RNA-Seq Analysis Reveals Different Dynamics of Differentiation of Human Dermis- and Adipose-Derived Stromal Stem Cells

Jääger, Kersti; Islam, Saiful; Zając, Paweł; Linnarsson, Sten; Neuman, Toomas

doi:10.1371/journal.pone.0038833

Cited by 59 publications

(50 citation statements)

References 32 publications

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“…54,000 probe sets / 38,500 genes. Differentiated cells include FIB, osteoblasts, adipocytes and chondrocytes.14 genes in the MSC lineage signature: ADAMTS5 , CCND1 , FHL2, GDF15, IGFBP3 , LOX , LOXL2 , MAP4K4, MCFD2 , SH3RF1, SLC16A4, SMURF2 , UGCG, VEGFCJääger et al 2012 [41] Human AD-MSC or FIB vs their lineage derived cells211 genes UP versus cells differentiate to 3 lineagesANOVA (1% FDR)AD-MSC and FIB were in vitro differentiated towards osteogenic, chondrogenic and adipogenic lineages.16 genes in the MSC lineage signature: CRISPLD2, HTRA1, IGFBP5, LAMB1, MARCKS, NNMT , PSAT1, REXO2, RPS27L, S100A11 , SARS, SERPINF1 , TMEM165, TMEM47, VAMP3, WARSJääger et al 2012 [41] Human AD-MSC or FIB vs their lineage derived cells333 genes DOWN versus cells differentiate to 3 lineagesANOVA (1% FDR)AD-MSC and FIB were in vitro differentiated towards osteogenic, chondrogenic and adipogenic lineages.38 genes in the MSC lineage signature: ACTN1 , ADAM9 , ANXA5 , ARF4, C1R, C1S, CALU , CAV1 , CCND1 , CD63, CKAP4, CLIC4, CORO1C, CTGF, CYB5A, DDAH1, DDR2 , DSP, ELL2, FRMD6, FTL, HEG1, HEXA, HNMT, IER3IP1, ISLR, KDELR3 , LAMA4, LAMC1, LASP1, LMO7, MYH9, NRP1, NUPR1, PTRF, SERPINE1 , SRPX, TUBB6Jääger et al 2012 [41] Human AD-MSC or FIB vs their lineage derived cellsgenes UP or DOWN in distinct contrasts versus cells differentiate to 3 lineagesANOVA (1% FDR)AD-MSC and FIB were in vitro differentiated towards osteogenic, chondrogenic and adipogenic lineages.10 genes in the MSC lineage signature: IGFBP3 , MT1E, MYOF, NAV1, NTM, PDLIM7, PTPN21, RHOC , SH2D4A, TPM1 Pedemonte et al 2007 [30] Mouse BM-MSCs vs any given tissue or cell type of the 12 included (brain, heart, skeletal muscle, liver, kidney, lung, dendritic cells, ESCs, MEFs, NSCs, HSCs, T-cells)403 genes (translated into 249 human orthologs)F-test p < 0.0001Affymetrix Mouse Genome 430 2.0 arrays, covering 39,000 transcripts. 7 BM-MSC samples against 486 publicly available samples from different origins.54 orthologs genes in the MSC lineage signature: ADAMTS5 , ANTXR1, ANXA2, ASNS, BGN, C6orf89, CALD1, CDC42EP3, CNN3, COL3A1, COL4A1 , COL5A1 , COL5A2, COL6A3, CSRP1, DAP, DBN1, DDR2 , DKK3, DPYSL3, ERRFI1, FGF7, FSTL1, FZD2, GJA1, GPR124, HTRA1, KDELR3 , LGALS1, LOX , MMP2, MRC2, NID2, NNMT , NUPR1, OSMR, PDGFRB, PHLDA3, PLOD2 , PLS3, POSTN, PSAT1, PYCR1, RCN1, RHOC, RNASE4, TNFRSF12A, TPBG, TPM4 , TSPAN6, SERPINF1 , SERPINH1 , SNAI2, SPARC

Genes appearing in more than one published signature are highlighted in bold

…”

Section: Resultsmentioning

confidence: 99%

“…M1, M2 & M3 refer to different culture conditions.9 genes UP in FIB vs MSCs: APCDD1, CCRL1, KIT , MMP1 , MMP3, MOXD1, PSG3, PSG9, TBX5,Jääger et al 2012 [41] Human AD-MSC vs FIB119 genes UP in FIBANOVA (5% FDR)Multiplex mRNA-sequencing14 genes UP in FIB vs MSCs: ANPEP, CDC25B, CLDN11, CTSK, CXCL12, DNM1, IGFBP3, MMP3 , PBX3, S100A4, SLIT2, STEAP1, TRAF3IP2, VITWagner et al 2005 [7] Human All tissue MSCs (BM-MSC-M1; BM-MSC-M2; AD-MSC-M1; Cord Blood MSC-M3) vs HS68-FIB25 genes UP in MSCs (based on 47 ESTs)> 2-fold changeHuman Transcriptome Microarray representing 51,144 different cDNA clones of the UniGene set RZPD3 (two colour arrays). M1, M2 & M3 refer to different culture conditions.4 genes DOWN in FIB vs MSCs: GPC4, HOXA5 , PLOD2 , TM4SF1Jääger et al 2012 [41] Human AD-MSC vs FIB59 genes UP in AD-MSCANOVA (5% FDR)Multiplex mRNA-sequencing13 genes DOWN in FIB vs MSCs: BGN, CDH2, GGT5, ID3, COL4A1 , COL5A1 , COL11A1, KRT18, LOXL2 , NDFIP2, TAGLN, TNS1, TPM1 Genes appearing in more than one published signature are highlighted in bold …”

Section: Resultsmentioning

confidence: 99%

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Insights into the human mesenchymal stromal/stem cell identity through integrative transcriptomic profiling

et al. 2016

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BackgroundMesenchymal Stromal/Stem Cells (MSCs), isolated under the criteria established by the ISCT, still have a poorly characterized phenotype that is difficult to distinguish from similar cell populations. Although the field of transcriptomics and functional genomics has quickly grown in the last decade, a deep comparative analysis of human MSCs expression profiles in a meaningful cellular context has not been yet performed. There is also a need to find a well-defined MSCs gene-signature because many recent biomedical studies show that key cellular interaction processes (i.e. inmuno-modulation, cellular cross-talk, cellular maintenance, differentiation, epithelial-mesenchymal transition) are dependent on the mesenchymal stem cells within the stromal niche.ResultsIn this work we define a core mesenchymal lineage signature of 489 genes based on a deep comparative analysis of multiple transcriptomic expression data series that comprise: (i) MSCs of different tissue origins; (ii) MSCs in different states of commitment; (iii) other related non-mesenchymal human cell types. The work integrates several public datasets, as well as de-novo produced microarray and RNA-Seq datasets. The results present tissue-specific signatures for adipose tissue, chorionic placenta, and bone marrow MSCs, as well as for dermal fibroblasts; providing a better definition of the relationship between fibroblasts and MSCs. Finally, novel CD marker patterns and cytokine-receptor profiles are unravelled, especially for BM-MSCs; with MCAM (CD146) revealed as a prevalent marker in this subtype of MSCs.ConclusionsThe improved biomolecular characterization and the released genome-wide expression signatures of human MSCs provide a comprehensive new resource that can drive further functional studies and redesigned cell therapy applications.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3230-0) contains supplementary material, which is available to authorized users.

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Genes appearing in more than one published signature are highlighted in bold

…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Insights into the human mesenchymal stromal/stem cell identity through integrative transcriptomic profiling

et al. 2016

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“…Analysis of the gene expression of stem cells isolated from different individuals also exhibited interindividual differences due to genetic variability resulting in a unique gene expression signature [121,122]. The same situation occurs with the gene expression of the DNA repair system, and, in apoptosis induction after cytotoxic treatment in hematopoietic stem cells isolated from umbilical cord blood [80], cells displayed different levels of donor-specific responses.…”

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confidence: 99%

Cytokinesis-Block Micronucleus Assay Adapted for Analyzing Genomic Instability of Human Mesenchymal Stem Cells

Cornélio

Tavares

Pimentel

et al. 2014

Stem Cells and Development

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Human mesenchymal stem cells (hMSCs) are multipotent cells used in cell therapy research. One of the problems involving hMSCs is the possibility of genetic instability during in vitro expansion required to obtain a suitable number of cells for clinical applications. The cytokinesis-block micronucleus (CBMN) assay measures genetic instability by analyzing the presence of micronucleus (MN), nucleoplasmic bridges (NPBs), and nuclear buds (NBUDs) in binucleated cells. The present study describes modifications in the CBMN assay methodology to analyze genetic instability in hMSCs isolated from the umbilical vein and in vitro expanded. The best protocol to achieve binucleated hMSCs with preserved cytoplasm was as follows: cytochalasin B concentration (4.0 μg/mL), use of hypotonic treatment (3 min), and the fixative solution (9 methanol:1 acetic acid). These adaptations were reproduced in three hMSC primary cell cultures and also in XP4PA and A549 cell lines. The frequency of hMSCs treated with mitomycin-C presenting MN was lower than that with other nuclear alterations, indicating that the hMSCs contain mechanisms to avoid a high level of chromosomal breaks. However, a high frequency of cells with NPBs was detected and spontaneous anaphase bridges under normal hMSC in vitro culture were observed. Considering that anaphase bridges are characteristic alterations in tumor cells, the CBMN assay is indicated as an important tool associated with other genetic analyses in order to ensure the safe clinical use of hMSCs in cell therapy.

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“…Because expression of ribosomal protein RPL19 remains rather constant throughout adipogenesis, these results indicate that Brd8, p400, and H2A.Z are specifically induced during the differentiation program of 3T3-L1, supporting the idea of a role for these proteins in the control of adipogenesis. To further strengthen these results, we compared mRNA expression levels from undifferentiated and differentiated 3T3-L1 cells with published data from human AdMSCs (44) for PPARG, Brd8, p400, H2A.Z, and RPL19. To establish the specificity of the implication of p400 and Brd8, we also included a comparison of mRNA expression levels of other subunits of the p400 complex such as ING3, Tip60, MRG15, and TRRAP as well as SRCAP, the other complex involved in the incorporation of H2A.Z into nucleosomes.…”

Section: Resultsmentioning

confidence: 99%

The p400/Brd8 Chromatin Remodeling Complex Promotes Adipogenesis by Incorporating Histone Variant H2A.Z at PPARγ Target Genes

et al. 2012

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Adipogenesis, the biological process by which preadipocytes differentiate into mature fat cells, is coordinated by a tightly regulated gene expression program. Indeed, it has been reported that a large number of genetic events, from fat cell-specific transcription factors expression, such as the master regulator of fat cell differentiation peroxisome proliferator-activated receptor (PPAR)γ2 to epigenetic modifications, govern the acquisition of a mature adipocyte phenotype. Here, we provide evidence that the E1A-binding protein p400 (p400) complex subunit bromo-containing protein 8 (Brd8) plays an important role in the regulation of PPARγ target genes during adipogenesis by targeting and incorporating the histone variant H2A.Z in transcriptional regulatory regions. The results reported here indicate that expression of both Brd8 and p400 increases during fat cell differentiation. In addition, small hairpin RNA-mediated knockdown of Brd8 or H2A.Z completely abrogated the ability of 3T3-L1 preadipocyte to differentiate into mature adipocyte, as evidenced by a lack of lipid accumulation. Chromatin immunoprecipitation experiments also revealed that the knockdown of Brd8 blocked the accumulation of PPARγ, p400, and RNA polymerase II and prevented the incorporation of H2A.Z at two PPARγ target genes. Taken together, these results indicate that the incorporation of the histone variant H2A.Z at the promoter regions of PPARγ target genes by p400/Brd8 is essential to allow fat cell differentiation.

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RNA-Seq Analysis Reveals Different Dynamics of Differentiation of Human Dermis- and Adipose-Derived Stromal Stem Cells

Cited by 59 publications

References 32 publications

Insights into the human mesenchymal stromal/stem cell identity through integrative transcriptomic profiling

Insights into the human mesenchymal stromal/stem cell identity through integrative transcriptomic profiling

Cytokinesis-Block Micronucleus Assay Adapted for Analyzing Genomic Instability of Human Mesenchymal Stem Cells

The p400/Brd8 Chromatin Remodeling Complex Promotes Adipogenesis by Incorporating Histone Variant H2A.Z at PPARγ Target Genes

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