ZnT8 loss of function mutation increases resistance of human embryonic stem cell-derived beta cells to apoptosis in low zinc condition
The rare SLC30A8 mutation encoding a truncating p.Arg138* variant (R138X) in zinc transporter 8 (ZnT8) is associated with a 65% reduced risk for type 2 diabetes. To determine whether ZnT8 is required for beta cell development and function, we derived human pluripotent stem cells carrying the R138X m...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/169483 |
| _version_ | 1826126338200698880 |
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| author | Sui, Lina Du, Qian Romer, Anthony Su, Qi Chabosseau, Pauline L. Xin, Yurong Kim, Jinrang Kleiner, Sandra Rutter, Guy A. Egli, Dieter |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Sui, Lina Du, Qian Romer, Anthony Su, Qi Chabosseau, Pauline L. Xin, Yurong Kim, Jinrang Kleiner, Sandra Rutter, Guy A. Egli, Dieter |
| author_sort | Sui, Lina |
| collection | NTU |
| description | The rare SLC30A8 mutation encoding a truncating p.Arg138* variant (R138X) in zinc transporter 8 (ZnT8) is associated with a 65% reduced risk for type 2 diabetes. To determine whether ZnT8 is required for beta cell development and function, we derived human pluripotent stem cells carrying the R138X mutation and differentiated them into insulin-producing cells. We found that human pluripotent stem cells with homozygous or heterozygous R138X mutation and the null (KO) mutation have normal efficiency of differentiation towards insulin-producing cells, but these cells show diffuse granules that lack crystalline zinc-containing insulin granules. Insulin secretion is not compromised in vitro by KO or R138X mutations in human embryonic stem cell-derived beta cells (sc-beta cells). Likewise, the ability of sc-beta cells to secrete insulin and maintain glucose homeostasis after transplantation into mice was comparable across different genotypes. Interestingly, sc-beta cells with the SLC30A8 KO mutation showed increased cytoplasmic zinc, and cells with either KO or R138X mutation were resistant to apoptosis when extracellular zinc was limiting. These findings are consistent with a protective role of zinc in cell death and with the protective role of zinc in T2D. |
| first_indexed | 2024-10-01T06:51:05Z |
| format | Journal Article |
| id | ntu-10356/169483 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:51:05Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1694832023-07-23T15:38:11Z ZnT8 loss of function mutation increases resistance of human embryonic stem cell-derived beta cells to apoptosis in low zinc condition Sui, Lina Du, Qian Romer, Anthony Su, Qi Chabosseau, Pauline L. Xin, Yurong Kim, Jinrang Kleiner, Sandra Rutter, Guy A. Egli, Dieter Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Stem Cell Biology Stem Cell The rare SLC30A8 mutation encoding a truncating p.Arg138* variant (R138X) in zinc transporter 8 (ZnT8) is associated with a 65% reduced risk for type 2 diabetes. To determine whether ZnT8 is required for beta cell development and function, we derived human pluripotent stem cells carrying the R138X mutation and differentiated them into insulin-producing cells. We found that human pluripotent stem cells with homozygous or heterozygous R138X mutation and the null (KO) mutation have normal efficiency of differentiation towards insulin-producing cells, but these cells show diffuse granules that lack crystalline zinc-containing insulin granules. Insulin secretion is not compromised in vitro by KO or R138X mutations in human embryonic stem cell-derived beta cells (sc-beta cells). Likewise, the ability of sc-beta cells to secrete insulin and maintain glucose homeostasis after transplantation into mice was comparable across different genotypes. Interestingly, sc-beta cells with the SLC30A8 KO mutation showed increased cytoplasmic zinc, and cells with either KO or R138X mutation were resistant to apoptosis when extracellular zinc was limiting. These findings are consistent with a protective role of zinc in cell death and with the protective role of zinc in T2D. Published version This research was funded by American Diabetes Association 1-16-ICTS-029, by NIDDK UC4 DK104207, NIH P30 DK26687-36, R01 DK 057846-16 (to Kevan Herold), by NIH P30 DK0636- 08 funding to the Columbia University flow core, the Weezie family foundation to D.E., and by a Columbia University Diabetes Research Center Pilot and Feasibility award to L.S., G.A.R. was supported by a Wellcome Trust Investigator Award (WT212625/Z/18/Z), an MRC Programme grant (MR/R022259/1), a start-up grant from the Université de Montréal, and a John R. Evans Leaders Award from Innovation Canada. 2023-07-20T03:02:30Z 2023-07-20T03:02:30Z 2023 Journal Article Sui, L., Du, Q., Romer, A., Su, Q., Chabosseau, P. L., Xin, Y., Kim, J., Kleiner, S., Rutter, G. A. & Egli, D. (2023). ZnT8 loss of function mutation increases resistance of human embryonic stem cell-derived beta cells to apoptosis in low zinc condition. Cells, 12(6), 903-. https://dx.doi.org/10.3390/cells12060903 2073-4409 https://hdl.handle.net/10356/169483 10.3390/cells12060903 36980244 2-s2.0-85151109858 6 12 903 en Cells © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). application/pdf |
| spellingShingle | Science::Medicine Stem Cell Biology Stem Cell Sui, Lina Du, Qian Romer, Anthony Su, Qi Chabosseau, Pauline L. Xin, Yurong Kim, Jinrang Kleiner, Sandra Rutter, Guy A. Egli, Dieter ZnT8 loss of function mutation increases resistance of human embryonic stem cell-derived beta cells to apoptosis in low zinc condition |
| title | ZnT8 loss of function mutation increases resistance of human embryonic stem cell-derived beta cells to apoptosis in low zinc condition |
| title_full | ZnT8 loss of function mutation increases resistance of human embryonic stem cell-derived beta cells to apoptosis in low zinc condition |
| title_fullStr | ZnT8 loss of function mutation increases resistance of human embryonic stem cell-derived beta cells to apoptosis in low zinc condition |
| title_full_unstemmed | ZnT8 loss of function mutation increases resistance of human embryonic stem cell-derived beta cells to apoptosis in low zinc condition |
| title_short | ZnT8 loss of function mutation increases resistance of human embryonic stem cell-derived beta cells to apoptosis in low zinc condition |
| title_sort | znt8 loss of function mutation increases resistance of human embryonic stem cell derived beta cells to apoptosis in low zinc condition |
| topic | Science::Medicine Stem Cell Biology Stem Cell |
| url | https://hdl.handle.net/10356/169483 |
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