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Global miRNA expression of bone marrow mesenchymal stem/stromal cells derived from Fanconi anemia patients

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Fanconi anemia (FA) is a rare genetic disorder characterized by genomic instability, developmental defects, and bone marrow (BM) failure. Hematopoietic stem cells (HSCs) in BM interact with the mesenchymal stem/stromal cells (MSCs); and this partly sustains the tissue homeostasis. MicroRNAs (miRNAs) can play a critical role during these interactions possibly via paracrine mechanisms. This is the first study addressing the miRNA profile of FA BM–MSCs obtained before and after BM transplantation (preBMT and postBMT, respectively). Non-coding RNA expression profiling and quality control analyses were performed in Donors (n = 13), FA preBMT (n = 11), and FA postBMT (n = 6) BM–MSCs using GeneChip miRNA 2.0 Array. Six Donor-FA preBMT pairs were used to identify a differentially expressed miRNA expression signature containing 50 miRNAs, which exhibited a strong correlation with the signature obtained from unpaired samples. Five miRNAs (hsa-miR-146a-5p, hsa-miR-148b-3p, hsa-miR-187-3p, hsa-miR-196b-5p, and hsa-miR-25-3p) significantly downregulated in both the paired and unpaired analyses were used to generate the BM–MSCs’ miRNA—BM mononuclear mRNA networks upon integration of a public dataset (GSE16334; studying Donor versus FA samples). Functionally enriched KEGG pathways included cellular senescence, miRNAs, and pathways in cancer. Here, we showed that hsa-miR-146a-5p and hsa-miR-874-3p were rescued upon BMT (n = 3 triplets). The decrease in miR-146a-5p was also validated using RT-qPCR and emerged as a strong candidate as a modulator of BM mRNAs in FA patients.

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Acknowledgements

This study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK; project no: 110S021) in conjunction with EU COST Action BM0805 designated as ‘HOX and TALE transcription factors in Development and Disease’.

Funding

This work was supported by The Scientific and Technological Research Council of Turkey (TUBITAK; project no: 110S021) in conjunction with EU COST Action BM0805 designated as ‘HOX and TALE transcription factors in Development and Disease’.

Author information

Author notes

  1. Ilgin Cagnan

    Present address: Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, 99628, Famagusta, North Cyprus, via Mersin-10, Turkey

  2. Ilgin Cagnan, Mustafa Keles, Ayse Gokce Keskus and Melike Tombaz have equally contributed to this manuscript and are ordered according to the alphabetic list of their surnames.

Authors and Affiliations

  1. Department of Stem Cell Sciences, Graduate School of Health Sciences, Center for Stem Cell Research and Development, Hacettepe University, 06100, Sihhiye, Ankara, Turkey

    Ilgin Cagnan, Mustafa Keles, Ozge Burcu Sahan, Fatima Aerts-Kaya, Duygu Uckan-Cetinkaya & Aysen Gunel-Ozcan

  2. Center for Stem Cell Research and Development, PEDI-STEM, Hacettepe University, 06100, Sihhiye, Ankara, Turkey

    Mustafa Keles, Ozge Burcu Sahan, Fatima Aerts-Kaya, Duygu Uckan-Cetinkaya & Aysen Gunel-Ozcan

  3. Interdisciplinary Neuroscience Program, Bilkent University, Ankara, Turkey

    Ayse Gokce Keskus & Ozlen Konu

  4. Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey

    Melike Tombaz & Ozlen Konu

  5. Department of Pediatrics, Division of Bone Marrow Transplantation Unit, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Duygu Uckan-Cetinkaya

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Contributions

AGO designed the study and supervised the experiments. OK supervised the bioinformatics analysis. AGO, OK, IC, and MK drafted the introduction and discussion. IC, MK, AGK, MT, OBS, and FAK performed the experiments and/or data analysis. IC, MK, AGK, and MT drafted methods and results. DUC provided the bone marrow samples. All the authors approved the final version of manuscript.

Corresponding authors

Correspondence to Ozlen Konu or Aysen Gunel-Ozcan.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. This study was approved by the Local Ethical Committee (Number 14, 24/08/2009).

Informed consent

Informed consent was obtained from all individual participants/their parents included in the study.

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Online Resource 1 Representative images of FA postBMT BM–MSCs (i.e. HUSCS-FA11) showing a) flow cytometry analysis of CD29, CD44, CD166, CD90, CD106, CD146, CD144, CD200, CD133, CD34, CD105, CD45, CD14, CD73, HLA-ABC, HLA-DR, CD140b, CD31 surface markers, and b) differentiation potential of postBMT BM–MSCs on day 21 following induction; image on the left depicts control (undifferentiated) BM–MSCs; image at the middle depicts BM–MSCs differentiated to adipogenic lineage and stained with Oil-Red O dye; image on the right depicts BM–MSCs differentiated to osteogenic lineage and stained with Alizarin Red S dye). Intriguingly, postBMT samples obtained from HUSCS-FA04, HUSCS-FA09a and HUSCS-FA10 did not show any osteogenic differentiation potential (data not shown). Due to low cell number, CD133, CD34, CD45, CD14, HLA-ABC and HLA-DR levels were not analyzed for HUSCS-FA09a (EPS 53829 KB)

Supplementary File2 (Online Resource 2) (DOCX 25 KB)

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Online Resource 3 Quality Control analysis of the microarray data (n = 30). a) Boxplot of NUSE values. Outliers were labeled with red. b) Multidimensional scaling (MDS) plot for the microarray data. Outliers were labelled. Samples were colored according to the patient group. ‘T’ in the labelling designates postBMT samples. FA09a and FA09b are affected siblings from the same family (EPS 104129 KB)

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Online Resource 4 Heatmap of paired samples (a) and samples without pairs (b) created by 50 miRNAs that have been obtained to be significantly differentially expressed in paired analysis (EPS 63032 KB)

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Online Resource 5 Boxplots of the expression values of the five significantly altered miRNAs obtained from the paired samples analysis (a) and samples without pairs (b). P-values obtained from limma analysis were reported on the plot (EPS 112573 KB)

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Online Resource 6 miRNAs commonly downregulated in FA MSCs in paired and unpaired analyses integrated with FA bone marrow mononuclear cells. BM–MNC mRNAs downregulated at least 0.5 log FC. The miRNA-mRNA interaction data obtained from miRnet.ca were used in Cytoscape (v3.8.2) and coloring and size of mRNAs indicate the degree of downregulation. The edge width indicates the number of experimental evidence for the gene targets (EPS 61046 KB)

Supplementary File2 (Online Resource 7) (DOCX 15 KB)

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Online Resource 8 Upregulated targets of hsa-miR-146a-5p and hsa-miR-874-3p in FA bone marrow mononuclear cells. mRNAs were upregulated at least 0.5 log FC. The miRNA-mRNA interaction data obtained from miRnet.ca were used in Cytoscape (v3.8.2) and coloring and size of mRNAs indicate the degree of upregulation. The edge width indicates the number of experimental evidence for the gene targets (EPS 52343 KB)

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Cagnan, I., Keles, M., Keskus, A.G. et al. Global miRNA expression of bone marrow mesenchymal stem/stromal cells derived from Fanconi anemia patients. Human Cell 35, 111–124 (2022). https://doi.org/10.1007/s13577-021-00626-9

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