Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress
The maintenance of pancreatic islet architecture is crucial for proper β-cell function. We previously reported that disruption of human islet integrity could result in altered β-cell identity. Here we combine β-cell lineage tracing and single-cell transcriptomics to investigate the mechanisms underl...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-12-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/10/12/3585 |
| _version_ | 1797505930330374144 |
|---|---|
| author | Nathalie Groen Floris Leenders Ahmed Mahfouz Amadeo Munoz-Garcia Mauro J. Muraro Natascha de Graaf Ton. J. Rabelink Rob Hoeben Alexander van Oudenaarden Arnaud Zaldumbide Marcel J. T. Reinders Eelco J. P. de Koning Françoise Carlotti |
| author_facet | Nathalie Groen Floris Leenders Ahmed Mahfouz Amadeo Munoz-Garcia Mauro J. Muraro Natascha de Graaf Ton. J. Rabelink Rob Hoeben Alexander van Oudenaarden Arnaud Zaldumbide Marcel J. T. Reinders Eelco J. P. de Koning Françoise Carlotti |
| author_sort | Nathalie Groen |
| collection | DOAJ |
| description | The maintenance of pancreatic islet architecture is crucial for proper β-cell function. We previously reported that disruption of human islet integrity could result in altered β-cell identity. Here we combine β-cell lineage tracing and single-cell transcriptomics to investigate the mechanisms underlying this process in primary human islet cells. Using drug-induced ER stress and cytoskeleton modification models, we demonstrate that altering the islet structure triggers an unfolding protein response that causes the downregulation of β-cell maturity genes. Collectively, our findings illustrate the close relationship between endoplasmic reticulum homeostasis and β-cell phenotype, and strengthen the concept of altered β-cell identity as a mechanism underlying the loss of functional β-cell mass. |
| first_indexed | 2024-03-10T04:25:21Z |
| format | Article |
| id | doaj.art-f3c90ac516944d4881188fb096b01cc1 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T04:25:21Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-f3c90ac516944d4881188fb096b01cc12023-11-23T07:39:50ZengMDPI AGCells2073-44092021-12-011012358510.3390/cells10123585Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER StressNathalie Groen0Floris Leenders1Ahmed Mahfouz2Amadeo Munoz-Garcia3Mauro J. Muraro4Natascha de Graaf5Ton. J. Rabelink6Rob Hoeben7Alexander van Oudenaarden8Arnaud Zaldumbide9Marcel J. T. Reinders10Eelco J. P. de Koning11Françoise Carlotti12Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsDepartment of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsLeiden Computational Biology Center, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsDepartment of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsHubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, The NetherlandsDepartment of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsDepartment of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsDepartment of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsHubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), 3584 CT Utrecht, The NetherlandsDepartment of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsLeiden Computational Biology Center, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsDepartment of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsDepartment of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The NetherlandsThe maintenance of pancreatic islet architecture is crucial for proper β-cell function. We previously reported that disruption of human islet integrity could result in altered β-cell identity. Here we combine β-cell lineage tracing and single-cell transcriptomics to investigate the mechanisms underlying this process in primary human islet cells. Using drug-induced ER stress and cytoskeleton modification models, we demonstrate that altering the islet structure triggers an unfolding protein response that causes the downregulation of β-cell maturity genes. Collectively, our findings illustrate the close relationship between endoplasmic reticulum homeostasis and β-cell phenotype, and strengthen the concept of altered β-cell identity as a mechanism underlying the loss of functional β-cell mass.https://www.mdpi.com/2073-4409/10/12/3585human pancreatic isletsβ-cellsER stressislet integritysingle-cell RNAseqtype 2 diabetes |
| spellingShingle | Nathalie Groen Floris Leenders Ahmed Mahfouz Amadeo Munoz-Garcia Mauro J. Muraro Natascha de Graaf Ton. J. Rabelink Rob Hoeben Alexander van Oudenaarden Arnaud Zaldumbide Marcel J. T. Reinders Eelco J. P. de Koning Françoise Carlotti Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress Cells human pancreatic islets β-cells ER stress islet integrity single-cell RNAseq type 2 diabetes |
| title | Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress |
| title_full | Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress |
| title_fullStr | Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress |
| title_full_unstemmed | Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress |
| title_short | Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress |
| title_sort | single cell transcriptomics links loss of human pancreatic β cell identity to er stress |
| topic | human pancreatic islets β-cells ER stress islet integrity single-cell RNAseq type 2 diabetes |
| url | https://www.mdpi.com/2073-4409/10/12/3585 |
| work_keys_str_mv | AT nathaliegroen singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT florisleenders singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT ahmedmahfouz singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT amadeomunozgarcia singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT maurojmuraro singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT nataschadegraaf singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT tonjrabelink singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT robhoeben singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT alexandervanoudenaarden singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT arnaudzaldumbide singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT marceljtreinders singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT eelcojpdekoning singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress AT francoisecarlotti singlecelltranscriptomicslinkslossofhumanpancreaticbcellidentitytoerstress |