Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo

Rezania, Alireza; Bruin, Jennifer E.; Xu, Jean; Narayan, Kavitha; Fox, Jessica K.; O’Neil, John J.; Kieffer, Timothy J.

doi:10.1002/stem.1489

Cited by 242 publications

(247 citation statements)

References 36 publications

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“…After the 14-day differentiation in vitro, hESC-derived cells were ;99.5% PDX1 + and 70% NKX6.1 + before transplant ( Supplementary Fig. 1), consistent with previous studies (5)(6)(7)13). The progenitor population also contained ;14% endocrine cells, which coexpressed NKX2.2, but were largely NKX6.1 2 ( Supplementary Fig.…”

Section: Thyroid Hormone Deficiency Hinders the Development Of Hesc-dsupporting

confidence: 88%

Hypothyroidism Impairs Human Stem Cell–Derived Pancreatic Progenitor Cell Maturation in Mice

et al. 2016

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Pancreatic progenitors derived from human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating diabetes and are currently being tested in clinical trials. Yet, how the milieu of pancreatic progenitor cells, including exposure to different factors after transplant, may influence their maturation remains unclear. Here, we examined the effect of thyroid dysregulation on the development of hESC-derived progenitor cells in vivo. Hypothyroidism was generated in SCID-beige mice using an iodine-deficient diet containing 0.15% propyl-2-thiouracil, and hyperthyroidism was generated by addition of L-thyroxine (T4) to drinking water. All mice received macroencapsulated hESC-derived progenitor cells, and thyroid dysfunction was maintained for the duration of the study (“chronic”) or for 4 weeks posttransplant (“acute”). Acute hyperthyroidism did not affect graft function, but acute hypothyroidism transiently impaired human C-peptide secretion at 16 weeks posttransplant. Chronic hypothyroidism resulted in severely blunted basal human C-peptide secretion, impaired glucose-stimulated insulin secretion, and elevated plasma glucagon levels. Grafts from chronic hypothyroid mice contained fewer β-cells, heterogenous MAFA expression, and increased glucagon+ and ghrelin+ cells compared to grafts from euthyroid mice. Taken together, these data suggest that long-term thyroid hormone deficiency may drive the differentiation of human pancreatic progenitor cells toward α- and ε-cell lineages at the expense of β-cell formation.

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Section: Thyroid Hormone Deficiency Hinders the Development Of Hesc-dsupporting

confidence: 88%

Hypothyroidism Impairs Human Stem Cell–Derived Pancreatic Progenitor Cell Maturation in Mice

et al. 2016

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“…Their abundance appeared to decline progressively from the onset of endocrine differentiation at 8 wpc and they were barely detected in adult pancreas. Although the dual-stained cells expressed the α-cell transcription factor ARX, they lacked β-cell ones, PDX1, NKX6.1 and MAFA, consistent with the in vitro PSC-derived bihormonal cells, which seem capable of forming monohormonal glucagonpositive cells upon transplantation (Kelly et al, 2011;Rezania et al, 2013). However, coupled with data from mouse, there is no evidence that the native bihormonal cells are the natural forerunner of any mature type of endocrine cell and, indeed, data imply the contrary (Herrera, 2000).…”

Section: Mapping Human Psc Differentiation Onto Human Pancreas Develosupporting

confidence: 71%

Human pancreas development

et al. 2015

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A wealth of data and comprehensive reviews exist on pancreas development in mammals, primarily mice, and other vertebrates. By contrast, human pancreatic development has been less comprehensively reviewed. Here, we draw together those studies conducted directly in human embryonic and fetal tissue to provide an overview of what is known about human pancreatic development. We discuss the relevance of this work to manufacturing insulin-secreting β-cells from pluripotent stem cells and to different aspects of diabetes, especially permanent neonatal diabetes, and its underlying causes.

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“…This was also the case for subcutaneous implants in a TheraCyte macroencapsulation device (TheraCyte Laguna Hills, CA), but with low plasma huC-peptide levels and poor glucose responsiveness (2). Later studies showed formation of glucose-responsive ␤-cells when only the NKX6.1-enriched fraction was implanted (31). The appearance of plasma huCpeptide levels, increasing after glucose injection with a decrease in glycemia, is in itself insufficient evidence for formation of metabolically adequate ␤-cells, a requirement to qualify for ␤-cell replacement.…”

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confidence: 89%

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

Motté

Szepessy

Suenens

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo

Abstract: Human embryonic stem cells (hESCs) are considered a potential alternative to cadaveric islets as a source of transplantable cells for treating patients with diabetes.

Cited by 242 publications

References 36 publications

Hypothyroidism Impairs Human Stem Cell–Derived Pancreatic Progenitor Cell Maturation in Mice

Hypothyroidism Impairs Human Stem Cell–Derived Pancreatic Progenitor Cell Maturation in Mice

Human pancreas development

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

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