Comparative and Integrative Single Cell Analysis Reveals New Insights into the Transcriptional Immaturity of Stem Cell-derived β Cells

Overview

Journal BMC Genomics

Publisher Biomed Central

Specialty Genetics

Date 2024 Jan 24

PMID 38267908

Authors

Mason D Schmidt

Matthew Ishahak

Punn Augsornworawat

Jeffrey R Millman

Affiliations

Soon will be listed here.

Abstract

Diabetes cell replacement therapy has the potential to be transformed by human pluripotent stem cell-derived β cells (SC-β cells). However, the precise identity of SC-β cells in relationship to primary fetal and adult β-cells remains unclear. Here, we used single-cell sequencing datasets to characterize the transcriptional identity of islets from in vitro differentiation, fetal islets, and adult islets. Our analysis revealed that SC-β cells share a core β-cell transcriptional identity with human adult and fetal β-cells, however SC-β cells possess a unique transcriptional profile characterized by the persistent expression and activation of progenitor and neural-biased gene networks. These networks are present in SC-β cells, irrespective of the derivation protocol used. Notably, fetal β-cells also exhibit this neural signature at the transcriptional level. Our findings offer insights into the transcriptional identity of SC-β cells and underscore the need for further investigation of the role of neural transcriptional networks in their development.

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References

Hogrebe N, Maxwell K, Augsornworawat P, Millman J . Generation of insulin-producing pancreatic β cells from multiple human stem cell lines. Nat Protoc. 2021; 16(9):4109-4143. PMC: 8529911. DOI: 10.1038/s41596-021-00560-y. View

Riedel M, Asadi A, Wang R, Ao Z, Warnock G, Kieffer T . Immunohistochemical characterisation of cells co-producing insulin and glucagon in the developing human pancreas. Diabetologia. 2011; 55(2):372-81. DOI: 10.1007/s00125-011-2344-9. View

Weng C, Xi J, Li H, Cui J, Gu A, Lai S . Single-cell lineage analysis reveals extensive multimodal transcriptional control during directed beta-cell differentiation. Nat Metab. 2020; 2(12):1443-1458. PMC: 7744443. DOI: 10.1038/s42255-020-00314-2. View

Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov J . Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011; 27(12):1739-40. PMC: 3106198. DOI: 10.1093/bioinformatics/btr260. View

Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov J, Tamayo P . The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2016; 1(6):417-425. PMC: 4707969. DOI: 10.1016/j.cels.2015.12.004. View

Hrvatin S, ODonnell C, Deng F, Millman J, Pagliuca F, DiIorio P . Differentiated human stem cells resemble fetal, not adult, β cells. Proc Natl Acad Sci U S A. 2014; 111(8):3038-43. PMC: 3939927. DOI: 10.1073/pnas.1400709111. View

van Arensbergen J, Garcia-Hurtado J, Moran I, Maestro M, Xu X, Van de Casteele M . Derepression of Polycomb targets during pancreatic organogenesis allows insulin-producing beta-cells to adopt a neural gene activity program. Genome Res. 2010; 20(6):722-32. PMC: 2877569. DOI: 10.1101/gr.101709.109. View

Martens G, Jiang L, Hellemans K, Stange G, Heimberg H, Nielsen F . Clusters of conserved beta cell marker genes for assessment of beta cell phenotype. PLoS One. 2011; 6(9):e24134. PMC: 3166300. DOI: 10.1371/journal.pone.0024134. View

Moon J, Kim Y, Kim K, Osonoi S, Wang S, Saunders D . Serotonin Regulates Adult β-Cell Mass by Stimulating Perinatal β-Cell Proliferation. Diabetes. 2019; 69(2):205-214. PMC: 6971487. DOI: 10.2337/db19-0546. View

10.

Portela-Gomes G, Gayen J, Grimelius L, Stridsberg M, Mahata S . The importance of chromogranin A in the development and function of endocrine pancreas. Regul Pept. 2008; 151(1-3):19-25. DOI: 10.1016/j.regpep.2008.07.005. View

11.

Millman J, Pagliuca F . Autologous Pluripotent Stem Cell-Derived β-Like Cells for Diabetes Cellular Therapy. Diabetes. 2017; 66(5):1111-1120. DOI: 10.2337/db16-1406. View

12.

Lipsitz Y, Timmins N, Zandstra P . Quality cell therapy manufacturing by design. Nat Biotechnol. 2016; 34(4):393-400. DOI: 10.1038/nbt.3525. View

13.

Hogrebe N, Ishahak M, Millman J . Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes. Cell Stem Cell. 2023; 30(5):530-548. PMC: 10167558. DOI: 10.1016/j.stem.2023.04.002. View

14.

Chen E, Tan C, Kou Y, Duan Q, Wang Z, Meirelles G . Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013; 14:128. PMC: 3637064. DOI: 10.1186/1471-2105-14-128. View

15.

Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P . The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature. 1997; 386(6623):399-402. DOI: 10.1038/386399a0. View

16.

de Krijger R, Aanstoot H, Kranenburg G, Reinhard M, Visser W, Bruining G . The midgestational human fetal pancreas contains cells coexpressing islet hormones. Dev Biol. 1992; 153(2):368-75. DOI: 10.1016/0012-1606(92)90121-v. View

17.

Augsornworawat P, Hogrebe N, Ishahak M, Schmidt M, Marquez E, Maestas M . Single-nucleus multi-omics of human stem cell-derived islets identifies deficiencies in lineage specification. Nat Cell Biol. 2023; 25(6):904-916. PMC: 10264244. DOI: 10.1038/s41556-023-01150-8. View

18.

Lioubinski O, Muller M, Wegner M, Sander M . Expression of Sox transcription factors in the developing mouse pancreas. Dev Dyn. 2003; 227(3):402-8. DOI: 10.1002/dvdy.10311. View

19.

Wheeler M, Sheu L, Ghai M, Bouquillon A, Grondin G, Weller U . Characterization of SNARE protein expression in beta cell lines and pancreatic islets. Endocrinology. 1996; 137(4):1340-8. DOI: 10.1210/endo.137.4.8625909. View

20.

Baron M, Veres A, Wolock S, Faust A, Gaujoux R, Vetere A . A Single-Cell Transcriptomic Map of the Human and Mouse Pancreas Reveals Inter- and Intra-cell Population Structure. Cell Syst. 2016; 3(4):346-360.e4. PMC: 5228327. DOI: 10.1016/j.cels.2016.08.011. View