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A Systems-level Characterization of the Differentiation of Human Embryonic Stem Cells into Mesenchymal Stem Cells*[S]

journal contribution
submitted on 2024-07-07, 13:05 and posted on 2024-07-07, 13:05 authored by Anja M. Billing, Shaima S. Dib, Aditya M. Bhagwat, Israel T. da Silva, Rodrigo D. Drummond, Shahina Hayat, Rasha Al-Mismar, Hisham Ben-Hamidane, Neha Goswami, Kasper Engholm-Keller, Martin R. Larsen, Karsten Suhre, Arash Rafii, Johannes Graumann

Mesenchymal stem/stromal cells (MSCs) are self-renewing multipotent cells with regenerative, secretory and immunomodulatory capabilities that are beneficial for the treatment of various diseases. To avoid the issues that come with using tissue-derived MSCs in therapy, MSCs may be generated by the differentiation of human embryonic stems cells (hESCs) in culture. However, the changes that occur during the differentiation process have not been comprehensively characterized. Here, we combined transcriptome, proteome and phosphoproteome profiling to perform an in-depth, multi-omics study of the hESCs-to-MSCs differentiation process. Based on RNA-to-protein correlation, we determined a set of high confidence genes that are important to differentiation. Among the earliest and strongest induced proteins with extensive differential phosphorylation was AHNAK, which we hypothesized to be a defining factor in MSC biology. We observed two distinct expression waves of developmental HOX genes and an AGO2-to-AGO3 switch in gene silencing. Exploring the kinetic of noncoding ORFs during differentiation, we mapped new functions to well annotated long noncoding RNAs (CARMN, MALAT, NEAT1, LINC00152) as well as new candidates which we identified to be important to the differentiation process. Phosphoproteome analysis revealed ESC and MSC-specific phosphorylation motifs with PAK2 and RAF1 as top predicted upstream kinases in MSCs. Our data represent a rich systems-level resource on ESC-to-MSC differentiation that will be useful for the study of stem cell biology.

Other Information

Published in: Molecular & Cellular Proteomics
License: http://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.1074/mcp.ra119.001356

Funding

Qatar National Research Fund (NPRP 4 - 1267 - 1 - 194), Quantitative Proteomics of the Differentiation of human Embryonic Stem Cells.

Lundbeck Foundation (R83–2011-8143).

History

Language

  • English

Publisher

Elsevier

Publication Year

  • 2019

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Weill Cornell Medicine - Qatar

Related Datasets

Billing, A. M., Dib, S. S., Bhagwat, A. M., da Silva, I. T., Drummond, R. D., Hayat, S., Al-Mismar, R., Ben-Hamidane, H., Goswami, N., Engholm-Keller, K., Larsen, M. R., Suhre, K., Rafii, A., & Graumann, J. (2019). A Systems-level Characterization of the Differentiation of Human Embryonic Stem Cells into Mesenchymal Stem Cells*[S]. Molecular & Cellular Proteomics, 18(10), 1950–1966. https://doi.org/10.1074/mcp.ra119.001356. ProteomeXchange Consortium DataSets : Identifier PXD004652. https://proteomecentral.proteomexchange.org/?search=PXD004652. National Institutes of Health : National Center for Biotechnology Information : Sequence Read Archive (SRA) : DataSet identifier PRJNA507603.https://www.ncbi.nlm.nih.gov/sra/PRJNA507603