TY - JOUR
T1 - A hydrogel platform for in vitro three dimensional assembly of human stem cell-derived islet cells and endothelial cells
AU - Augsornworawat, Punn
AU - Velazco-Cruz, Leonardo
AU - Song, Jiwon
AU - Millman, Jeffrey R.
N1 - Funding Information:
This work was supported by the NIH (R01DK114233), JDRF Career Development Award (5-CDA-2017-391-A-N), Washington University Center of Regenerative Medicine, and startup funds from Washington University School of Medicine Department of Medicine. L.V.C. was supported by the NIH (R25GM103757). Microscopy was performed through the Washington University Center for Cellular Imaging (WUCCI), which is supported by Washington University School of Medicine, CDI (CDI-CORE-2015-505) and the Foundation for Barnes-Jewish Hospital (3770). The Washington University Diabetes Research Center (P30DK020579) provided support for the microscopy. We thank Madeleine Goedegebuure, Nicholas White, and Shriya Swaminathan for technical assistance. We thank Dr. Nathaniel J. Hogrebe for reading of this manuscript. L.V.C. J.S. and J.R.M. are inventors on patent filings for the stem cell technology.
Funding Information:
This work was supported by the NIH ( R01DK114233 ), JDRF Career Development Award ( 5-CDA-2017-391-A-N ), Washington University Center of Regenerative Medicine , and startup funds from Washington University School of Medicine Department of Medicine. L.V.C. was supported by the NIH ( R25GM103757 ). Microscopy was performed through the Washington University Center for Cellular Imaging (WUCCI), which is supported by Washington University School of Medicine, CDI (CDI-CORE-2015-505) and the Foundation for Barnes-Jewish Hospital (3770). The Washington University Diabetes Research Center ( P30DK020579 ) provided support for the microscopy. We thank Madeleine Goedegebuure, Nicholas White, and Shriya Swaminathan for technical assistance. We thank Dr. Nathaniel J. Hogrebe for reading of this manuscript.
Publisher Copyright:
© 2019 Acta Materialia Inc.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Differentiation of stem cells into functional replacement cells and tissues is a major goal of the regenerative medicine field. However, one limitation has been organization of differentiated cells into multi-cellular, three-dimensional assemblies. The islets of Langerhans contain many endocrine and non-endocrine cell types, such as insulin-producing β cells and endothelial cells. Despite the potential importance of endothelial cells to islet function, facilitating interactions between endothelial cells and islet endocrine cell types already differentiated from human embryonic stem cells has been difficult in vitro. We have developed a strategy of assembling human embryonic stem cell-derived islet cells with endothelial cells into three-dimensional aggregates on a hydrogel. The resulting islet organoids express β cell and other endocrine markers and are functional, capable of undergoing glucose-stimulated insulin secretion. This assembly was not observed on traditional tissue culture plastic and in aggregates generated in suspension culture, highlighting how physical culture conditions greatly influence the interactions among these cell types. These results provide a platform for evaluating the effects of the islet tissue microenvironment on human embryonic stem cell-derived β cells and other islet endocrine cells to develop tissue engineered islets. Statement of Significance: Differentiation of insulin-producing cells and tissues from human pluripotent stem cells is being investigated for diabetes cell replacement therapies. Despite successes generating β cells, the cell type responsible for glucose-stimulated insulin secretion within the islets of Langerhans found in the pancreas, successful assembly with other non-endocrine cell types, particularly endothelial cells, has been technically challenging. The present study provides a platform for the assembly of endothelial cells with SC-β and other endocrine cells, producing islet organoids that are functional and express β cell markers, that can be used to study the islet microenvironment and islet tissue engineering.
AB - Differentiation of stem cells into functional replacement cells and tissues is a major goal of the regenerative medicine field. However, one limitation has been organization of differentiated cells into multi-cellular, three-dimensional assemblies. The islets of Langerhans contain many endocrine and non-endocrine cell types, such as insulin-producing β cells and endothelial cells. Despite the potential importance of endothelial cells to islet function, facilitating interactions between endothelial cells and islet endocrine cell types already differentiated from human embryonic stem cells has been difficult in vitro. We have developed a strategy of assembling human embryonic stem cell-derived islet cells with endothelial cells into three-dimensional aggregates on a hydrogel. The resulting islet organoids express β cell and other endocrine markers and are functional, capable of undergoing glucose-stimulated insulin secretion. This assembly was not observed on traditional tissue culture plastic and in aggregates generated in suspension culture, highlighting how physical culture conditions greatly influence the interactions among these cell types. These results provide a platform for evaluating the effects of the islet tissue microenvironment on human embryonic stem cell-derived β cells and other islet endocrine cells to develop tissue engineered islets. Statement of Significance: Differentiation of insulin-producing cells and tissues from human pluripotent stem cells is being investigated for diabetes cell replacement therapies. Despite successes generating β cells, the cell type responsible for glucose-stimulated insulin secretion within the islets of Langerhans found in the pancreas, successful assembly with other non-endocrine cell types, particularly endothelial cells, has been technically challenging. The present study provides a platform for the assembly of endothelial cells with SC-β and other endocrine cells, producing islet organoids that are functional and express β cell markers, that can be used to study the islet microenvironment and islet tissue engineering.
KW - Biomaterials
KW - Diabetes
KW - Organoids
KW - Stem cells
KW - Tissue engineering
UR - http://www.scopus.com/inward/record.url?scp=85071435828&partnerID=8YFLogxK
U2 - 10.1016/j.actbio.2019.08.031
DO - 10.1016/j.actbio.2019.08.031
M3 - Article
C2 - 31446050
AN - SCOPUS:85071435828
SN - 1742-7061
VL - 97
SP - 272
EP - 280
JO - Acta Biomaterialia
JF - Acta Biomaterialia
ER -