Generation of functional human pancreatic β cells in vitro

doi:10.1016/J.CELL.2014.09.040

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Generation of functional human pancreatic β cells in vitro

Journal Article•DOI•

Generation of functional human pancreatic β cells in vitro

Felicia W. Pagliuca¹, Jeffrey R. Millman¹, Mads Gürtler¹, Michael Saris Segel¹, Alana Van Dervort¹, Jennifer Hyoje Ryu¹, Quinn P. Peterson¹, Dale L. Greiner², Douglas A. Melton¹ - Show less +5 more•Institutions (2)

Harvard University¹, University of Massachusetts Medical School²

09 Oct 2014-Cell (NIH Public Access)-Vol. 159, Iss: 2, pp 428-439

TL;DR: A scalable differentiation protocol is reported that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro that secrete human insulin into the serum of mice shortly after transplantation in a glucose-regulated manner, and transplantation of these cells ameliorates hyperglycemia in diabetic mice.

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About: This article is published in Cell.The article was published on 2014-10-09 and is currently open access. It has received 1596 citations till now. The article focuses on the topics: Stem cell & Adult stem cell.

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Journal Article•DOI•

Type 2 diabetes mellitus.

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Ralph A. DeFronzo¹, Ele Ferrannini, Leif Groop², Robert R. Henry³, William H. Herman⁴, Jens J. Holst⁵, Frank B. Hu⁶, C. Ronald Kahn⁶, Itamar Raz, Gerald I. Shulman⁷, Donald C. Simonson⁶, Marcia A. Testa⁶, Ram Weiss⁸ - Show less +9 more•Institutions (8)

University of Texas Health Science Center at San Antonio¹, Lund University², University of California, San Diego³, University of Michigan⁴, University of Copenhagen⁵, Harvard University⁶, Yale University⁷, Hebrew University of Jerusalem⁸

23 Jul 2015

TL;DR: The greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications.

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Abstract: Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN.

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1,757 citations

Journal Article•DOI•

A Single-Cell Transcriptomic Map of the Human and Mouse Pancreas Reveals Inter- and Intra-cell Population Structure.

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Maayan Baron¹, Adrian Veres², Samuel L. Wolock², Aubrey L. Faust², Renaud Gaujoux¹, Amedeo Vetere³, Jennifer Hyoje Ryu², Bridget K. Wagner³, Shai S. Shen-Orr¹, Allon M. Klein², Douglas A. Melton², Itai Yanai¹ - Show less +8 more•Institutions (3)

Technion – Israel Institute of Technology¹, Harvard University², Broad Institute³

26 Oct 2016-Cell systems

TL;DR: A droplet-based, single-cell RNA-seq method is implemented to determine the transcriptomes of over 12,000 individual pancreatic cells from four human donors and two mouse strains and provides a resource for the discovery of novel cell type-specific transcription factors, signaling receptors, and medically relevant genes.

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Abstract: Although the function of the mammalian pancreas hinges on complex interactions of distinct cell types, gene expression profiles have primarily been described with bulk mixtures. Here we implemented a droplet-based, single-cell RNA-seq method to determine the transcriptomes of over 12,000 individual pancreatic cells from four human donors and two mouse strains. Cells could be divided into 15 clusters that matched previously characterized cell types: all endocrine cell types, including rare epsilon-cells; exocrine cell types; vascular cells; Schwann cells; quiescent and activated stellate cells; and four types of immune cells. We detected subpopulations of ductal cells with distinct expression profiles and validated their existence with immuno-histochemistry stains. Moreover, among human beta- cells, we detected heterogeneity in the regulation of genes relating to functional maturation and levels of ER stress. Finally, we deconvolved bulk gene expression samples using the single-cell data to detect disease-associated differential expression. Our dataset provides a resource for the discovery of novel cell type-specific transcription factors, signaling receptors, and medically relevant genes.

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1,046 citations

Journal Article•DOI•

Progress in 3D bioprinting technology for tissue/organ regenerative engineering

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Ishita Matai¹, Gurvinder Kaur¹, Amir Seyedsalehi², Aneesah McClinton³, Cato T. Laurencin - Show less +1 more•Institutions (3)

Council of Scientific and Industrial Research¹, University of Connecticut², University of Connecticut Health Center³

01 Jan 2020-Biomaterials

TL;DR: This review outlines recent progress in several bioprinting technologies used to engineer scaffolds with requisite mechanical, structural, and biological complexity and examines the process parameters affecting biop printing and bioink-biomaterials and concludes with the future perspective of biopprinting technology.

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562 citations

Journal Article•DOI•

Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice

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Arturo J. Vegas¹, Arturo J. Vegas², Arturo J. Vegas³, Omid Veiseh³, Omid Veiseh¹, Mads Gürtler⁴, Jeffrey R. Millman⁴, Felicia W. Pagliuca⁴, Andrew Bader², Andrew Bader³, Andrew Bader¹, Joshua C. Doloff³, Joshua C. Doloff¹, Jie Li¹, Jie Li³, Michael Chen³, Michael Chen¹, Karsten Olejnik¹, Karsten Olejnik³, Hok Hei Tam¹, Hok Hei Tam³, Siddharth Jhunjhunwala¹, Siddharth Jhunjhunwala³, Erin Langan¹, Erin Langan³, Stephanie Aresta-Dasilva³, Stephanie Aresta-Dasilva¹, Srujan Gandham¹, Srujan Gandham³, James J. McGarrigle⁵, Matthew A. Bochenek⁵, Jennifer Hollister-Lock⁶, Jose Oberholzer⁵, Dale L. Greiner⁷, Gordon C. Weir⁶, Douglas A. Melton⁸, Douglas A. Melton⁴, Robert Langer, Daniel G. Anderson - Show less +35 more•Institutions (8)

Massachusetts Institute of Technology¹, Washington University in St. Louis², Boston Children's Hospital³, Harvard University⁴, University of Illinois at Chicago⁵, Joslin Diabetes Center⁶, University of Massachusetts Medical School⁷, Howard Hughes Medical Institute⁸

01 Mar 2016-Nature Medicine

TL;DR: The first long-term glycemic correction of a diabetic, immunocompetent animal model using human SC-β cells is reported, which induced glycemic Correction without any immunosuppression until their removal at 174 d after implantation.

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Abstract: When encapsulated with alginate derivatives that resist the foreign-body response, human embryonic stem cell–derived beta cells restore long-term normoglycemia in immunocompetent mice without the need for immunosuppression.

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546 citations

Journal Article•DOI•

Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell– and patient-derived tumor organoids

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Ling Huang¹, Audrey Holtzinger¹, Ishaan Jagan¹, Michael Begora¹, Ines Lohse¹, Nicholas Ngai¹, Cristina Nostro¹, Rennian Wang², Lakshmi Muthuswamy¹, Howard C. Crawford³, Cheryl H. Arrowsmith¹, Cheryl H. Arrowsmith⁴, Steve E. Kalloger⁵, Daniel J. Renouf⁶, Ashton A. Connor⁷, Sean P. Cleary⁷, David F. Schaeffer⁵, David F. Schaeffer⁶, Michael H.A. Roehrl¹, Ming-Sound Tsao¹, Steven Gallinger⁷, Gordon Keller¹, Senthil K. Muthuswamy¹ - Show less +19 more•Institutions (7)

University Health Network¹, University of Western Ontario², University of Michigan³, Structural Genomics Consortium⁴, Vancouver General Hospital⁵, University of British Columbia⁶, University of Toronto⁷

26 Oct 2015-Nature Medicine

TL;DR: Pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

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Abstract: There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

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541 citations

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Journal Article•DOI•

Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

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Kazutoshi Takahashi¹, Shinya Yamanaka¹•Institutions (1)

Kyoto University¹

25 Aug 2006-Cell

TL;DR: Induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions is demonstrated and iPS cells, designated iPS, exhibit the morphology and growth properties of ES cells and express ES cell marker genes.

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23,959 citations

"Generation of functional human panc..." refers background in this paper

...…genetic background. hiPSC, which function like hESC, can be generated from any fibroblasts or other somatic cell types through introduction of a small set of pluripotency genes (Takahashi and Yamanaka, 2006). hiPSC cells from patients with diabetes or other metabolic syndromes have been derived....
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...hiPSC, which function like hESC, can be generated from any fibroblasts or other somatic cell types through introduction of a small set of pluripotency genes (Takahashi and Yamanaka, 2006)....
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Journal Article•DOI•

Production of pancreatic hormone–expressing endocrine cells from human embryonic stem cells

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Kevin A. D'Amour¹, Anne G. Bang¹, Susan Eliazer¹, Olivia Kelly¹, Alan D. Agulnick¹, Nora G Smart¹, Mark A. Moorman¹, Evert Kroon¹, Melissa K Carpenter¹, Emmanuel E. Baetge¹ - Show less +6 more•Institutions (1)

General Atomics¹

19 Oct 2006-Nature Biotechnology

TL;DR: A differentiation process that converts human embryonic stem cells to endocrine cells capable of synthesizing the pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin is developed.

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Abstract: Of paramount importance for the development of cell therapies to treat diabetes is the production of sufficient numbers of pancreatic endocrine cells that function similarly to primary islets We have developed a differentiation process that converts human embryonic stem (hES) cells to endocrine cells capable of synthesizing the pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, gut-tube endoderm, pancreatic endoderm and endocrine precursor--en route to cells that express endocrine hormones The hES cell-derived insulin-expressing cells have an insulin content approaching that of adult islets Similar to fetal beta-cells, they release C-peptide in response to multiple secretory stimuli, but only minimally to glucose Production of these hES cell-derived endocrine cells may represent a critical step in the development of a renewable source of cells for diabetes cell therapy

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2,015 citations

"Generation of functional human panc..." refers background or result in this paper

...…pancreatic progenitors (PP2) could be further differentiated in vitro into some INS+ cells along with INS+/GCG+ or INS+/SST+ polyhormonal (PH) cells (Nostro et al., 2011; Rezania et al., 2012; Thowfeequ et al., 2007; Aguayo-Mazzucato et al., 2013; D’Amour et al., 2006; Hrvatin et al., 2014)....
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...…or PDX1, abnormally coexpress other hormones like glucagon (GCG), fail to function after transplantation in vivo, or display a combination of these abnormal features (D’Amour et al., 2006; Cheng et al., 2012; Hrvatin et al., 2014; Narayanan et al., 2014; Xie et al., 2013; Nostro et al., 2011)....
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...insulin secretion in vitro, fail to express appropriate b cell markers such as NKX6-1 or PDX1, abnormally coexpress other hormones like glucagon (GCG), fail to function after transplantation in vivo, or display a combination of these abnormal features (D’Amour et al., 2006; Cheng et al., 2012; Hrvatin et al., 2014; Narayanan et al., 2014; Xie et al., 2013; Nostro et al., 2011)....
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...…for the pancreatic lineage, and these have been effectively used to form cells in the b cell lineage in vitro from hPSC. Definitive endoderm and subsequent pancreatic progenitors can now be differentiated with high efficiencies (Kroon et al., 2008; D’Amour et al., 2005, 2006; Rezania et al., 2012)....
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...And previous studies had shown that these PDX1+/ NKX6-1+ pancreatic progenitors (PP2) could be further differentiated in vitro into some INS+ cells along with INS+/GCG+ or INS+/SST+ polyhormonal (PH) cells (Nostro et al., 2011; Rezania et al., 2012; Thowfeequ et al., 2007; Aguayo-Mazzucato et al., 2013; D’Amour et al., 2006; Hrvatin et al., 2014)....
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Journal Article•DOI•

Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo

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Evert Kroon¹, Laura Martinson, Kuniko Kadoya, Anne G. Bang, Olivia Kelly, Susan Eliazer, Holly Y. Young, Mike Richardson, Nora G. Smart, Justine J Cunningham, Alan D. Agulnick, Kevin A. D'Amour, Melissa K. Carpenter, Emmanuel E. Baetge - Show less +10 more•Institutions (1)

General Atomics¹

20 Feb 2008-Nature Biotechnology

TL;DR: It is shown that pancreatic endoderm derived from human embryonic stem (hES) cells efficiently generates glucose-responsive endocrine cells after implantation into mice, and it is demonstrated that implantation of hES cell–derived pancreaticEndoderm protects against streptozotocin-induced hyperglycemia.

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Abstract: Development of a cell therapy for diabetes would be greatly aided by a renewable supply of human β-cells. Here we show that pancreatic endoderm derived from human embryonic stem (hES) cells efficiently generates glucose-responsive endocrine cells after implantation into mice. Upon glucose stimulation of the implanted mice, human insulin and C-peptide are detected in sera at levels similar to those of mice transplanted with ~3,000 human islets. Moreover, the insulin-expressing cells generated after engraftment exhibit many properties of functional β-cells, including expression of critical β-cell transcription factors, appropriate processing of proinsulin and the presence of mature endocrine secretory granules. Finally, in a test of therapeutic potential, we demonstrate that implantation of hES cell–derived pancreatic endoderm protects against streptozotocin-induced hyperglycemia. Together, these data provide definitive evidence that hES cells are competent to generate glucose-responsive, insulin-secreting cells. Development of a cellular therapy for the amelioration of diabetes requires a renewable source of human insulin–secreting cells that respond to glucose in a physiologic manner. Currently, cellular replacement is performed either by whole-pancreas transplant or by infusion of isolated primary islets into the portal vein 1 . These procedures, although effective, are not suitable for the general diabetes population, primarily because of the inadequate supply of organs and the necessity of chronic immunosuppression. One approach to overcoming the problem of insufficient supply is to generate islets from proliferative stem cell populations. Currently, the only stem cell population with sufficient proliferative capacity to achieve this goal is human embryonic stem (hES) cells, which proliferate in culture at a rate of >250 population doublings per year 2,3 . Of equal importance, hES cells are capable of efficiently and rapidly differentiating through a series of defined developmental transitions to generate cells of all somatic lineages. This competence has allowed us to produce definitive endoderm cells 4 , foregut, pancreatic and endocrine precursor cells 5 and ultimately insulin-secreting cells 5 . However, in previous studies, functional characterization of hES cells differentiated to endocrine populations showed insulin secretion in response to various secretagogues but not to glucose in vitro 5 or in vivo 6 . Fetal human pancreatic tissues at 14–20 weeks 7–9 or 6–9 weeks 10,11 of age have been shown to develop functionally after implantation in animals. At 6–9 weeks, only a few hormone-expressing endocrine cells, which do not respond to glucose, are present in the fetal human pancreatic anlagen. After implantation, these tissues differentiate

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1,849 citations

"Generation of functional human panc..." refers background or result in this paper

...Transplantation of pancreatic progenitors expressing PDX1+/ NKX6-1+ (PP2 in Figure 1A) into mice gives rise to functional b cells in vivo after 3–4 months (Kroon et al., 2008; Rezania et al., 2012)....
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...Conversely, when 5 million pancreatic progenitor cells are transplanted into mice, no insulin is detected at 2 weeks posttransplant (data not shown) (Kroon et al., 2008; Schulz et al., 2012; Rezania et al., 2012)....
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...…for the pancreatic lineage, and these have been effectively used to form cells in the b cell lineage in vitro from hPSC. Definitive endoderm and subsequent pancreatic progenitors can now be differentiated with high efficiencies (Kroon et al., 2008; D’Amour et al., 2005, 2006; Rezania et al., 2012)....
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...These cells can differentiate into functional b cells within 3–4 months following transplantation into rodents (Kroon et al., 2008; Rezania et al., 2012), indicating that some cells in the preparation contain the developmental potential to develop into b cells if provided enough time and…...
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...See also Figu Scale bar = 100 mm. pancreatic progenitors, neither of which secreted significant levels of insulin in vivo within 2 weeks, as has been previously published (Kroon et al., 2008) (data not shown and Figure 5A)....
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Journal Article•DOI•

International Trial of the Edmonton Protocol for Islet Transplantation

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A. M. James Shapiro¹, Camillo Ricordi², Bernhard J. Hering³, Hugh Auchincloss⁴, Robert Lindblad, R. Paul Robertson⁵, Antonio Secchi, Mathias D. Brendel⁶, Thierry Berney⁷, Daniel C. Brennan⁸, Enrico Cagliero⁴, Rodolfo Alejandro², Edmond A. Ryan¹, Barbara S. Dimercurio⁹, Philippe Morel⁷, Kenneth S. Polonsky⁸, Jo Anna Reems⁵, Reinhard G. Bretzel⁶, Federico Bertuzzi, Tatiana Froud², Raja Kandaswamy³, David E.R. Sutherland³, George S. Eisenbarth¹⁰, Miriam Segal³, Jutta K. Preiksaitis¹, Gregory S. Korbutt¹, Franca B. Barton, Lisa Viviano⁹, Vicki Seyfert-Margolis, Jeffrey A. Bluestone, Jonathan R. T. Lakey¹ - Show less +27 more•Institutions (10)

University of Alberta¹, University of Miami², University of Minnesota³, Harvard University⁴, University of Washington⁵, University of Giessen⁶, University of Geneva⁷, Washington University in St. Louis⁸, National Institutes of Health⁹, University of Colorado Boulder¹⁰

28 Sep 2006-The New England Journal of Medicine

TL;DR: Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable.

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Abstract: Background Islet transplantation offers the potential to improve glycemic control in a subgroup of patients with type 1 diabetes mellitus who are disabled by refractory hypoglycemia. We conducted an international, multicenter trial to explore the feasibility and reproducibility of islet transplantation with the use of a single common protocol (the Edmonton protocol). Methods We enrolled 36 subjects with type 1 diabetes mellitus, who underwent islet transplantation at nine international sites. Islets were prepared from pancreases of deceased donors and were transplanted within 2 hours after purification, without culture. The primary end point was defined as insulin independence with adequate glycemic control 1 year after the final transplantation. Results Of the 36 subjects, 16 (44%) met the primary end point, 10 (28%) had partial function, and 10 (28%) had complete graft loss 1 year after the final transplantation. A total of 21 subjects (58%) attained insulin independence with good glycemic control at any point throughout the trial. Of these subjects, 16 (76%) required insulin again at 2 years; 5 of the 16 subjects who reached the primary end point (31%) remained insulin-independent at 2 years. Conclusions Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable. Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin. (ClinicalTrials.gov number, NCT00014911.)

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1,784 citations

"Generation of functional human panc..." refers background in this paper

...A single 68 kg (150 lb) patient requires roughly 340– 750 million transplanted islet cells to effectively resolve type 1 diabetes via islet transplantation (McCall and Shapiro, 2012; Shapiro et al., 2006)....
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Journal Article•DOI•

Efficient differentiation of human embryonic stem cells to definitive endoderm.

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Kevin A. D'Amour¹, Alan D. Agulnick¹, Susan Eliazer¹, Olivia Kelly¹, Evert Kroon¹, Emmanuel E. Baetge¹ - Show less +2 more•Institutions (1)

General Atomics¹

01 Dec 2005-Nature Biotechnology

TL;DR: The process of definitive endoderm formation in differentiating hES cell cultures includes an apparent epithelial-to-mesenchymal transition and a dynamic gene expression profile that are reminiscent of vertebrate gastrulation that may facilitate the use of hES cells for therapeutic purposes and as in vitro models of development.

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Abstract: The potential of human embryonic stem (hES) cells to differentiate into cell types of a variety of organs has generated much excitement over the possible use of hES cells in therapeutic applications. Of great interest are organs derived from definitive endoderm, such as the pancreas. We have focused on directing hES cells to the definitive endoderm lineage as this step is a prerequisite for efficient differentiation to mature endoderm derivatives. Differentiation of hES cells in the presence of activin A and low serum produced cultures consisting of up to 80% definitive endoderm cells. This population was further enriched to near homogeneity using the cell-surface receptor CXCR4. The process of definitive endoderm formation in differentiating hES cell cultures includes an apparent epithelial-to-mesenchymal transition and a dynamic gene expression profile that are reminiscent of vertebrate gastrulation. These findings may facilitate the use of hES cells for therapeutic purposes and as in vitro models of development.

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1,758 citations

"Generation of functional human panc..." refers background in this paper

...…for the pancreatic lineage, and these have been effectively used to form cells in the b cell lineage in vitro from hPSC. Definitive endoderm and subsequent pancreatic progenitors can now be differentiated with high efficiencies (Kroon et al., 2008; D’Amour et al., 2005, 2006; Rezania et al., 2012)....
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