Cited by 1,843Pancreatic function and diabetesPluripotent Stem Cells ResearchDiabetes and associated disorders

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

Kroon, Evert, Martinson, Laura A, Kadoya, Kuniko, Bang, Anne G, Kelly, Olivia G, Eliazer, Susan, Young, Holly, Richardson, Mike, Smart, Nora G, Cunningham, Justine, Agulnick, Alan D, D'Amour, Kevin A, Carpenter, Melissa K, Baetge, Emmanuel E·2008·Nature Biotechnology

DOI 10.1038/nbt1393

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Abstract

Development of a cell therapy for diabetes would be greatly aided by a renewable supply of human beta-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 approximately 3,000 human islets. Moreover, the insulin-expressing cells generated after engraftment exhibit many properties of functional beta-cells, including expression of critical beta-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.

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Assessment of Human Pancreatic Islet Architecture and Composition by Laser Scanning Confocal Microscopy
Brissova, M., Fowler, M. J., Nicholson, W. E., Chu, A., Hirshberg, B., Harlan, D. M., & Powers, A. C. (2005) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.5c6684.2005 · Cited by 797
Successful Islet Transplantation
Ryan, E. A., Lakey, J. R. T., Paty, B. W., Imes, S., Korbutt, G. S., Kneteman, N. M., Bigam, D., Rajotte, R. V., & Shapiro, A. M. J. (2002) · Diabetes · doi:10.2337/diabetes.51.7.2148 · Cited by 719

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Background
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Lahmy, R., Soleimani, M., Sanati, M., Behmanesh, M., Kouhkan, F., & Mobarra, N. (2016) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.1787 · Cited by 31
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Background
Reprogramming of Pancreatic Exocrine Cells AR42J Into Insulin-producing Cells Using mRNAs for Pdx1, Ngn3, and MafA Transcription Factors
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Background
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Background
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Background
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Cell therapy for type 1 diabetes
Muir, K. R., Lima, M., Docherty, H., & Docherty, K. (2014) · QJM : monthly journal of the Association of Physicians · doi:10.1093/qjmed/hcu025 · Cited by 30
DELETION OF RETINOIC ACID RECEPTOR β (RARβ) IMPAIRS PANCREATIC ENDOCRINE DIFFERENTIATION
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“…in the pancreatic primordium compared with surrounding organs, two Hedgehog signal inhibitors (cyclopamine and KADD-cyclopamine) have been used in many other methods (D’Amour et al., 2006, 2007; Kroon et al., 2008; Chen et al., 2009; Thatava et al., 2011; Nostro et al., 2011; Rezania et al., 2011).”
Method
G Protein-Coupled Receptor Signaling and Sphingosine-1-Phosphate Play a Phylogenetically Conserved Role in Endocrine Pancreas Morphogenesis
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“The elucidation of the genetic networks in pancreas morphogenesis could contribute to the efficient generation of cells from embryonic and induced pluripotent stem (ES and iPS, respectively) cells and also to the stimulation of islet clustering after in vivo reprogramming of exocrine cells to endocrine cells (28, 53,…”
Background
Using stem cells to study and possibly treat type 1 diabetes
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“To protect the transplanted cells from immune response, retrieval encapsulation devices were also created [160–162].”
Background
The Current Status of Allogenic Islet Cell Transplantation
Czarnecka, Z., Dadheech, N., Razavy, H., Pawlick, R. L., & Shapiro, A. M. J. (2023) · Cells · doi:10.3390/cells12202423 · Cited by 41
“They successfully transplanted these cells into diabetic mice and showed that over several months, these cells differentiated into functional ß-cells and maintained euglycemia by secreting insulin in response to glucose levels [23].”
Background
Cell therapy for type 1 diabetes
Loretelli, C., Assi, E., Seelam, A. J., Nasr, M. B., & Fiorina, P. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2020.1748596 · Cited by 47
“normoglycemia in streptozotocin-induced diabetic mice after 2–3months [60,61].”
Background
Lineage- and developmental stage-specific mechanomodulation of induced pluripotent stem cell differentiation
Maldonado, M., Luu, R., Ico, G., Ospina, A., Myung, D., Shih, H., & Nam, J. (2017) · Stem cell research & therapeutics · doi:10.1186/s13287-017-0667-2 · Cited by 29
“Pancreatic endoderm differentiation was induced by high concentrations of activin A followed by primitive gut tube, posterior foregut, and pancreatic endoderm/endocrine precursor induction using fetal bovine serum (FBS), KAAD-cyclopamine, and retinoic acid [15].”
Method
Neural differentiation of human embryonic stem cells induced by the transgene-mediated overexpression of single transcription factors.
Matsushita, M., Nakatake, Y., Arai, I., Ibata, K., Kohda, K., Goparaju, S., Murakami, M., Sakota, M., Chikazawa-Nohtomi, N., Ko, S., et al. (2017) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2017.06.039 · Cited by 29
Immunological Issues After Stem Cell-Based β Cell Replacement
Sordi, V., Pellegrini, S., & Piemonti, L. (2017) · Current Diabetes Reports · doi:10.1007/s11892-017-0901-4 · Cited by 30
FTIR Spectroscopic and Molecular Analysis during Differentiation of Pluripotent Stem Cells to Pancreatic Cells
Vázquez-Zapién, G. J., Mata-Miranda, M. M., Sánchez-Monroy, V., Delgado-Macuil, R., Pérez-Ishiwara, D. G., & Rojas-López, M. (2016) · Stem Cells International · doi:10.1155/2016/6709714 · Cited by 29
“Experimental studies in animals and some clinical trials employing SCs have shown the therapeutic potential of SCs and have brought hope to patients suffering devastating pathologies of different organs and systems as diabetes, renal failure, and ocular diseases, among others [4–6].”
The Human Endocrine Pancreas: New Insights on Replacement and Regeneration
Domínguez‐Bendala, J., Lanzoni, G., Klein, D., Álvarez-Cubela, S., & Pastori, R. L. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.12.003 · Cited by 36
“Cell product exhibits glucose responsiveness before transplantation [6–8] Cell product is not functional before transplantation [5,14,22,23]”
Influential
Derivation of Endodermal Progenitors From Pluripotent Stem Cells
Ikonomou, L., & Kotton, D. N. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24771 · Cited by 34
“Use of Noggin at the posterior foregut endoderm stage increased the derivation efficiency of PDX1þ progenitors (Jiang et al., 2007; Kroon et al., 2008; Zhang et al., 2009), putatively by blocking hepatic specification (Nostro et al., 2011).”
Endothelial Cells Mediate Islet-Specific Maturation of Human Embryonic Stem Cell-Derived Pancreatic Progenitor Cells
Jaramillo, M., Mathew, S., Mamiya, H., Goh, S.-K., & Banerjee, I. (2014) · Tissue Engineering. Part A · doi:10.1089/ten.tea.2014.0013 · Cited by 29
“These cells also have the potential for functional maturation upon implantation in diabetic mice models.(12) However, maturing these cells into functional isletlike cells in an in vitro setting is yet to be demonstrated.”
Background
Nanofibrous Microposts and Microwells of Controlled Shapes and Their Hybridization with Hydrogels for Cell Encapsulation
Song, W., An, D., Kao, D.-I., Lu, Y.-C., Dai, G., Chen, S.-B., & Ma, M.-L. (2014) · ACS Applied Materials and Interfaces · doi:10.1021/am502046h · Cited by 29
Preventing p38 MAPK-mediated MafA degradation ameliorates β-cell dysfunction under oxidative stress.
Khattabi, I. E., & Sharma, A. J. (2013) · Molecular Endocrinology · doi:10.1210/me.2012-1346 · Cited by 29
Transplantation of Human Embryonic Stem Cell-Derived Pancreatic Endoderm Reveals a Site-Specific Survival, Growth, and Differentiation
Sui, L., Mfopou, J. K., Chen, B., Sermon, K., & Bouwens, L. (2012) · Cell Transplantation · doi:10.3727/096368912x636812 · Cited by 27
“(12) in vivo, similar results could not be replicated by other research groups with different hESC lines in vitro (3,17,22) or a different animal model in vivo (15).”
BackgroundResult
Differentiation of Stem Cells into Insulin-Producing Cells: Current Status and Challenges
Pokrywczyńska, M., Krzyzanowska, S., Jundziłł, A., Adamowicz, J., & Drewa, T. A. (2013) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-012-0213-y · Cited by 38
Differentiation of PDX1 gene-modified human umbilical cord mesenchymal stem cells into insulin-producing cells in vitro
He, D. (2011) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2011.774 · Cited by 29
“Recent studies described differentiation protocols to produce insulin-positive cells from embryonic stem cells (1,9), hepatic stem cells (10), bone marrow-derived cells (11,12), umbilical cord blood cells (13), human umbilical cord cells (14), or genetically modified stem cells using several…”
Stem cell-derived islet cells for transplantation
Domínguez‐Bendala, J., Inverardi, L., & Ricordi, C. (2010) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0b013e32834252b5 · Cited by 29
“Inasmuch as the formation of teratomas is a common occurrence in pre-clinical experiments [18, 19], safety remains a concern.”
Background
Differentiation of Mouse Embryonic Stem Cells into Endoderm without Embryoid Body Formation
Kim, P., Hoffman, B., Plesner, A., Helgason, C., Verchere, C. B., Chung, S., Warnock, G., Mui, A., & Ong, C. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014146 · Cited by 29
“In addition, fluorescence immunohistochemistry was performed to determine cellular protein levels of insulin, glucagon, C-peptide, PDX-1, Ngn-3, carboxypeptidase E (CPE), pan-cytokeratin (pan-CK), somatostatin, pancreatic polypeptide and ghrelin.”
BackgroundInfluential
Platforms for Manufacturing Allogeneic, Autologous and iPSC Cell Therapy Products: An Industry Perspective
Abraham, E., Baghbaderani, B. A., Holderness, K., Levinson, Y., & McAfee, E. (2017) · Advances in biochemical engineering, biotechnology · doi:10.1007/10_2017_14 · Cited by 37
“Functional insulinsecreting beta islet cells have been generated from iPSCs using a multistage directed differentiation process [49, 50].”
Method
New Bioprocessing Strategies: Development and Manufacturing of Recombinant Antibodies and Proteins
Pohlscheidt, M., & Gottschalk, U. (2018) · doi:10.1007/978-3-319-97110-0 · Cited by 29
Update on islet cell transplantation
Verhoeff, K., Marfil-Garza, B. A., & Shapiro, A. M. J. (2021) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0000000000000891 · Cited by 29
“All rights rese concept’, whereas hESC-derived islets attest to a well described pathway to differentiate stem cells into islets [30].”
Background
Epigenetic Memory: Lessons From iPS Cells Derived From Human β Cells
Efrat, S. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.614234 · Cited by 29
Engineering Strategies to Improve Islet Transplantation for Type 1 Diabetes Therapy
White, A. M., Shamul, J. G., Xu, J., Stewart, S., Bromberg, J. S., & He, X. (2019) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.9b01406 · Cited by 33
Applications of stem cells and bioprinting for potential treatment of diabetes
Kumar, S. A., Delgado, M. A. T., Mendez, V. E., & Joddar, B. (2019) · World Journal of Stem Cells · doi:10.4252/wjsc.v11.i1.13 · Cited by 30
β‐cell differentiation status in type 2 diabetes
Jeffery, N. M., & Harries, L. W. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12778 · Cited by 30
High-efficiency generation of induced pluripotent mesenchymal stem cells from human dermal fibroblasts using recombinant proteins
Chen, F., Zhang, G., Yu, L.-J., Feng, Y., Li, X., Zhang, Z., Wang, Y.-T., Sun, D., & Pradhan, S. (2016) · Stem cell research & therapeutics · doi:10.1186/s13287-016-0358-4 · Cited by 28
“For pancreatic islet differentiation [21–23]: day 1, RPMI (without FBS), activin A (100 ng/ml), and Wnt3a (25 ng/ml); days 2–3, RPMI with 0.”
Method
Differentiation of pluripotent stem cells for regenerative medicine
Li, K., Kong, Y., Zhang, M., Xie, F., Liu, P., & Xu, S. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.01.182 · Cited by 34
Improvement of Cell Survival During Human Pluripotent Stem Cell Definitive Endoderm Differentiation
Wang, H., Luo, X., Yao, L., Lehman, D. M., & Wang, P. (2015) · Stem Cells and Development · doi:10.1089/scd.2015.0018 · Cited by 29
“(A) Schematic of IPCs differentiated through optimized DE protocols subsequent to the pancreatic hormone– expressing endocrine cell differentiation protocol [19].”
MethodInfluential
How important is differentiation in the therapeutic effect of mesenchymal stromal cells in liver disease?
Wang, H., Zhao, T., Xu, F., Li, Y., Wu, M., Zhu, D., Cong, X., & Liu, Y.-J. (2013) · Cytotherapy · doi:10.1016/j.jcyt.2013.07.011 · Cited by 26
Diabetes treatment: A rapid review of the current and future scope of stem cell research
Abdulazeez, S. S. (2013) · Saudi Pharmaceutical Journal · doi:10.1016/j.jsps.2013.12.012 · Cited by 36
“Later, this response was achieved by Kroon et al.(2008) as the hyperglycaemic responsiveness is a crucial characteristic that is needed for any potential cellular diabetic therapy.”
Role of BMP Signaling in Pancreatic Progenitor Differentiation from Human Embryonic Stem Cells
Sui, L., Geens, M., Sermon, K., Bouwens, L., & Mfopou, J. K. (2013) · Stem Cell Reviews and Reports · doi:10.1007/s12015-013-9435-6 · Cited by 28
“However, the functional beta cells obtained upon in vivo implantation of these progenitors are indirect evidence of their pancreatic nature [3, 14].”
Background
Birth and Death of Human β-Cells in Pancreases from Cadaver Donors, Autopsies, Surgical Specimens, and Islets Transplanted into Mice
Caballero, F., Siniakowicz, K., Hollister‐Lock, J., Duran, L., Katsuta, H., Yamada, T., Lei, J., Deng, S., Westermark, G. T., Markmann, J. F., et al. (2013) · Cell Transplantation · doi:10.3727/096368912x659916 · Cited by 27
“Impressive progress has been made in directing human embryonic stem cells to mature functional b-cells (12).”
Concise Review: In Search of Unlimited Sources of Functional Human Pancreatic Beta Cells
Scharfmann, R., Rachdi, L., & Ravassard, P. (2012) · Stem Cells Translational Medicine · doi:10.5966/sctm.2012-0120 · Cited by 34
Efficient differentiation of AR42J cells towards insulin-producing cells using pancreatic transcription factors in combination with growth factors
Lima, M. J., Docherty, H. M., Chen, Y., & Docherty, K. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.02.024 · Cited by 27
“An understanding of the transcription factors that control the developing pancreas (Gittes, 2009) has provided protocols that reproducibly generate pancreatic progenitors from embryonic stem cells which can develop into functional b-cells when engrafted in mice (Kroon et al., 2008).”
Background
Angiotensin II Type 2 Receptor Is Critical for the Development of Human Fetal Pancreatic Progenitor Cells into Islet‐like Cell Clusters and Their Potential for Transplantation
Leung, K.-K., Liang, J., Ma, M.-T., & Leung, P. (2012) · Stem Cells · doi:10.1002/stem.1008 · Cited by 28
The functional performance of microencapsulated human pancreatic islet-derived precursor cells.
Montanucci, P., Pennoni, I., Pescara, T., Blasi, P., Bistoni, G., Basta, G., & Calafiore, R. (2011) · Biomaterials · doi:10.1016/j.biomaterials.2011.08.052 · Cited by 28
Clinical Allogeneic and Autologous Islet Cell Transplantation: Update
Matsumoto, S. (2011) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2011.35.3.199 · Cited by 31
“[55] demonstrated that pancreatic endoderm derived from human embryonic stem cells generated glucose-responsive insulin-secreting cells in vivo.”
Background
Minireview: β-Cell Replacement Therapy for Diabetes in the 21st Century: Manipulation of Cell Fate by Directed Differentiation
Yechoor, V. K., & Chan, L. (2010) · Molecular Endocrinology · doi:10.1210/me.2009-0311 · Cited by 26
G-protein Coupled Receptors in Stem Cell Self-Renewal and Differentiation
Kobayashi, N., Hawes, S. M., Crook, J. M., & Pébay, A. (2010) · Stem Cell Reviews and Reports · doi:10.1007/s12015-010-9167-9 · Cited by 30
“A number of studies have included Wnt3a in protocols to differentiate hESC towards definitive endoderm and subsequent hepaocytes and pancreatic β-cells, although its requirement/inclusion remain controversial [69, 79, 80].”
Background
Overexpression of Heme Oxygenase-1 in Mesenchymal Stem Cells Augments Their Protection on Retinal Cells In Vitro and Attenuates Retinal Ischemia/Reperfusion Injury In Vivo against Oxidative Stress
Li, L., Du, G., Wang, D.-J., Zhou, J., Jiang, G.-M., & Jiang, H. (2017) · Stem Cells International · doi:10.1155/2017/4985323 · Cited by 27
“Furthermore, the developing technologies of cell culture and genetic engineering [17, 18] further promote the therapeutic application of MSC through integrating other positive treatments [19, 20], which also can overcome the possible side effects from monotherapy in clinical practice [21].”
Background
Mass production of functional human pancreatic β‐cells: why and how?
Scharfmann, R., Didiesheim, M., Richards, P., Chandra, V., Oshima, M., & Albagli, O. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12728 · Cited by 31
“pancreatic progenitors derived from hESC can give rise to functional β-cells.(30) Specifically, the authors transplanted cultures enriched in hESC-derived pancreatic progenitors into immune-deficient mice”
Background
Embryonic stem cell-derived pancreatic endoderm transplant with MCT1-suppressing miR-495 attenuates type II diabetes in mice
Liang, D. S., Zhang, Y., Han, J., Wang, W., Liu, Y., Li, J., & Jiang, X. (2015) · Endocrine Journal · doi:10.1507/endocrj.ej15-0186 · Cited by 30
Endothelium-derived essential signals involved in pancreas organogenesis
Talavera‐Adame, D. (2015) · World Journal of Experimental Medicine · doi:10.5493/wjem.v5.i2.40 · Cited by 26
The fetal liver as cell source for the regenerative medicine of liver and pancreas.
Semeraro, R., Cardinale, V., Carpino, G., Gentile, R., Napoli, C., Venere, R., Gatto, M., Brunelli, R., Gaudio, E., & Alvaro, D. (2013) · Annals of Translational Medicine · doi:10.3978/j.issn.2305-5839.2012.10.02 · Cited by 27
Obestatin Enhances In Vitro Generation of Pancreatic Islets through Regulation of Developmental Pathways
Baragli, L., Grande, C., Gesmundo, I., Settanni, F., Taliano, M., Gallo, D. J., Gargantini, E., Ghigo, E., & Granata, R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064374 · Cited by 27
“Pancreatic b-cells obtained from human and rodent isletderived pancreatic progenitors have shown deficient insulin synthesis and glucose-induced insulin/C-peptide secretion [1,11,12,14,15,40].”
Background
Generating insulin-producing cells for diabetic therapy: Existing strategies and new development
Shen, J., Cheng, Y., Han, Q., Mu, Y., & Han, W. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2013.01.001 · Cited by 23
In vivo imaging of embryonic stem cell therapy
Jiang, H., Cheng, Z., Tian, M., & Zhang, H. (2011) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-010-1667-y · Cited by 27
“Currently, in order to realize this goal, the only stem cell population with sufficient proliferative capacity is hESCs, which proliferate in culture at a rate of >250 population doublings per year [71–73].”
Background
Regenerative medicine for insulin deficiency: creation of pancreatic islets and bioartificial pancreas
Sumi, S. (2010) · Journal of Hepato-Biliary-Pancreatic Sciences · doi:10.1007/s00534-010-0303-3 · Cited by 31
“[42] recently reported that pancreatic endoderm derived from human ESCs efficiently generates glucose-responsive endocrine cells after implantation into mice.”
Background
Elimination of Tumorigenic Stem Cells from Differentiated Progeny and Selection of Definitive Endoderm Reveals a Pdx1+ Foregut Endoderm Stem Cell Lineage
Kahan, B. W., Magliocca, J., Merriam, F., Treff, N., Budde, M. L., Nelson, J., Browning, V., Ziehr, B., & Odorico, J. (2010) · Stem Cell Research · doi:10.1016/j.scr.2010.10.003 · Cited by 27
“Recent studies, however, have yielded both encouragement and caution, with restoration of function evident to some degree in many cases, but coexisting in others with the troubling finding that the grafts contained evidence of cancerous growth (Fujikawa et al., 2005; Ishii et al., 2007; Kroon et al., 2008; Leor et al.…”
Influential
High dosage of Exendin-4 increased early insulin secretion in differentiated beta cells from mouse embryonic stem cells
Li, H., Lam, A. K. M., Xu, A.-M., Lam, K. S., & Kim-Chung, S. (2010) · Acta Pharmacologica Sinica · doi:10.1038/aps.2010.38 · Cited by 27
Insulin-producing cells derived from stem/progenitor cells: therapeutic implications for diabetes mellitus
Hori, Y. (2009) · Medical Molecular Morphology · doi:10.1007/s00795-009-0471-x · Cited by 28
“Recent reports have shown the effi cient differentiation of pancreatic lineage from ESCs.18,19 The fi rst step from ESCs toward the pancreatic lineage is defi nitive endoderm (DE) formation.”
BackgroundMethodResultInfluential
Efficient differentiation of insulin‐producing cells from skin‐derived stem cells
Guo, W., Miao, C., Liu, S., Qiu, Z., Li, J., & Duan, E. (2009) · Cell Proliferation · doi:10.1111/j.1365-2184.2008.00573.x · Cited by 24
Slow and steady is the key to β‐cell replication
Brennand, K., & Melton, D. A. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00635.x · Cited by 29
“First, -cells might be differentiated in vitro from embryonic stem (ES) cells [24, 25].”
Background
Stem Cells, Self-Renewal, and Lineage Commitment in the Endocrine System
Mariniello, K., Ruiz‐Babot, G., McGaugh, E. C., Nicholson, J. G., Gualtieri, A., Gaston‐Massuet, C., Nostro, M. C., & Guasti, L. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00772 · Cited by 33
“Pancreatic progenitors offer an appealing source of cells for transplantation as they give rise to all cells of the pancreas following transplantation in mice and can normalize glycemia in an streptozotocin-induced diabetic mouse model of diabetes (367, 368, 371).”
Background
Islet-Like Structures Generated In Vitro from Adult Human Liver Stem Cells Revert Hyperglycemia in Diabetic SCID Mice
Navarro-Tableros, V., Gai, C., Gomez, Y., Giunti, S., Pasquino, C., Deregibus, M., Tapparo, M., Pitino, A., Tetta, C., Brizzi, M., et al. (2018) · Stem Cell Reviews and Reports · doi:10.1007/s12015-018-9845-6 · Cited by 26
“[35] the observation of a latency in reduction of glycemia may depend on a further in vivo maturation of transplanted islet-like structures and/or on the need of a longer”
Background
Identification of a small molecule that facilitates the differentiation of human iPSCs/ESCs and mouse embryonic pancreatic explants into pancreatic endocrine cells
Kondo, Y., Toyoda, T., Ito, R., Funato, M., Hosokawa, Y., Matsui, S., Sudo, T., Nakamura, M., Okada, C., Zhuang, X., et al. (2017) · Diabetologia · doi:10.1007/s00125-017-4302-7 · Cited by 33

Authors: Kroon, E., Martinson, L. A., Kadoya, K., Bang, A. G., Kelly, O. G., Eliazer, S., Young, H., Richardson, M., Smart, N. G., Cunningham, J., Agulnick, A. D., D'Amour, K. A., Carpenter, M. K., & Baetge, E. E.
ORCID: Kroon, Evert
Kadoya, Kuniko
Bang, Anne G
Kelly, Olivia G
Eliazer, Susan
Carpenter, Melissa K
Venue: Nature Biotechnology
Publisher: Springer Science and Business Media LLC
Published: 2008-02-20
Volume: 26
Issue: 4
Pages: 443-452
ISSN: 0733-222X (ISSN-L)
1087-0156
1546-1696
DOI: 10.1038/nbt1393
OpenAlex: W2106219965
Cited by: 1,843
References: 0
Citations by year: 2026: 26 · 2025: 44 · 2024: 46 · 2023: 88 · 2022: 67 · 2021: 81 · 2020: 85 · 2019: 76 · 2018: 87 · 2017: 98 · 2016: 122 · 2015: 116 · 2014: 156 · 2013: 168 · 2012: 154
FWCI: 150.73
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Biotechnology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords: human embryonic stem cells, beta cell differentiation, glucose-dependent insulin secretion, islet transplantation, diabetes cell therapy, C-peptide, proinsulin processing, streptozotocin-induced hyperglycemia
MeSH terms: Animals, Cell Differentiation, Cells, Cultured, Endoderm, Glucose, Humans, Insulin, Cell Culture Techniques, Pancreas, Artificial, Tissue Engineering, Cell Proliferation, Insulin-Secreting Cells, Mice, Embryonic Stem Cells

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

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