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Implantation underneath the abdominal anterior rectus sheath enables effective and functional engraftment of stem-cell-derived islets
Abstract
Human pluripotent stem cell-derived islets (hPSC islets) are a promising alternative to primary human islets for the treatment of insulin-deficient diabetes. We previously demonstrated the feasibility of this approach in nonhuman primates; however, the therapeutic effects of hPSC islets can be limited by the maladaptive processes at the transplantation site. Here, we demonstrate successful implantation of hPSC-derived islets in a new transplantation site in the abdomen, the subanterior rectus sheath, in eight nonhuman primates (five male and three female). In this proof-of-principle study, we find that hPSC islets survive and gradually mature after transplantation, leading to improved glycemic control in diabetic primates. Notably, C-peptide secretion responds to meal challenge from 6 weeks post-transplantation (wpt), with stimulation indices comparable to those of native islets. The average post-prandial C-peptide level reaches approximately 2.0 ng ml -1 from 8 wpt, which is five times higher than the peak value we previously obtained after portal vein infusion of hPSC islets and was associated with a decrease of glycated hemoglobin levels by 44% at 12 wpt. Although additional studies in larger cohorts involving long-term follow-up of transplants are needed, our results indicate that the subanterior rectus sheath supports functional maturation and maintenance of hPSC islets, suggesting that it warrants further exploration as a transplantation target site in the context of fo…
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While the primates did not achieve complete insulin independence, the transplanted SC-islets significantly reduced their insulin requirements and greatly improved their glycemic control.
“While the primates did not achieve complete insulin independence, the transplanted SC-islets significantly reduced their insulin requirements and greatly improved their glycemic control, further illustrating their potential utility as a therapy.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [46]
SC-islets were used to help treat diabetic non-human primates.
“Recently, these SC-islets were also used to help treat diabetic non-human primates.45,46”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [46]
In non-human primates, transplantation of SC-islets between the rectus abdominis muscle and its surrounding rectus sheath demonstrated better cell survival than intramuscular or subcutaneous locations.
“In non-human primates, transplantation of SC-islets between the rectus abdominis muscle in the abdomen and its surrounding rectus sheath demonstrated better cell survival than in intramuscular or subcutaneous locations.46”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [46]
Transplantation between the rectus abdominis muscle and rectus sheath promoted robust vascularization by week 12 and allowed for SC-islet maturation.
“Furthermore, this location promoted robust vascularization by week 12 and promoted an environment that allowed for SC-islet maturation.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [46]
A similar dispersion freezing method has been successfully used in SC-islet transplantation into non-human primates.
“A similar dispersion freezing method has been successfully used in the context of SC-islet transplantation into non-human primates.45,46”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [46]
A suitable transplantation strategy for hPSC-islets was developed in preclinical studies.
“Importantly, in these preclinical studies, we also developed a suitable transplantation strategy for hPSC-islets.”
From Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. (2024) · cites this paper as [21]
In two systematic preclinical studies in nonhuman primates, CiPSC-islets ameliorated diabetes.
“The safety and efficacy of CiPSC-islets were evaluated in two systematic preclinical studies in nonhuman primates, in which amelioration of diabetes and no tumorigenicity during long-term observation were demonstrated”
From Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. (2024) · cites this paper as [21]
Four transplanted monkeys assessed at 13 weeks post-transplantation by systemic ultrasonography and full autopsies showed no evidence of teratoma formation or abnormalities at any major organs.
“Four transplanted monkeys were assessed at 13 weeks post-transplantation by systemic ultrasonography and full autopsies, which showed no evidence of teratoma formation or abnormalities at any major organs.21”
From Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. (2024) · cites this paper as [21]
In those preclinical studies, no tumorigenicity was observed during long-term observation.
“The safety and efficacy of CiPSC-islets were evaluated in two systematic preclinical studies in nonhuman primates, in which amelioration of diabetes and no tumorigenicity during long-term observation were demonstrated”
From Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. (2024) · cites this paper as [21]
Transplantation to an extrahepatic site, underneath the abdominal anterior rectus sheath, led to superior CiPSC-islet survival and maturation, resulting in secretion levels of C-peptide and stimulation indices approaching those of non-diabetic humans.
“We found that transplantation to an extrahepatic site, underneath the abdominal anterior rectus sheath, led to superior CiPSC-islet survival and maturation, resulting in secretion levels of C-peptide (a marker of endogenous insulin secretion) and stimulation indices approaching those of non-diabetic humans.”
From Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. (2024) · cites this paper as [21]
In comparison to intraportal transplantation, the abdominal rectus sheath site encompasses other safety considerations, such as ease of access for transplantation and imaging and site retention of graft.
“In comparison to intraportal transplantation, the abdominal rectus sheath site also encompasses other safety considerations, such as ease of access for transplantation and imaging and site retention of graft.21”
From Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. (2024) · cites this paper as [21]
The positive metabolic data seen in this clinical study are consistent with that seen in the preclinical study in nonhuman primates.
“The positive metabolic data seen in this clinical study are consistent with that seen in our preclinical study in nonhuman primates, in which we sought to identify an optimal transplant site for CiPSC-islets.21”
From Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. (2024) · cites this paper as [21]
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“This achievement came after extensive preclinical testing, including the transplantation of these islets into immunodeficient mice and nonhuman primates[51,52].”
Jeyagaran, A., & Schenke‐Layland, K. (2025) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2025.115766 · Cited by 1
Chen, L., Hu, X.-H., Zheng, C., Huang, Q., Xu, J.-N., You, X.-B., & Wang, C.-F. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1981945
The evolution of iPSC-based cell therapy across autologous and allogeneic pathways
Wang, A., Zhang, Y., Deng, H., & Gu, M. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2026.102992
Self-citationHuang, X., Chen, Q.-G., & Lu, H. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1856373
Yin, R., Jiang, X., Ao, S.-T., Zhai, Y., & Zhao, Q. (2026) · Stem Cell Reviews and Reports · doi:10.1007/s12015-026-11166-w
“Therefore, stem cell therapy is considered a good candidate for regenerative medicine [1].”
Wang, Y., Nozhat, Z., Duan, T., Chen, S., Ni, Y., Wang, Y., Shen, C., & You, M. (2026) · Cancer Biome and Targeted Therapy · doi:10.66505/cbtt.v1i2.37
Ouahmi, H., Massa, F., Allart, E., Cougnon, M., Rouleau, M., Obberghen, E. V., Shkreli, M., Sicard, A., & Pisani, D. F. (2025) · bioRxiv · doi:10.1101/2025.11.24.689446
“This oxygen problem could be more severe if the islets are transplanted in the subcutaneous space or intra-abdominally, two alternative grafting procedures suggested by recent papers [38, 39].”
Ziobro, O., Błaszczyk, K., Bulski, J. M., Maj, F. J., Sornat, K. B., Estreicher, A., Klasa, A. M., Sobaś, A. E., & Biedka, K. (2025) · Archiv Euromedica · doi:10.35630/2025/15/2.203
“Unfortunately, this conventional method often leads to complications that may result in graft loss [70,71]. n performing the CiPSC-islet transplantation, Wang et al. opted for an alternative transplantation site to optimize graft survival.”
Metadata
- Authors
- Liang, Z., Sun, D., Lu, S., Lei, Z., Wang, S., Luo, Z., Zhan, J., Wu, S., Jiang, Y., Lu, Z., Sun, S., Shi, Y., Long, H., Wei, Y., Yu, W., Wang, Z., Yi, L. S., Zhang, Y., Sun, W., Fang, X., Li, Y., Lu, S., Lv, J., Sui, W., Shen, Z., Peng, X., Du, Y., & Deng, H.
- Affiliations
- Peking University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Nankai University (CN)
- Guilin Medical University (CN)
- First Affiliated Hospital of Kunming Medical University (CN)
- Corresponding author
- Peng, Xiaozhong
- Du, Yuanyuan
- Deng, Hongkui
- ORCID
- Venue
- Nature Metabolism
- Published
- 2023-01-09
- Volume
- 5
- Issue
- 1
- Pages
- 29-40
- ISSN
- 2522-5812 (ISSN-L)
- OpenAlex
- W4313893393
- Cited by
- 59
- References
- 0
- Citations by year
- 2026: 14 · 2025: 21 · 2024: 16 · 2023: 8
- FWCI
- 15.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (32288102)
- 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
- islet transplantation, transplantation site, islet engraftment, islet maturation, C-peptide secretion, glycemic control, type 1 diabetes, non-human primates, HbA1c, cell replacement therapy
- MeSH terms
- Abdomen, Animals, C-Peptide, Female, Humans, Islets of Langerhans, Male, Primates, Islets of Langerhans Transplantation
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