Maturation of Human Embryonic Stem Cell–Derived Pancreatic Progenitors Into Functional Islets Capable of Treating Pre-existing Diabetes in Mice

Rezania, Alireza; Bruin, Jennifer E.; Riedel, Michael; Mahdavi, Majid; Asadi, Ali; Xu, Jean; Gauvin, Rebecca; Narayan, Kavitha; Karanu, Francis; O’Neil, John J.; Ao, Ziliang; Warnock, Garth L.; Kieffer, Timothy J.

doi:10.2337/db11-1711

Cited by 520 publications

(647 citation statements)

References 33 publications

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“…Although induced SLCs were able to produce and secrete insulin, they did not respond to glucose stimulation. This was in line with previous reports indicating that induced ESCs might present immature b-like cells and more induction is required to reach a higher degree of differentiation (Gao et al 2008;Kroon et al 2008;Rezania et al 2012;Schulz et al 2012). To further study differentiated SLCs, expression of Ins, Pax6 and Glut4 was assayed by RT-PCR.…”

Section: Discussionsupporting

confidence: 86%

Blastema cells derived from New Zealand white rabbit’s pinna carry stemness properties as shown by differentiation into insulin producing, neural, and osteogenic lineages representing three embryonic germ layers

et al. 2014

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Stem cells (SCs) are known as undifferentiated cells with self-renewal and differentiation capacities. Regeneration is a phenomenon that occurs in a limited number of animals after injury, during which blastema tissue is formed. It has been hypothesized that upon injury, the dedifferentiation of surrounding tissues leads into the appearance of cells with SC characteristics. In present study, stem-like cells (SLCs) were obtained from regenerating tissue of New Zealand white rabbit's pinna and their stemness properties were examined by their capacity to differentiate toward insulin producing cells (IPCs), as well as neural and osteogenic lineages. Differentiation was induced by culture of SLCs in defined medium, and cell fates were monitored by specific staining, RT-PCR and flow cytometry assays. Our results revealed that dithizone positive cells, which represent IPCs, and islet-like structures appeared 1 week after induction of SLCs, and this observation was confirmed by the elevated expression of Ins, Pax6 and Glut4 at mRNA level. Furthermore, SLCs were able to express neural markers as early as 1 week after retinoic acid treatment. Finally, SLCs were able to differentiate into osteogenic lineage, as confirmed by Alizarin Red S staining and RT-PCR studies. In conclusion, SLCs, which could successfully differentiate into cells derived from all three germ layers, can be considered as a valuable model to study developmental biology and regenerative medicine.

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Section: Discussionsupporting

confidence: 86%

Blastema cells derived from New Zealand white rabbit’s pinna carry stemness properties as shown by differentiation into insulin producing, neural, and osteogenic lineages representing three embryonic germ layers

et al. 2014

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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: 77%

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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“…1,4,5 To date, production of multilineage islet-like clusters from hESC-derived pancreas progenitors has only been reported following implantation and maturation under the kidney capsule in vivo, allowing the transplant to adopt a complex 3-D structure. 6 Recent studies indicate that Neurog3 is just as critical to human pancreatic endocrine development as in mice, with true Neurog3 null mutations leading to neonatal diabetes and a block in b-cell differentiation from hESC. 7 Therefore, it seems plausible that knowledge of how the cell cycle connects to the behavior and lineage potential of endocrine-biased Neurog3 TA.LO progenitors, during both mouse and human endocrine-lineage specification, will be key to understanding the engineering principles that guide the formation of, and endocrine specification from, a 3-D epithelial plexus state endocrine-birth niche.…”

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confidence: 99%

New ideas connecting the cell cycle and pancreatic endocrine-lineage specification

Bechard

Wright

2017

Cell Cycle

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Neurogenin 3 (Neurog3) is a pro-endocrine transcription factor required for endocrine-lineage specification during mouse pancreas development. It was a long-standing notion that Neurog3 activation in Sox9 C epithelial cells, a subset of early multipotent progenitors that produce ductal and endocrine lineages, triggers a rapid progression to a post-mitotic, Neurog3 HI endocrine-committed precursor state. We challenged this model by demonstrating that a mitotic progenitor state, in which Neurog3 is transcriptionally active but at a low level (Neurog3 TA.LO ), pre-empts endocrine-commitment. 1 We postulated a new model in which this Neurog3 TA.LO progenitor state is a mitotic, metastable condition in which low Neurog3 levels regulate decisions regarding progenitor maintenance and endocrine-lineage specification. 1 Our work showed that Neurog3 TA.LO progenitors resemble other progenitor populations, such as intestinal and haematopoietic progenitors, in their ability to undergo multiple rounds of division that seem to be symmetric and produce either more Neurog3 TA.LO progenitors, or two endocrine-committed daughters. 1 This modification of the endocrine-lineage specification model focuses attention on the Neurog3 TA.LO progenitor state as being the stage wherein the critical decision is made as to which endocrine cell fate will be established within committed cells emerging from Neurog3 TA.LO progenitors. Below, we discuss potential connections between the cell cycle and Neurog3 protein levels in Neurog3 TA.LO progenitors, and the implications of bringing this model together with a systems-level understanding of the 3-dimensional and dynamic nature of an epithelial plexus state that represents the endocrine-birth niche. Understanding how cycling Neurog3 TA.LO progenitors integrate their behavior within the surrounding dynamics of a developing epithelial endocrine birth niche will be important. For example, what determines progenitor-maintaining or symmetric endocrinebirth divisions, and the end-fate endocrine potential of Neurog3 TA.LO progenitors, could inform on how to generate multilineage islets rather than simply populations of b cells.Gain and loss of function studies show the power of Neurog3 in instructing endocrine differentiation, but other studies had already begun to suggest correlations between a more finely adjusted Neurog3 expression level and the potential of the Neurog3 TA.LO population to produce endocrine cells (Fig. 1). Wang et al. (2010) reported that a strong Neurog3 hypomorphic condition significantly decreased the degree of endocrine biasing, diverting many cells to non-endocrine acinar or ductal fates (Fig. 1). 2 Our analysis of the same hypomorphic condition showed a doubling of the mitotic index of Neurog3 TA.LO progenitors, but not of the surrounding nonendocrine-biased cells, and expansion of the Neurog3 TA.LO pool at the expense of endocrine-committed cells.

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Maturation of Human Embryonic Stem Cell–Derived Pancreatic Progenitors Into Functional Islets Capable of Treating Pre-existing Diabetes in Mice

Cited by 520 publications

References 33 publications

Blastema cells derived from New Zealand white rabbit’s pinna carry stemness properties as shown by differentiation into insulin producing, neural, and osteogenic lineages representing three embryonic germ layers

Blastema cells derived from New Zealand white rabbit’s pinna carry stemness properties as shown by differentiation into insulin producing, neural, and osteogenic lineages representing three embryonic germ layers

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

New ideas connecting the cell cycle and pancreatic endocrine-lineage specification

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