Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance.

Gerace, D; Zhou, Q; Kenty, JH-R; Veres, A; Sintov, E; Wang, X; Boulanger, KR; Li, H; Melton, DA

Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance.

Gerace, D

Zhou, Q Kenty, JH-R Veres, A Sintov, E Wang, X Boulanger, KR Li, H Melton, DA

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Cell Rep Med, 2023, 4, (1), pp. 100879
Issue Date:: 2023-01-17

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Field	Value	Language
dc.contributor.author	Gerace, D https://orcid.org/0000-0001-9154-0624
dc.contributor.author	Zhou, Q
dc.contributor.author	Kenty, JH-R
dc.contributor.author	Veres, A
dc.contributor.author	Sintov, E
dc.contributor.author	Wang, X
dc.contributor.author	Boulanger, KR
dc.contributor.author	Li, H
dc.contributor.author	Melton, DA
dc.date.accessioned	2024-04-25T03:21:03Z
dc.date.available	2022-12-08
dc.date.available	2024-04-25T03:21:03Z
dc.date.issued	2023-01-17
dc.identifier.citation	Cell Rep Med, 2023, 4, (1), pp. 100879
dc.identifier.issn	2666-3791
dc.identifier.issn	2666-3791
dc.identifier.uri	http://hdl.handle.net/10453/178364
dc.description.abstract	Immunological protection of transplanted stem cell-derived islet (SC-islet) cells is yet to be achieved without chronic immunosuppression or encapsulation. Existing genetic engineering approaches to produce immune-evasive SC-islet cells have so far shown variable results. Here, we show that targeting human leukocyte antigens (HLAs) and PD-L1 alone does not sufficiently protect SC-islet cells from xenograft (xeno)- or allograft (allo)-rejection. As an addition to these approaches, we genetically engineer SC-islet cells to secrete the cytokines interleukin-10 (IL-10), transforming growth factor β (TGF-β), and modified IL-2 such that they promote a tolerogenic local microenvironment by recruiting regulatory T cells (Tregs) to the islet grafts. Cytokine-secreting human SC-β cells resist xeno-rejection and correct diabetes for up to 8 weeks post-transplantation in non-obese diabetic (NOD) mice. Thus, genetically engineering human embryonic SCs (hESCs) to induce a tolerogenic local microenvironment represents a promising approach to provide SC-islet cells as a cell replacement therapy for diabetes without the requirement for encapsulation or immunosuppression.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Cell Rep Med
dc.relation.isbasedon	10.1016/j.xcrm.2022.100879
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.classification	32 Biomedical and clinical sciences
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Cytokines
dc.subject.mesh	Immune Tolerance
dc.subject.mesh	Islets of Langerhans
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Stem Cells
dc.subject.mesh	Cell Engineering
dc.subject.mesh	Islets of Langerhans
dc.subject.mesh	Stem Cells
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Cytokines
dc.subject.mesh	Immune Tolerance
dc.subject.mesh	Cell Engineering
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Cytokines
dc.subject.mesh	Immune Tolerance
dc.subject.mesh	Islets of Langerhans
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Stem Cells
dc.subject.mesh	Cell Engineering
dc.title	Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance.
dc.type	Journal Article
utslib.citation.volume	4
utslib.location.activity	United States
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
utslib.copyright.status	open_access	*
dc.date.updated	2024-04-25T03:20:59Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	4
utslib.citation.issue	1

Abstract:

Immunological protection of transplanted stem cell-derived islet (SC-islet) cells is yet to be achieved without chronic immunosuppression or encapsulation. Existing genetic engineering approaches to produce immune-evasive SC-islet cells have so far shown variable results. Here, we show that targeting human leukocyte antigens (HLAs) and PD-L1 alone does not sufficiently protect SC-islet cells from xenograft (xeno)- or allograft (allo)-rejection. As an addition to these approaches, we genetically engineer SC-islet cells to secrete the cytokines interleukin-10 (IL-10), transforming growth factor β (TGF-β), and modified IL-2 such that they promote a tolerogenic local microenvironment by recruiting regulatory T cells (Tregs) to the islet grafts. Cytokine-secreting human SC-β cells resist xeno-rejection and correct diabetes for up to 8 weeks post-transplantation in non-obese diabetic (NOD) mice. Thus, genetically engineering human embryonic SCs (hESCs) to induce a tolerogenic local microenvironment represents a promising approach to provide SC-islet cells as a cell replacement therapy for diabetes without the requirement for encapsulation or immunosuppression.

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http://hdl.handle.net/10453/178364