Treating Diet-Induced Diabetes and Obesity with Human Embryonic Stem Cell-Derived Pancreatic Progenitor Cells and Antidiabetic Drugs

Bruin, Jennifer E.; Saber, Nelly; Braun, Natalie N.; Fox, Jessica K.; Mahdavi, Majid; Asadi, Ali; Drohan, Campbell; O’Dwyer, Shannon; Rosman-Balzer, Diana S.; Swiss, Victoria A.; Rezania, Alireza; Kieffer, Timothy J.

doi:10.1016/j.stemcr.2015.02.011

Cited by 64 publications

(38 citation statements)

References 41 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%

“…The other half of each device was stored in 4% paraformaldehyde, as described below. The procedure for isolating RNA from engrafted tissue within devices and qPCR analysis has been described in detail elsewhere (7). Data were analyzed using Expression Suite 1.0.3 software (Thermo Fisher Scientific/ Life Technologies) and normalized to adult human islets (n = 2 donors) using the DDCt method.…”

Section: Metabolic Assessmentsmentioning

confidence: 99%

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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%

Section: Metabolic Assessmentsmentioning

confidence: 99%

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

et al. 2016

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“…Knowledge gained from developmental biology has been instrumental in deriving glucose-responsive, insulin-secreting pancreatic β cells from embryonic stem (ES) cells or induced pluripotent stem (iPS) cells to generate a cell-based therapy for the treatment of diabetes (Bruin et al, 2015; Pagliuca et al, 2014; Russ et al, 2015). Of particular interest are signaling molecules and transcriptional regulators that direct the β-cell fate or generate fully functional β cells.…”

Section: Introductionmentioning

confidence: 99%

Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and β-Cell Function

et al. 2016

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Summary Pdx1 and Oc1 are co-expressed in multipotent pancreatic progenitors and regulate the pro-endocrine gene Neurog3. Their expression diverges in later organogenesis, with Oc1 absent from hormone+ cells and Pdx1 maintained in mature β cells. In a classical genetic test for cooperative functional interactions, we derived mice with combined Pdx1 and Oc1 heterozygosity. Endocrine development in double-heterozygous pancreata was normal at embryonic day (e)13.5, but defects in specification and differentiation were apparent at e15.5, the height of the second wave of differentiation. Pancreata from double heterozygotes showed alterations in the expression of genes crucial for β-cell development and function, decreased numbers and altered allocation of Neurog3-expressing endocrine progenitors, and defective endocrine differentiation. Defects in islet gene expression and β-cell function persisted in double heterozygous neonates. These results suggest that Oc1 and Pdx1 cooperate prior to their divergence, in pancreatic progenitors, to allow for proper differentiation and functional maturation of β cells.

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“…Perhaps the ultimate cure for type 1 diabetes will require islet cell replacement with designer cells in conjunction with targeted therapies to suppress local autoimmunity. In addition to type 1 diabetes, it is possible that stem cell derived beta cells might prove useful as a treatment for type 2 diabetes and other conditions associated with beta cell dysfunction [69].…”

Section: Remaining Obstacles-beyond Beta Cell Generationmentioning

confidence: 99%

The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds

Johnson

2016

Diabetologia

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The production of fully functional insulin-secreting cells to treat diabetes is a major goal of regenerative medicine. In this article, I review progress towards this goal over the last 15 years from the perspective of a beta cell biologist. I describe the current state-of-the-art, and speculate on the general approaches that will be required to identify and achieve our ultimate goal of producing functional beta cells. The need for deeper phenotyping of heterogeneous cultures of stem cell derived islet-like cells in parallel with a better understanding of the heterogeneity of the target cell type(s) is emphasised. This deep phenotyping should include high-throughput single-cell analysis, as well as comprehensive 'omics technologies to provide unbiased characterisation of cell products and human beta cells. There are justified calls for more detailed and well-powered studies of primary human pancreatic beta cell physiology, and I propose online databases of standardised human beta cell responses to physiological stimuli, including both functional and metabolomic/proteomic/ transcriptomic profiles. With a concerted, community-wide effort, including both basic and applied scientists, beta cell replacement will become a clinical reality for patients with diabetes.Keywords Embryonic stem cells . Glucose-stimulated insulin release . Human pancreatic islet beta cells . Review Abbreviation PDX1 Pancreatic and duodenal homeobox 1The case for beta cell replacement in diabetes Diabetes mellitus was recognised early in the era of regenerative medicine research as an obvious indication for a stem cell based therapy. Type 1 diabetes results from the loss of more than 80% of an individual's pancreatic beta cells, while type 2 diabetes occurs when there is insufficient functional beta cell mass to meet the body's needs. The replacement of lost or dysfunctional beta cells in all patients that require it is one of the most important, but elusive, goals of diabetes research. The rationale for beta cell replacement is clear, given the success with which islet cell transplants reduce dangerous hypoglycaemic events and slow the progression of complications [1][2][3]. Pancreatic beta cells have evolved as master regulators of metabolic homeostasis, sensing glucose and other nutrients and releasing appropriate insulin to induce their storage. We understand the basics of beta cell biology, especially the ionic mechanisms underlying insulin release in response to large and abrupt glucose stimuli, which include a rapid rise in cytosolic Ca 2+ subsequent to the metabolismdriven closure of K ATP channels, as well as a plethora of coupling factors [4]. However, we do not understand precisely how human beta cells respond to physiological stimuli and make fate decisions.There are a number of possible ways to replace beta cells in patients with diabetes. Beta cell proliferation could theoretically be induced from the few remaining beta cells in people Electronic supplementary material The online version of this article

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Treating Diet-Induced Diabetes and Obesity with Human Embryonic Stem Cell-Derived Pancreatic Progenitor Cells and Antidiabetic Drugs

Cited by 64 publications

References 41 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

Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and β-Cell Function

The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds

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