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Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes
Open accessAbstract
An open-label, first-in-human phase 1/2 study is being conducted to evaluate the safety and efficacy of pancreatic endoderm cells (PECs) implanted in non-immunoprotective macroencapsulation devices for the treatment of type 1 diabetes. We report an analysis on 1 year of data from the first cohort of 15 patients from a single trial site that received subcutaneous implantation of cell products combined with an immunosuppressive regimen. Implants were well tolerated with no teratoma formation or severe graft-related adverse events. After implantation, patients had increased fasting C-peptide levels and increased glucose-responsive C-peptide levels and developed mixed meal-stimulated C-peptide secretion. There were immunosuppression-related transient increases in circulating regulatory T cells, PD1 high T cells, and IL17A+CD4+ T cells. Explanted grafts contained cells with a mature β cell phenotype that were immunoreactive for insulin, islet amyloid polypeptide, and MAFA. These data, and associated findings (Shapiro et al., 2021), are the first reported evidence of meal-regulated insulin secretion by differentiated stem cells in patients.
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“Upon graft removal, a majority of these graft-derived cells immunostained for the general endocrine marker chromogranin A (CHGA).”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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“While the observed circulating C-peptide levels in these studies were too low to induce a measurable clinical benefit attributable to the transplanted cells, these clinical trials have demonstrated that facilitating host-derived vascularization into the graft promoted long-term endocrine cell survival and function in humans.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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“In other regions of the device, however, host fibroblasts were the predominant cell type, resulting in the deposition of fibrotic tissue rather than host-derived vasculature.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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“While the observed circulating C-peptide levels in these studies were too low to induce a measurable clinical benefit attributable to the transplanted cells, these clinical trials have demonstrated that facilitating host-derived vascularization into the graft promoted long-term endocrine cell survival and function in humans.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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“As intended, the porous design promoted the growth of host-derived blood vessels inside the device, and this phenomenon was more prominent in regions containing the graft-derived cells.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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“In the ViaCyte clinical trial, the explanted grafts after months in vivo were observed to be highly heterogenous between patients since the cells were transplanted as pancreatic progenitors and allowed to finish differentiating in vivo.33,35”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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“Interestingly, while there were regions of C-peptide positive β-like cells, a majority of these endocrine cells stained for the α cell marker glucagon. Ductal cells and rare acinar cells were also observed.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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“While the transplanted PEC-Encap product was well tolerated with few adverse effects, the trial was halted due to insufficient functional product engraftment.33”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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“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 [33]
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“Importantly, these studies did not detect any serious safety concerns related to the transplanted cells, such as tumor formation.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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“An ongoing clinical trial was started in 2017 at seven sites to test this device (clinicaltrials.gov: NCT03163511), and the first round of results have recently been published.33,35”
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“While some endocrine cells were observed, fibrosis around the capsule resulted in graft loss, and no insulin secretion from the device was detected.33,34”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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“They demonstrated glucose responsive C-peptide production 6-9 months post-transplant as the grafted cells matured from pancreatic progenitors into pancreatic endocrine cells.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [33]
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Metadata
- Authors
- Ramzy, A., Thompson, D. M., Ward-Hartstonge, K. A., Ivison, S., Cook, L., Garcia, R. V., Loyal, J., Kim, P. T. W., Warnock, G. L., Levings, M. K., & Kieffer, T. J.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Kieffer, Timothy J.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 28
- Issue
- 12
- Pages
- 2047-2061.e5
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W3214753991
- Cited by
- 342
- References
- 55
- Citations by year
- 2026: 46 · 2025: 75 · 2024: 75 · 2023: 66 · 2022: 76 · 2021: 3
- FWCI
- 51.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 366 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Stem Cell Network
- California Institute for Regenerative Medicine
- Juvenile Diabetes Research Foundation United States of America
- BC Children’s Hospital
- Juvenile Diabetes Research Foundation Canada
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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
- type 1 diabetes, pluripotent stem cells, cell therapy, macroencapsulation, C-peptide secretion, glucose-dependent insulin secretion, beta cell differentiation, regulatory T cells, immunosuppression, graft safety, amylin, MafA
- MeSH terms
- C-Peptide, Cell Differentiation, Diabetes Mellitus, Type 1, Endoderm, Glucose, Humans, Insulin, Insulin-Secreting Cells
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