. 75.

    Lin, H. Y., Tsai, C. C., Chen, L. L., Chiou, S. H., Wang, Y. J., & Hung, S. C. (2010). Fibronectin and laminin promote differentiation of human mesenchymal stem cells into insulin producing cells through activating Akt and ERK. Journal of Biomedical Science, 17, 56.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Sabek, O. M., Farina, M., Fraga, D. W., et al. (2016). Three-dimensional printed polymeric system to encapsulate human mesenchymal stem cells differentiated into islet-like insulin-producing aggregates for diabetes treatment. Journal of Tissue Engineering, 7. https://doi.org/10.1177/2041731416638198.

  77. 77.

    Villa-Diaz, L. G., Ross, A. M., Lahann, J., & Krebsbach, P. H. (2013). Concise review: the evolution of human pluripotent stem cell culture: from feeder cells to synthetic coatings. Stem Cells, 31, 1–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Lin, P. Y., Hung, S. H., Yang, Y. C., et al. (2014). A synthetic peptide-acrylate surface for production of insulin-producing cells from human embryonic stem cells. Stem Cells and Development, 23, 372–379.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Oktay, M., Wary, K. K., Dans, M., Birge, R. B., & Giancotti, F. G. (1999). Integrin-mediated activation of focal adhesion Kinase is required for signaling to Jun NH2-terminal Kinase and progression through the G1 phase of the cell cycle. The Journal of Cell Biology, 145, 1461–1470.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Belkin, A. M., & Stepp, M. A. (2000). Integrins as receptors for laminins. Microscopy Research and Technique, 51, 280–301.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Kim, J. H., Kim, H. W., Cha, K. J., et al. (2016). Nanotopography promotes pancreatic differentiation of human embryonic stem cells and induced pluripotent stem cells. ACS Nano, 10, 3342–3355.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Brown, B. N., & Badylak, S. F. (2014). Extracellular matrix as an inductive scaffold for functional tissue reconstruction. Translational Research, 163, 268 – 285.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Sicari, B. M., Rubin, J. P., Dearth, C. L., et al. (2014). An acellular biologic scaffold promotes skeletal muscle formation in mice and humans with volumetric muscle loss. Science Translational Medicine, 6, 234ra58.

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Bejjani, G. K., & Zabramski, J. (2007). Safety and efficacy of the porcine small intestinal submucosa dural substitute: results of a prospective multicenter study and literature review. Journal of Neurosurgery, 106, 1028–1033.

    PubMed  Article  Google Scholar 

  85. 85.

    Ning, L. J., Zhang, Y. J., Zhang, Y., et al. (2015). The utilization of decellularized tendon slices to provide an inductive microenvironment for the proliferation and tenogenic differentiation of stem cells. Biomaterials, 52, 539 – 550.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    De Carlo, E., Baiguera, S., Conconi, M. T., et al. (2009). Pancreatic acellular matrix supports islet survival and function in a synthetic tubular device: in vitro and in vivo studies. International Journal of Molecular Medicine, 25.

  87. 87.

    Li, W., Lee, S., Ma, M., et al. (2013). Microbead-based biomimetic synthetic neighbors enhance survival and function of rat pancreatic beta-cells. Scientific Reports, 3, 2863.

    PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Chaimov, D., Baruch, L., Krishtul, S., Meivar-levy, I., Ferber, S., & Machluf, M. (2016). Innovative encapsulation platform based on pancreatic extracellular matrix achieve substantial insulin delivery. Journal of Controlled Release.

  89. 89.

    Wang, X., Wang, K., Zhang, W., Qiang, M., & Luo, Y. (2017). A bilaminated decellularized scaffold for islet transplantation: structure, properties and functions in diabetic mice. Biomaterials, 138, 80–90.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Goh, S. K., Bertera, S., Olsen, P., et al. (2013). Perfusion-decellularized pancreas as a natural 3D scaffold for pancreatic tissue and whole organ engineering. Biomaterials, 34, 6760–6772.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Mirmalek-Sani, S. H., Orlando, G., McQuilling, J. P., et al. (2013). Porcine pancreas extracellular matrix as a platform for endocrine pancreas bioengineering. Biomaterials, 34, 5488–5495.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Katsuki, Y., Yagi, H., Okitsu, T., et al. (2016). Endocrine pancreas engineered using porcine islets and partial pancreatic scaffolds. Pancreatology, 16, 922 – 930.

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Spector, M. (2016). Decellularized tissues and organs: an historical perspective and prospects for the future. Biomedical Materials, 11, 020201.

    PubMed  Article  CAS  Google Scholar 

  94. 94.

    Parmaksiz, M., Dogan, A., Odabas, S., Elcin, A. E., & Elcin, Y. M. (2016). Clinical applications of decellularized extracellular matrices for tissue engineering and regenerative medicine. Biomedical Materials, 11, 022003.

    PubMed  Article  CAS  Google Scholar 

  95. 95.

    Borg, D. J., & Bonifacio, E. (2011). The use of biomaterials in islet transplantation. Current Diabetes Reports, 11, 434 – 44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Smink, A. M., de Haan, B. J., Paredes-Juarez, G. A., et al. (2016). Selection of polymers for application in scaffolds applicable for human pancreatic islet transplantation. Biomedical Materials, 11, 035006.

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Montazeri, L., Hojjati-Emami, S., Bonakdar, S., et al. (2016). Improvement of islet engrafts by enhanced angiogenesis and microparticle-mediated oxygenation. Biomaterials, 89, 157 – 165.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Buitinga, M., Assen, F., Hanegraaf, M., et al. (2017). Micro-fabricated scaffolds lead to efficient remission of diabetes in mice. Biomaterials, 135, 10–22.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Gibly, R. F., Zhang, X., Lowe, W. L. Jr., & Shea, L. D. (2013). Porous scaffolds support extrahepatic human islet transplantation, engraftment, and function in mice. Cell Transplantation, 22, 811–819.

    PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Smink, A. M., Li, S., Swart, D. H., et al. (2017). Stimulation of vascularization of a subcutaneous scaffold applicable for pancreatic islet-transplantation enhances immediate post-transplant islet graft function but not long-term normoglycemia. Journal of Biomedical Materials Research Part A, 105, 2533–2542.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Mao, D., Zhu, M., Zhang, X., et al. (2017). A macroporous heparin-releasing silk fibroin scaffold improves islet transplantation outcome by promoting islet revascularisation and survival. Acta Biomaterialia, 59, 210–220.

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Hlavaty, K. A., Gibly, R. F., Zhang, X., et al. (2014). Enhancing human islet transplantation by localized release of trophic factors from PLG scaffolds. American Journal of Transplantation, 14, 1523–1532.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Konstantinova, I., & Lammert, E. (2004). Microvascular development: learning from pancreatic islets. BioEssays: news and reviews in molecular. Cellular and Developmental Biology, 26, 1069–1075.

    CAS  Google Scholar 

  104. 104.

    Henderson, J. R., & Moss, M. C. (1985). A morphometric study of the endocrine and exocrine capillaries of the pancreas. Quarterly Journal of Experimental Physiology, 70, 347–356.

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Bonner-Weir, S. (1988). Morphological evidence for pancreatic polarity of beta-cell within islets of Langerhans. Diabetes, 37, 616 – 621.

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Eberhard, D., Kragl, M., & Lammert, E. (2010). ‘Giving and taking’: endothelial and beta-cells in the islets of Langerhans. Trends in Endocrinology and Metabolism: TEM, 21, 457 – 463.

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Watada, H. (2010). Role of VEGF-A in pancreatic beta cells. Endocrine Journal, 57, 185 – 191.

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Zanone, M. M., Favaro, E., & Camussi, G. (2008). From endothelial to beta cells: insights into pancreatic islet microendothelium. Current Diabetes Reviews, 4, 1–9.

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Olsson, R., & Carlsson, P. O. (2006). The pancreatic islet endothelial cell: emerging roles in islet function and disease. The International Journal of Biochemistry & Cell Biology, 38, 492–497.

    CAS  Article  Google Scholar 

  110. 110.

    Quaranta, P., Antonini, S., Spiga, S., et al. (2014). Co-transplantation of endothelial progenitor cells and pancreatic islets to induce long-lasting normoglycemia in streptozotocin-treated diabetic rats. PloS One, 9, e94783.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  111. 111.

    Phelps, E. A., Headen, D. M., Taylor, W. R., Thule, P. M., & Garcia, A. J. (2013). Vasculogenic bio-synthetic hydrogel for enhancement of pancreatic islet engraftment and function in type 1 diabetes. Biomaterials, 34, 4602–4611.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Linn, T., Erb, D., Schneider, D., et al. (2003). Polymers for induction of revascularization in the rat fascial flap: application of vascular endothelial growth factor and pancreatic islet cells. Cell Transplantation, 12, 769 – 778.

    PubMed  Article  Google Scholar 

  113. 113.

    Ozhikandathil, J., Badilescu, S., & Packirisamy, M. (2017). A brief review on microfluidic platforms for hormones detection. Journal of Neural Transmission, 124, 47–55.

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Yi, L., Wang, X., Dhumpa, R., Schrell, A. M., Mukhitov, N., & Roper, M. G. (2015). Integrated perfusion and separation systems for entrainment of insulin secretion from islets of Langerhans. Lab on a Chip, 15, 823 – 832.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Shackman, J. G., Reid, K. R., Dugan, C. E., & Kennedy, R. T. (2012). Dynamic monitoring of glucagon secretion from living cells on a microfluidic chip. Analytical and Bioanalytical Chemistry, 402, 2797 – 2803.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Adewola, A. F., Lee, D., Harvat, T., et al. (2010). Microfluidic perifusion and imaging device for multi-parametric islet function assessment. Biomedical Microdevices, 12, 409 – 417.

    PubMed  Article  Google Scholar 

  117. 117.

    Mohammed, J. S., Wang, Y., Harvat, T. A., Oberholzer, J., & Eddington, D. T. (2009). Microfluidic device for multimodal characterization of pancreatic islets. Lab on a Chip, 9, 97–106.

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Nourmohammadzadeh, M., Lo, J. F., Bochenek, M., et al. (2013). Microfluidic array with integrated oxygenation control for real-time live-cell imaging: effect of hypoxia on physiology of microencapsulated pancreatic islets. Analytical Chemistry, 85, 11240–11249.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Hirano, K., Konagaya, S., Turner, A., et al. (2017). Closed-channel culture system for efficient and reproducible differentiation of human pluripotent stem cells into islet cells. Biochemical and Biophysical Research Communications, 487, 344 – 350.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

DR is funded by the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7 (2007–2013) under REA grant agreement n˚ [607842]. PW-S also acknowledge the Wallenberg Foundation, Chalmers Foundation and the Swedish Research Council.

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Correspondence to Diana Ribeiro or Anna Forslöw.

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The authors declare a conflict of interest. DR, AK, RH and AF are employees and shareholders of AstraZeneca. PW-S is employed by Chalmers University of Technology and funded described in the acknowledge section. The funders did not have any role in the decision to publish or preparation of the manuscript.

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Ribeiro, D., Kvist, A.J., Wittung-Stafshede, P. et al. 3D-Models of Insulin-Producing β-Cells: from Primary Islet Cells to Stem Cell-Derived Islets. Stem Cell Rev and Rep 14, 177–188 (2018). https://doi.org/10.1007/s12015-017-9783-8

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Keywords

  • Human pancreatic islets
  • Stem cell-derived β-cells
  • Insulin
  • GSIS
  • 3D-models
  • Pancreatic ECM
  • Decellularized scaffolds