Composition and function of macroencapsulated human embryonic stem cell-derived implants: comparison with clinical human islet cell grafts

Motté, Evi; Szepessy, Edit; Suenens, Krista; Stangé, Geert; Bomans, Myriam; Jacobs‐Tulleneers‐Thevissen, Daniel; Ling, Zhidong; Kroon, Evert; Pipeleers, Daniël

doi:10.1152/ajpendo.00219.2014

Cited by 90 publications

(100 citation statements)

References 35 publications

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“…These results and comparison with human islets have been reported [22]. Here, expression of HLA was assessed on the cell surface of hESC-PEs and hESC-ECs.…”

Section: Resultssupporting

confidence: 52%

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Immunogenicity of human embryonic stem cell-derived beta cells

et al. 2016

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Aims/hypothesis To overcome the donor shortage in the treatment of advanced type 1 diabetes by islet transplantation, human embryonic stem cells (hESCs) show great potential as an unlimited alternative source of beta cells. hESCs may have immune privileged properties and it is important to determine whether these properties are preserved in hESC-derived cells. Methods We comprehensively investigated interactions of both innate and adaptive auto-and allo-immunity with hESC-derived pancreatic progenitor cells and hESC-derived endocrine cells, retrieved after in-vivo differentiation in capsules in the subcutis of mice. Results We found that hESC-derived pancreatic endodermal cells expressed relatively low levels of HLA endorsing protection from specific immune responses. HLA was upregulated when exposed to IFNγ, making these endocrine progenitor cells vulnerable to cytotoxic T cells and alloreactive antibodies. In vivo-differentiated endocrine cells were protected from complement, but expressed more HLA and were targets for alloreactive antibody-dependent cellular cytotoxicity and alloreactive cytotoxic T cells. After HLA compatibility was provided by transduction with HLA-A2, preproinsulin-specific T cells killed insulin-producing cells. Conclusions/interpretation hESC-derived pancreatic progenitors are hypoimmunogenic, while in vivo-differentiated endocrine cells represent mature targets for adaptive immune responses. Our data support the need for immune intervention in transplantation of hESC-derived pancreatic progenitors. Cell-impermeable macro-encapsulation may suffice.

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“…These results and comparison with human islets have been reported [22]. Here, expression of HLA was assessed on the cell surface of hESC-PEs and hESC-ECs.…”

Section: Resultssupporting

confidence: 52%

“…Preproinsulin (PPI)-specific T cell clone 1E6 generation was described previously [23]. Briefly, PBMCs from an individual with type 1 diabetes were stimulated with PPI [15][16][17][18][19][20][21][22][23][24] peptide. PPI-specific cytotoxic T lymphocytes (CTLs) were sorted by FACS and expanded.…”

Section: Methodsmentioning

confidence: 99%

Immunogenicity of human embryonic stem cell-derived beta cells

et al. 2016

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“…However, PEG-encapsulation is ineffective in protecting islets from cytokine-mediated cell injury and it has also been demonstrated that PEG is less biocompatible than alginate and similar hydrogels [86]. Nanolayers composed of alginate and chitosan [158], membranes made of polylysine and poly(glutamic acid) [87], poly(L-lysine)-poly(ethylene glycol) (biotin) (PPB) and streptavidin (SA) [160], complement receptor-1 and heparin [88], and PEG lipid and poly(vinyl alcohol) (PVA) [89,90] are some of the many biomaterials currently being evaulated for use in stem cell and islet nanoencapsulation.…”

Section: Nanoencapsulationmentioning

confidence: 99%

“…Pancreatic stem cells [160,161], hESCs [162][163][164], induced pluripotent stem cells (iPSCs) [165][166][167][168][169], mesenchymal [170][171][172][173][174] and adipose-derived stem cells (ADSCs) [175,176] have all been used to derive islet-like cell clusters or insulin-producing cells (IPCs) that are viable, express markers similar to terminally differentiated β-cells (Insulin, GLUT2) and are able to respond to a glucose challenge. These cells have all demonstrated good function after encapsulation within bioencapsulation devices and several in vivo studies have also been conducted.…”

Section: Recent Developments In Stem Cell Therapy For T1dmentioning

confidence: 99%

“…In 2005, Todorov et al reported the existence of multipotent pancreatic progenitor cells that could be successfully differentiated into insulin-producing cells [160]. A year later, Noguchi et al reported the induction of pancreatic progenitor cells into insulin-producing cells, albeit with the use of adenoviral gene transfer [161].…”

Section: Pancreatic Progenitor Stem Cellsmentioning

confidence: 99%

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Encapsulation technologies in beta cell replacement therapies for Type 1 diabetes

Krishnan¹,

Imagawa²,

Foster³

et al. 2016

Nanomaterials and Regenerative Medicine

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Cell Mass Increase Associated with Formation of Glucose-Controlling β-Cell Mass in Device-Encapsulated Implants of hiPS-Derived Pancreatic Endoderm

Robert¹,

Mesmaeker²,

Hulle³

et al. 2019

Stem Cells Translational Medicine

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Device‐encapsulated human stem cell‐derived pancreatic endoderm (PE) can generate functional β‐cell implants in the subcutis of mice, which has led to the start of clinical studies in type 1 diabetes. Assessment of the formed functional β‐cell mass (FBM) and its correlation with in vivo metabolic markers can guide clinical translation. We recently reported ex vivo characteristics of device‐encapsulated human embryonic stem cell‐derived (hES)‐PE implants in mice that had established a metabolically adequate FBM during 50‐week follow‐up. Cell suspensions from retrieved implants indicated a correlation with the number of formed β cells and their maturation to a functional state comparable to human pancreatic β cells. Variability in metabolic outcome was attributed to differences in number of PE‐generated β cells. This variability hinders studies on processes involved in FBM‐formation. This study reports modifications that reduce variability. It is undertaken with device‐encapsulated human induced pluripotent stem cell‐derived‐PE subcutaneously implanted in mice. Cell mass of each cell type was determined on intact tissue inside the device to obtain more precise data than following isolation and dispersion. Implants in a preformed pouch generated a glucose‐controlling β‐cell mass within 20 weeks in over 60% of recipients versus less than 20% in the absence of a pouch, whether the same or threefold higher cell dose had been inserted. In situ analysis of implants indicated a role for pancreatic progenitor cell expansion and endocrine differentiation in achieving the size of β‐ and α‐cell mass that correlated with in vivo markers of metabolic control. stem cells translational medicine 2019;8:1296&1305

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Composition and function of macroencapsulated human embryonic stem cell-derived implants: comparison with clinical human islet cell grafts

Abstract: Therapy Consortium EU-FP7. Composition and function of macroencapsulated human embryonic stem cell-derived implants: comparison with clinical human islet cell grafts.

Cited by 90 publications

References 35 publications

Immunogenicity of human embryonic stem cell-derived beta cells

Immunogenicity of human embryonic stem cell-derived beta cells

Encapsulation technologies in beta cell replacement therapies for Type 1 diabetes

Cell Mass Increase Associated with Formation of Glucose-Controlling β-Cell Mass in Device-Encapsulated Implants of hiPS-Derived Pancreatic Endoderm

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