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Cited by 59Pancreatic function and diabetesDiabetes and associated disordersPluripotent Stem Cells Research

Inconsistent formation and nonfunction of insulin-positive cells from pancreatic endoderm derived from human embryonic stem cells in athymic nude rats

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Matveyenko, Aleksey V., Georgia, Senta, Bhushan, Anil, Butler, Peter C.·2010·American Journal of Physiology-Endocrinology and Metabolism
DOI 10.1152/ajpendo.00279.2010PMC PMC3774125
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Abstract

Embryonic stem cell therapy has been proposed as a therapeutic strategy to restore β-cell mass and function in T1DM. Recently, a group from Novocell (now ViaCyte) reported successful development of glucose-responsive islet-like structures after implantation of pancreatic endoderm (PE) derived from human embryonic stem cells (hESC) into immune-deficient mice. Our objective was to determine whether implantation of hESC-derived pancreatic endoderm from Novocell into athymic nude rats results in development of viable glucose-responsive pancreatic endocrine tissue. Athymic nude rats were implanted with PE derived from hESC either via implantation into the epididymal fat pads or by subcutaneous implantation into TheraCyte encapsulation devices for 20 wk. Blood glucose, weight, and human insulin/C-peptide secretion were monitored by weekly blood draws. Graft β-cell function was assessed by a glucose tolerance test, and graft morphology was assessed by immunohistochemistry and immunofluorescence. At 20 wk postimplantation, epididymal fat-implanted PE progressed to develop islet-like structures in 50% of implants, with a mean β-cell fractional area of 0.8 ± 0.3%. Human C-peptide and insulin were detectable, but at very low levels (C-peptide = 50 ± 26 pmol/l and insulin = 15 ± 7 pmol/l); however, there was no increase in human C-peptide/insulin levels after glucose challenge. There was no development of viable pancreatic tissue or meaningful secretory function when human PE was implanted in the TheraCyte encapsulation devices. These data confirm that islet-like structures develop from hESC differentiated to PE by the protocol developed by NovoCell. However, the extent of endocrine cell formation and secretory function is not yet sufficient to be clinically relevant.

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  • Macroencapsulation devices can promote fibrosis around the implant, further preventing nutrient diffusion.

    “these macroencapsulation devices can also promote fibrosis around the implant, further preventing nutrient diffusion.”

    From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [91]

    The Results report that implanted TheraCyte encapsulation devices were encased in fibrotic tissue. The paper does not report that this fibrosis prevented nutrient diffusion, so the proposed consequence is unsupported. (LLM, conf=0.88)

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Authors
Matveyenko, A. V., Georgia, S., Bhushan, A., & Butler, P. C.
Affiliations
University of California, Los Angeles (US)
Corresponding author
Butler, Peter C.
ORCID
Venue
American Journal of Physiology-Endocrinology and Metabolism
Publisher
American Physiological Society
Published
2010-11
Volume
299
Issue
5
Pages
E713-E720
ISSN
  • 0193-1849 (ISSN-L)
  • 1522-1555
DOI
10.1152/ajpendo.00279.2010
PMC
PMC3774125
OpenAlex
W2072414008
Cited by
59
References
27
Citations by year
2026: 1 · 2023: 1 · 2022: 1 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 11 · 2013: 8 · 2012: 8
FWCI
8.43
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of California, Los Angeles
  • National Institute of Diabetes and Digestive and Kidney Diseases (K01DK088995, K01DK089003, R01DK059579)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
human embryonic stem cells, islet-like structures, beta-cell function, type 1 diabetes, C-peptide secretion, insulin secretion, athymic nude rats, glucose tolerance, endocrine differentiation, cell therapy
MeSH terms
Animals, Blood Glucose, Body Weight, C-Peptide, Diabetes Mellitus, Type 1, Endoderm, Humans, Immunohistochemistry, Insulin, Longitudinal Studies, Male, Rats, Nude, Specific Pathogen-Free Organisms, Glucose Clamp Technique, Rats, Sprague-Dawley, Fluorescent Antibody Technique, Direct, Insulin-Secreting Cells, Rats, Embryonic Stem Cells

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