Stem cell-based multi-tissue platforms to model human autoimmune diabetes

Leavens, Karla F.; Alvarez-Dominguez, Juan R.; Vo, Linda T.; Russ, Holger A.; Parent, Audrey V.

doi:10.1016/j.molmet.2022.101610

Cited by 12 publications

(3 citation statements)

References 143 publications

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“…The diverse applications for human pluripotent stem cell-derived islets (SC-islets) in research, pharmacology, and transplantation necessitate their production at both small and large scales. 2 , 3 , 4 , 5 , 6 Given the widespread potential to treat millions of diabetics, a scalable culture method becomes necessary. Traditional culture formats cannot meet this need.…”

Section: Before You Beginmentioning

confidence: 99%

Scalable generation of 3D pancreatic islet organoids from human pluripotent stem cells in suspension bioreactors

Pollock,

Galicia-Silva,

Liu

et al. 2023

STAR Protocols

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Section: Before You Beginmentioning

confidence: 99%

Scalable generation of 3D pancreatic islet organoids from human pluripotent stem cells in suspension bioreactors

Pollock,

Galicia-Silva,

Liu

et al. 2023

STAR Protocols

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“…Human pluripotent stem-cell-derived islets (SC-islets) hold great promise for advancing diabetes research, pharmacology, and transplantation therapy [1][2][3] . However, SC-islets often exhibit immature function, marked by poor insulin stimulation capacity [4][5][6] .…”

Section: Main Textmentioning

confidence: 99%

Cyborg islets: implanted flexible electronics reveal principles of human islet electrical maturation

Li,

Liu,

Lin

et al. 2024

Preprint

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Flexible electronics implanted during tissue formation enable chronic studies of tissue-wide electrophysiology. Here, we integrate tissue-like stretchable electronics during organogenesis of human stem cell-derived pancreatic islets, stably tracing single-cell extracellular spike bursting dynamics over months of functional maturation. Adapting spike sorting methods from neural studies reveals maturation-dependent electrical patterns of α and β-like (SC-α and β) cells, and their stimulus-coupled dynamics. We identified two major electrical states for both SC-α and β cells, distinguished by their glucose threshold for action potential firing. We find that improved hormone stimulation capacity during extended culture reflects increasing numbers of SC-α/β cells in low basal firing states, linked to energy and hormone metabolism gene upregulation. Continuous recording during further maturation by entrainment to daily feeding cycles reveals that circadian islet-level hormone secretion rhythms reflect sustained and coordinate oscillation of cell-level SC-α and β electrical activities. We find that this correlates with cell-cell communication and exocytic network induction, indicating a role for circadian rhythms in coordinating system-level stimulus-coupled responses. Cyborg islets thus reveal principles of electrical maturation that will be useful to build fully functionalin vitroislets for research and therapeutic applications.

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“…New approaches are currently being developed to derive T-cells from hPSCs, as reviewed in ( 103 ). T-cells can be generated from hPSCs either directly or through differentiation to bona fide hematopoietic stem cells, which give rise to T lymphocytes and other immune cells.…”

Section: Islet-reactive Cd8 + T-cell Modelsmentioning

confidence: 99%

In vitro beta-cell killing models using immune cells and human pluripotent stem cell-derived islets: Challenges and opportunities

et al. 2023

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Type 1 diabetes (T1D) is a disease of both autoimmunity and β-cells. The β-cells play an active role in their own demise by mounting defense mechanisms that are insufficient at best, and that can become even deleterious in the long term. This complex crosstalk is important to understanding the physiological defense mechanisms at play in healthy conditions, their alterations in the T1D setting, and therapeutic agents that may boost such mechanisms. Robust protocols to develop stem-cell-derived islets (SC-islets) from human pluripotent stem cells (hPSCs), and islet-reactive cytotoxic CD8+ T-cells from peripheral blood mononuclear cells offer unprecedented opportunities to study this crosstalk. Challenges to develop in vitro β-cell killing models include the cluster morphology of SC-islets, the relatively weak cytotoxicity of most autoimmune T-cells and the variable behavior of in vitro expanded CD8+ T-cells. These challenges may however be highly rewarding in light of the opportunities offered by such models. Herein, we discuss these opportunities including: the β-cell/immune crosstalk in an islet microenvironment; the features that make β-cells more sensitive to autoimmunity; therapeutic agents that may modulate β-cell vulnerability; and the possibility to perform analyses in an autologous setting, i.e., by generating T-cell effectors and SC-islets from the same donor.

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Stem cell-based multi-tissue platforms to model human autoimmune diabetes

Cited by 12 publications

References 143 publications

Scalable generation of 3D pancreatic islet organoids from human pluripotent stem cells in suspension bioreactors

Scalable generation of 3D pancreatic islet organoids from human pluripotent stem cells in suspension bioreactors

Cyborg islets: implanted flexible electronics reveal principles of human islet electrical maturation

In vitro beta-cell killing models using immune cells and human pluripotent stem cell-derived islets: Challenges and opportunities

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