Comprehensive alpha, beta, and delta cell transcriptomics reveal an association of cellular aging with MHC class I upregulation

Willem Staels; Claire Berthault; Stephanie Bourgeois; Vincent Laville; Chloe Lourenço; Nico De Leu; Raphael Scharfmann

doi:10.1016/j.molmet.2024.101990

Comprehensive alpha, beta, and delta cell transcriptomics reveal an association of cellular aging with MHC class I upregulation

Willem Staels, Claire Berthault, Stephanie Bourgeois, Vincent Laville, Chloe Lourenço, Nico De Leu, Raphael Scharfmann

Research output: Contribution to journal › Article › peer-review

Abstract

Objectives
This study aimed to evaluate the efficacy of a purification method developed for isolating alpha, beta, and delta cells from pancreatic islets of adult mice, extending its application to islets from newborn and aged mice. Furthermore, it sought to examine transcriptome dynamics in mouse pancreatic endocrine islet cells throughout postnatal development and to validate age-related alterations within these cell populations.

Methods
We leveraged the high surface expression of CD71 on beta cells and CD24 on delta cells to FACS-purify alpha, beta, and delta cells from newborn (1-week-old), adult (12-week-old), and old (18-month-old) mice. Bulk RNA sequencing was conducted on these purified cell populations, and subsequent bioinformatic analyses included differential gene expression, overrepresentation, and intersection analysis.

Results
Alpha, beta, and delta cells from newborn and aged mice were successfully FACS-purified using the same method employed for adult mice. Our analysis of the age-related transcriptional changes in alpha, beta, and delta cell populations revealed a decrease in cell cycling and an increase in neuron-like features processes during the transition from newborn to adult mice. Progressing from adult to old mice, we identified an inflammatory gene signature related to aging (inflammaging) encompassing an increase in β-2 microglobulin and major histocompatibility complex (MHC) Class I expression.

Conclusions
Our study demonstrates the effectiveness of our cell sorting technique in purifying endocrine subsets from mouse islets at different ages. We provide a valuable resource for better understanding endocrine pancreas aging and identified an inflammaging gene signature with increased β-2 microglobulin and MHC Class I expression as a common hallmark of old alpha, beta, and delta cells, with potential implications for immune response regulation and age-related diabetes.

Original language	English
Article number	101990
Number of pages	14
Journal	Molecular Metabolism
Volume	87
Early online date	Sep 2024
DOIs	https://doi.org/10.1016/j.molmet.2024.101990
Publication status	Published - Sep 2024

Bibliographical note

Funding Information:
Research in the lab of WS and NDL is supported by the Wetenschappelijk Fonds Willy Gepts of UZ Brussel (WFWG), Research Foundation Flanders (FWO, G058122N and G099323N), Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2022-1200-S-B and CDA-2024-1491-S-B), and Diabetes Onderzoek Nederland (DON). WS holds an FWO senior clinical investigator grant (1806421N). During part of this work, WS was supported by a postdoctoral grant from Agence Nationale de la Recherche (Laboratoire d'Excellence Revive, Investissement d'Avenir; ANR-10-LABX-73). SB is an FWO doctoral fellow (1S89821N). The RS laboratory received funding from the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody, under grant agreement No 115881, supported by the European Union's Horizon 2020 research and innovation program, EFPIA and the Swiss State Secretariat for Education. Research and Innovation (SERI) under contract number 16.0097, resources of which are composed of a financial contribution from the European Union's Seventh Framework Programme (FP7/2007\u20132013); the DON foundation; the Dutch Diabetes Research Foundation; the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA; this Joint Undertaking receives support from the Union's Horizon 2020 research and innovation program and \u201CEFPIA\u201D (European Federation of Pharmaceutical Industries Associations) the Laboratoire d'Excellence consortium Revive, Fondation pour la Recherche M\u00E9dicale (EQU201903007793) and Fondation Francophone pour la Recherche sur le Diabete (FFRD).

Funding Information:
Research in the lab of WS and NDL is supported by the Wetenschappelijk Fonds Willy Gepts of UZ Brussel (WFWG) , Research Foundation Flanders (FWO, G058122N and G099323N ), Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2022-1200-S-B and CDA-2024-1491-S-B ), and Diabetes Onderzoek Nederland (DON) . WS holds an FWO senior clinical investigator grant ( 1806421N ). During part of this work, WS was supported by a postdoctoral grant from Agence Nationale de la Recherche ( Laboratoire d\u2019Excellence Revive, Investissement d\u2019Avenir ; ANR-10-LABX-73 ). SB is an FWO doctoral fellow ( 1S89821N ). The RS laboratory received funding from the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody, under grant agreement No 115881 , supported by the European Union\u2019s Horizon 2020 research and innovation program , EFPIA and the Swiss State Secretariat for Education. Research and Innovation (SERI) under contract number 16.0097 , resources of which are composed of a financial contribution from the European Union\u2019s Seventh Framework Programme ( FP7/2007\u20132013 ); the DON foundation ; the Dutch Diabetes Research Foundation ; the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA; this Joint Undertaking receives support from the Union\u2019s Horizon 2020 research and innovation program and \u201CEFPIA\u201D (European Federation of Pharmaceutical Industries Associations ) the Laboratoire d\u2019Excellence consortium Revive, Fondation pour la Recherche M\u00E9dicale ( EQU201903007793 ) and Fondation Francophone pour la Recherche sur le Diabete (FFRD) .

Publisher Copyright:
© 2024 The Author(s)

Keywords

Pancreatic islet
Alpha cell
Beta cell
Delta cell
Maturation
MHC class I

Access to Document

10.1016/j.molmet.2024.101990Licence: CC BY-NC-ND

114110926Final published version, 4.48 MBLicence: CC BY-NC-ND

Cite this

@article{2557a2cd0ddc4e36a95b5f969f726dd4,

title = "Comprehensive alpha, beta, and delta cell transcriptomics reveal an association of cellular aging with MHC class I upregulation",

abstract = "ObjectivesThis study aimed to evaluate the efficacy of a purification method developed for isolating alpha, beta, and delta cells from pancreatic islets of adult mice, extending its application to islets from newborn and aged mice. Furthermore, it sought to examine transcriptome dynamics in mouse pancreatic endocrine islet cells throughout postnatal development and to validate age-related alterations within these cell populations.MethodsWe leveraged the high surface expression of CD71 on beta cells and CD24 on delta cells to FACS-purify alpha, beta, and delta cells from newborn (1-week-old), adult (12-week-old), and old (18-month-old) mice. Bulk RNA sequencing was conducted on these purified cell populations, and subsequent bioinformatic analyses included differential gene expression, overrepresentation, and intersection analysis.ResultsAlpha, beta, and delta cells from newborn and aged mice were successfully FACS-purified using the same method employed for adult mice. Our analysis of the age-related transcriptional changes in alpha, beta, and delta cell populations revealed a decrease in cell cycling and an increase in neuron-like features processes during the transition from newborn to adult mice. Progressing from adult to old mice, we identified an inflammatory gene signature related to aging (inflammaging) encompassing an increase in β-2 microglobulin and major histocompatibility complex (MHC) Class I expression.ConclusionsOur study demonstrates the effectiveness of our cell sorting technique in purifying endocrine subsets from mouse islets at different ages. We provide a valuable resource for better understanding endocrine pancreas aging and identified an inflammaging gene signature with increased β-2 microglobulin and MHC Class I expression as a common hallmark of old alpha, beta, and delta cells, with potential implications for immune response regulation and age-related diabetes.",

keywords = "Pancreatic islet, Alpha cell, Beta cell, Delta cell, Maturation, MHC class I",

author = "Willem Staels and Claire Berthault and Stephanie Bourgeois and Vincent Laville and Chloe Louren{\c c}o and {De Leu}, Nico and Raphael Scharfmann",

note = "Funding Information: Research in the lab of WS and NDL is supported by the Wetenschappelijk Fonds Willy Gepts of UZ Brussel (WFWG), Research Foundation Flanders (FWO, G058122N and G099323N), Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2022-1200-S-B and CDA-2024-1491-S-B), and Diabetes Onderzoek Nederland (DON). WS holds an FWO senior clinical investigator grant (1806421N). During part of this work, WS was supported by a postdoctoral grant from Agence Nationale de la Recherche (Laboratoire d'Excellence Revive, Investissement d'Avenir; ANR-10-LABX-73). SB is an FWO doctoral fellow (1S89821N). The RS laboratory received funding from the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody, under grant agreement No 115881, supported by the European Union's Horizon 2020 research and innovation program, EFPIA and the Swiss State Secretariat for Education. Research and Innovation (SERI) under contract number 16.0097, resources of which are composed of a financial contribution from the European Union's Seventh Framework Programme (FP7/2007\u20132013); the DON foundation; the Dutch Diabetes Research Foundation; the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA; this Joint Undertaking receives support from the Union's Horizon 2020 research and innovation program and \u201CEFPIA\u201D (European Federation of Pharmaceutical Industries Associations) the Laboratoire d'Excellence consortium Revive, Fondation pour la Recherche M\u00E9dicale (EQU201903007793) and Fondation Francophone pour la Recherche sur le Diabete (FFRD). Funding Information: Research in the lab of WS and NDL is supported by the Wetenschappelijk Fonds Willy Gepts of UZ Brussel (WFWG) , Research Foundation Flanders (FWO, G058122N and G099323N ), Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2022-1200-S-B and CDA-2024-1491-S-B ), and Diabetes Onderzoek Nederland (DON) . WS holds an FWO senior clinical investigator grant ( 1806421N ). During part of this work, WS was supported by a postdoctoral grant from Agence Nationale de la Recherche ( Laboratoire d\u2019Excellence Revive, Investissement d\u2019Avenir ; ANR-10-LABX-73 ). SB is an FWO doctoral fellow ( 1S89821N ). The RS laboratory received funding from the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody, under grant agreement No 115881 , supported by the European Union\u2019s Horizon 2020 research and innovation program , EFPIA and the Swiss State Secretariat for Education. Research and Innovation (SERI) under contract number 16.0097 , resources of which are composed of a financial contribution from the European Union\u2019s Seventh Framework Programme ( FP7/2007\u20132013 ); the DON foundation ; the Dutch Diabetes Research Foundation ; the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA; this Joint Undertaking receives support from the Union\u2019s Horizon 2020 research and innovation program and \u201CEFPIA\u201D (European Federation of Pharmaceutical Industries Associations ) the Laboratoire d\u2019Excellence consortium Revive, Fondation pour la Recherche M\u00E9dicale ( EQU201903007793 ) and Fondation Francophone pour la Recherche sur le Diabete (FFRD) . Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = sep,

doi = "10.1016/j.molmet.2024.101990",

language = "English",

volume = "87",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier",

}

Comprehensive alpha, beta, and delta cell transcriptomics reveal an association of cellular aging with MHC class I upregulation. / Staels, Willem; Berthault, Claire; Bourgeois, Stephanie; Laville, Vincent; Lourenço, Chloe; De Leu, Nico; Scharfmann, Raphael.

In: Molecular Metabolism, Vol. 87, 101990, 09.2024.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Comprehensive alpha, beta, and delta cell transcriptomics reveal an association of cellular aging with MHC class I upregulation

AU - Staels, Willem

AU - Berthault, Claire

AU - Bourgeois, Stephanie

AU - Laville, Vincent

AU - Lourenço, Chloe

AU - De Leu, Nico

AU - Scharfmann, Raphael

N1 - Funding Information: Research in the lab of WS and NDL is supported by the Wetenschappelijk Fonds Willy Gepts of UZ Brussel (WFWG), Research Foundation Flanders (FWO, G058122N and G099323N), Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2022-1200-S-B and CDA-2024-1491-S-B), and Diabetes Onderzoek Nederland (DON). WS holds an FWO senior clinical investigator grant (1806421N). During part of this work, WS was supported by a postdoctoral grant from Agence Nationale de la Recherche (Laboratoire d'Excellence Revive, Investissement d'Avenir; ANR-10-LABX-73). SB is an FWO doctoral fellow (1S89821N). The RS laboratory received funding from the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody, under grant agreement No 115881, supported by the European Union's Horizon 2020 research and innovation program, EFPIA and the Swiss State Secretariat for Education. Research and Innovation (SERI) under contract number 16.0097, resources of which are composed of a financial contribution from the European Union's Seventh Framework Programme (FP7/2007\u20132013); the DON foundation; the Dutch Diabetes Research Foundation; the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA; this Joint Undertaking receives support from the Union's Horizon 2020 research and innovation program and \u201CEFPIA\u201D (European Federation of Pharmaceutical Industries Associations) the Laboratoire d'Excellence consortium Revive, Fondation pour la Recherche M\u00E9dicale (EQU201903007793) and Fondation Francophone pour la Recherche sur le Diabete (FFRD). Funding Information: Research in the lab of WS and NDL is supported by the Wetenschappelijk Fonds Willy Gepts of UZ Brussel (WFWG) , Research Foundation Flanders (FWO, G058122N and G099323N ), Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2022-1200-S-B and CDA-2024-1491-S-B ), and Diabetes Onderzoek Nederland (DON) . WS holds an FWO senior clinical investigator grant ( 1806421N ). During part of this work, WS was supported by a postdoctoral grant from Agence Nationale de la Recherche ( Laboratoire d\u2019Excellence Revive, Investissement d\u2019Avenir ; ANR-10-LABX-73 ). SB is an FWO doctoral fellow ( 1S89821N ). The RS laboratory received funding from the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody, under grant agreement No 115881 , supported by the European Union\u2019s Horizon 2020 research and innovation program , EFPIA and the Swiss State Secretariat for Education. Research and Innovation (SERI) under contract number 16.0097 , resources of which are composed of a financial contribution from the European Union\u2019s Seventh Framework Programme ( FP7/2007\u20132013 ); the DON foundation ; the Dutch Diabetes Research Foundation ; the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA; this Joint Undertaking receives support from the Union\u2019s Horizon 2020 research and innovation program and \u201CEFPIA\u201D (European Federation of Pharmaceutical Industries Associations ) the Laboratoire d\u2019Excellence consortium Revive, Fondation pour la Recherche M\u00E9dicale ( EQU201903007793 ) and Fondation Francophone pour la Recherche sur le Diabete (FFRD) . Publisher Copyright: © 2024 The Author(s)

PY - 2024/9

Y1 - 2024/9

N2 - ObjectivesThis study aimed to evaluate the efficacy of a purification method developed for isolating alpha, beta, and delta cells from pancreatic islets of adult mice, extending its application to islets from newborn and aged mice. Furthermore, it sought to examine transcriptome dynamics in mouse pancreatic endocrine islet cells throughout postnatal development and to validate age-related alterations within these cell populations.MethodsWe leveraged the high surface expression of CD71 on beta cells and CD24 on delta cells to FACS-purify alpha, beta, and delta cells from newborn (1-week-old), adult (12-week-old), and old (18-month-old) mice. Bulk RNA sequencing was conducted on these purified cell populations, and subsequent bioinformatic analyses included differential gene expression, overrepresentation, and intersection analysis.ResultsAlpha, beta, and delta cells from newborn and aged mice were successfully FACS-purified using the same method employed for adult mice. Our analysis of the age-related transcriptional changes in alpha, beta, and delta cell populations revealed a decrease in cell cycling and an increase in neuron-like features processes during the transition from newborn to adult mice. Progressing from adult to old mice, we identified an inflammatory gene signature related to aging (inflammaging) encompassing an increase in β-2 microglobulin and major histocompatibility complex (MHC) Class I expression.ConclusionsOur study demonstrates the effectiveness of our cell sorting technique in purifying endocrine subsets from mouse islets at different ages. We provide a valuable resource for better understanding endocrine pancreas aging and identified an inflammaging gene signature with increased β-2 microglobulin and MHC Class I expression as a common hallmark of old alpha, beta, and delta cells, with potential implications for immune response regulation and age-related diabetes.

AB - ObjectivesThis study aimed to evaluate the efficacy of a purification method developed for isolating alpha, beta, and delta cells from pancreatic islets of adult mice, extending its application to islets from newborn and aged mice. Furthermore, it sought to examine transcriptome dynamics in mouse pancreatic endocrine islet cells throughout postnatal development and to validate age-related alterations within these cell populations.MethodsWe leveraged the high surface expression of CD71 on beta cells and CD24 on delta cells to FACS-purify alpha, beta, and delta cells from newborn (1-week-old), adult (12-week-old), and old (18-month-old) mice. Bulk RNA sequencing was conducted on these purified cell populations, and subsequent bioinformatic analyses included differential gene expression, overrepresentation, and intersection analysis.ResultsAlpha, beta, and delta cells from newborn and aged mice were successfully FACS-purified using the same method employed for adult mice. Our analysis of the age-related transcriptional changes in alpha, beta, and delta cell populations revealed a decrease in cell cycling and an increase in neuron-like features processes during the transition from newborn to adult mice. Progressing from adult to old mice, we identified an inflammatory gene signature related to aging (inflammaging) encompassing an increase in β-2 microglobulin and major histocompatibility complex (MHC) Class I expression.ConclusionsOur study demonstrates the effectiveness of our cell sorting technique in purifying endocrine subsets from mouse islets at different ages. We provide a valuable resource for better understanding endocrine pancreas aging and identified an inflammaging gene signature with increased β-2 microglobulin and MHC Class I expression as a common hallmark of old alpha, beta, and delta cells, with potential implications for immune response regulation and age-related diabetes.

KW - Pancreatic islet

KW - Alpha cell

KW - Beta cell

KW - Delta cell

KW - Maturation

KW - MHC class I

UR - http://www.scopus.com/inward/record.url?scp=85198962204&partnerID=8YFLogxK

U2 - 10.1016/j.molmet.2024.101990

DO - 10.1016/j.molmet.2024.101990

M3 - Article

C2 - 39009220

VL - 87

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

M1 - 101990

ER -

Comprehensive alpha, beta, and delta cell transcriptomics reveal an association of cellular aging with MHC class I upregulation

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Research output