Stem Cell Therapies for Treating Diabetes: Progress and Remaining Challenges

Sneddon, Julie B.; Tang, Qizhi; Stock, Peter G.; Bluestone, Jeffrey A.; Roy, Shuvo; Desai, Tejal A.; Hebrok, Matthias

doi:10.1016/j.stem.2018.05.016

Cited by 197 publications

(161 citation statements)

References 142 publications

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“…Generating functional stem-cell-derived tissues is a major goal of regenerative medicine, yet current strategies yield products that often fail to recapitulate endogenous cellular function (Sances et al, 2016;Sneddon et al, 2018;Yang et al, 2014). Our group and others advanced methods to differentiate human pluripotent stem cells (hPSCs) into pancreatic islet cells Rezania et al, 2014;Russ et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Circadian Entrainment Triggers Maturation of Human In Vitro Islets

et al. 2020

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Highlights d Epigenome dynamics of human-stem-cell-derived islet differentiation and maturation d Pioneer factors coordinate pervasive enhancer priming to steer endocrine cell fates d Core regulatory circuits identify LMX1B as critical for endocrine cell generation d Circadian rhythms trigger islet maturation via clockcontrolled metabolic cycles SUMMARY Stem-cell-derived tissues could transform disease research and therapy, yet most methods generate functionally immature products. We investigate how human pluripotent stem cells (hPSCs) differentiate into pancreatic islets in vitro by profiling DNA methylation, chromatin accessibility, and histone modification changes. We find that enhancer potential is reset upon lineage commitment and show how pervasive epigenetic priming steers endocrine cell fates.Modeling islet differentiation and maturation regulatory circuits reveals genes critical for generating endocrine cells and identifies circadian control as limiting for in vitro islet function. Entrainment to circadian feeding/fasting cycles triggers islet metabolic maturation by inducing cyclic synthesis of energy metabolism and insulin secretion effectors, including antiphasic insulin and glucagon pulses. Following entrainment, hPSC-derived islets gain persistent chromatin changes and rhythmic insulin responses with a raised glucose threshold, a hallmark of functional maturity, and function within days of transplantation. Thus, hPSC-derived tissues are amenable to functional improvement by circadian modulation.

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Section: Introductionmentioning

confidence: 99%

Circadian Entrainment Triggers Maturation of Human In Vitro Islets

et al. 2020

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“…Intensive work on the biology of the pancreas has focused on developing better treatments for devastating pancreatic diseases, including diabetes mellitus, pancreatitis, and pancreatic cancer. Notably, elucidation of the embryonic development of the pancreas, particularly the mechanisms underlying endocrine cell specification, has provided important guidelines for deriving pancreatic cells from human pluripotent stem cells for therapeutic purposes (Sneddon et al , ).…”

Section: Single‐cell Transcriptomic Analyses Of Pancreatic Organogenementioning

confidence: 99%

Pancreatic development: one cell at a (pseudo)time

Liu

Sneddon

2019

The EMBO Journal

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Gaining a comprehensive understanding of the principles guiding lineage differentiation during organogenesis is a challenge. In this issue, Yu et al () tackle this venture by taking advantage of single‐cell transcriptomic analyses and multiple mouse genetic tools. Their work provides new insights into pancreatic endocrine and exocrine cell differentiation landscapes and identifies new pathways regulating pancreatic lineage allocation in vivo.

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“…The use of human primary tissues to address such questions is limited by inter-individual heterogeneity, unpredictable and restricted access to tissue from key developmental stages, and challenges implementing high-throughput molecular approaches. Likewise, reconstitution of islet development from stem cell sources or fetal human cell lines remains imperfect 8 , thereby limiting interpretation of developmental studies in those systems.…”

mentioning

confidence: 99%

Molecular and genetic regulation of pig pancreatic islet cell development

Kim

Whitener

Peiris

et al. 2019

Preprint

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Reliance on rodents for understanding pancreatic genetics, developmental biology and islet function could limit progress in developing interventions for human diseases like diabetes mellitus.Similarities of pancreas morphology and function, and pancreatic disease modeling in pigs suggest that porcine and human pancreas developmental biology may have useful homologies.However, little is known about pig pancreas development. To fill this knowledge gap, we investigated fetal and neonatal pig pancreas at multiple, crucial developmental stages using modern experimental approaches. Purification of islet β-, α-and d-cells via flow cytometry followed by high-throughput transcriptome analysis (RNA-Seq) provided comprehensive gene expression profiles. Morphometric analysis revealed dynamic developmental endocrine cell allocation and islet architectural similarities between pig and human islets. Gene expression analysis identified cell-and stage-specific expression in sorted pig β-and α-cells, and revealed that pig and human β-cells and α-cells shared characteristic molecular and developmental features not observed in mouse β-cells or α-cells. Over 150 causal or candidate 'diabetes risk' genes identified by human studies had dynamic developmental expression in pig β-and α-cells. Our analysis also unveiled scores of signaling pathways linked to native islet β-cell functional maturation. Thus, the findings, conceptual advances, and resources detailed here show how pig pancreatic islet studies complement or surpass other systems for understanding the developmental programs that generate functional β-and a-cells, and that are relevant to human diseases like diabetes mellitus.

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Stem Cell Therapies for Treating Diabetes: Progress and Remaining Challenges

Cited by 197 publications

References 142 publications

Circadian Entrainment Triggers Maturation of Human In Vitro Islets

Circadian Entrainment Triggers Maturation of Human In Vitro Islets

Pancreatic development: one cell at a (pseudo)time

Molecular and genetic regulation of pig pancreatic islet cell development

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