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Differential expression of mouse Grem1+ Vs. Grem1- bone-marrow cells

ABSTRACT: The gene expression of bone marrow cells of mice enriched for Gremlin1 vs control was measured (n=3). It is not known if endogenous adult mesenchymal stem cells (MSCs) exist.Following culture,perisinusoidal mesenchymal cells can clonally recapitulate the skeletal microenvironment, but this fails to confirm their endogenous lineage repertoire. Multipotential MSCs in vitro may be fate-restricted in vivo and specific perisinusoidal recombination does not trace bone or cartilage Reconciling in vitro MSCs with their in vivo potential has been challenging and remains untested outside of the bone. We prove that expression of the bone morphogenetic protein (BMP)-antagonist gremlin 1 (Grem1) identifies a population of self-renewing, multipotent bone, cartilage and stromal-primed MSCs in both health and healing that are completely distinct from the established Nes-GFP niche-supporting mesenchymal cells. Grem1 recombination also identifies small intestinal MSCs (siMSCs) that can be transplanted and clonally trace the self-renewing, multilineage periepithelial mesenchymal sheath. Our findings prove the existence of adult MSCs that are regionally and functionally distinct from perisinusoidal Nes-GFP cells. We also established that the mesenchyme undergoes ordered turnover outside of the bone and may help to preserve regional niches. Grem1 MSCs provide a new focus for investigating mesenchymal renewal and repair.

ORGANISM(S): Mus musculus

PROVIDER: GSE57729 | GEO | 2015/02/10

SECONDARY ACCESSION(S): PRJNA247959

REPOSITORIES: GEO

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Differential expression of mouse Grem1+ Vs. Grem1- bone-marrow cells

Project description:The gene expression of bone marrow cells of mice enriched for Gremlin1 vs control was measured (n=3). It is not known if endogenous adult mesenchymal stem cells (MSCs) exist.Following culture,perisinusoidal mesenchymal cells can clonally recapitulate the skeletal microenvironment, but this fails to confirm their endogenous lineage repertoire. Multipotential MSCs in vitro may be fate-restricted in vivo and specific perisinusoidal recombination does not trace bone or cartilage Reconciling in vitro MSCs with their in vivo potential has been challenging and remains untested outside of the bone. We prove that expression of the bone morphogenetic protein (BMP)-antagonist gremlin 1 (Grem1) identifies a population of self-renewing, multipotent bone, cartilage and stromal-primed MSCs in both health and healing that are completely distinct from the established Nes-GFP niche-supporting mesenchymal cells. Grem1 recombination also identifies small intestinal MSCs (siMSCs) that can be transplanted and clonally trace the self-renewing, multilineage periepithelial mesenchymal sheath. Our findings prove the existence of adult MSCs that are regionally and functionally distinct from perisinusoidal Nes-GFP cells. We also established that the mesenchyme undergoes ordered turnover outside of the bone and may help to preserve regional niches. Grem1 MSCs provide a new focus for investigating mesenchymal renewal and repair. a.Adult (6-8 weeks) Grem1;TdTomato mice were induced by oral tamoxifen and their bone marrow harvested by digestion sorted for Non-recombined CD45/CD31/Ter-119 triple negative bone marrow cells (n=3). b.Adult (6-8 weeks) Grem1;TdTomato mice were induced by oral tamoxifen and their bone marrow harvested by digestion sorted for Grem1 (n=3). Same mice as in a so that samples are matched.

2015-02-10 | E-GEOD-57729 | biostudies-arrayexpress

cis-regulation of Grem1 during limb development [4C-seq]

Project description:Spatiotemporal gene expression programs are orchestrated by transcriptional enhancers which interact with target-gene promoters to regulate gene expression. In this study, we identified cis regulatory modules (CRMs) within the Fmn1/Grem1 cis-regulatory landscape that participate in controlling spatiotemporal expression of Grem1. We generated different Grem1 alleles lacking either individual CRMs, combinations or entire enhancer clusters (EC1 and EC2) using CRISPR/Cas genome editing. To study potential interactions of these CRMs with the Grem1 promoter, we generated 4C-seq profiles of different alleles. Our analysis of 4C-seq shows that the overall structure of the Grem1 TAD is maintained in CRM2-/- and EC1-/- forelimb buds. Similar to EC1, the chromatin architecture of the Grem1 TAD is not disrupted outside the EC2 and EC1EC2 deletions. In all the genotypes, the contacts of the promoter with the remainder of the Grem1 TAD are rather increased. Thus, our results revealed that the spatio-temporal changes in Grem1 expression are caused by cis-regulatory alterations due to the deletions of EC1 and EC2 and not global changes in chromatin architecture.

2021-07-31 | GSE151645 | GEO

The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem-cell-niche function

Project description:Mesenchymal stem cells (MSCs) And osteolineage cells contribute to the hematopoietic stem cell (HSC) Niche in the bone marrow of long bones. However, Their developmental relationships remain unclear. Here we demonstrate that different MSC populations in the developing marrow of long bones have distinct functions. Proliferative mesoderm-derived nestin- MSCs participate in fetal skeletogenesis, And lose MSC activity soon after birth. In contrast, Quiescent neural-crest-derived nestin+ Cells in the same bones preserve MSC activity, But do not generate fetal chondrocytes. Instead, They differentiate into HSC-niche-forming MSCs, Helping to establish the HSC niche by secreting Cxcl12. Perineural migration of these cells to the bone marrow requires the ErbB3 receptor. The neonatal Nestin-GFP+ PDGFR- Cell population also contains Schwann-cell precursors, But does not comprise mature Schwann cells. Thus, In the developing bone marrow HSC-niche-forming MSCs share a common origin with sympathetic peripheral neurons and glial cells, And ontogenically distinct MSCs have non-overlapping functions in endochondrogenesis and HSC niche formation. Total RNA was isolated from small numbers of FACS sorted stromal cells, obtained from neonatal Nes-Gfp bone marrow preparations (2 biological replicates). Each independent set of samples was obtained from pooled skeletal elements (long bones and sterna) form multiple littermates.

2014-10-15 | E-GEOD-61695 | biostudies-arrayexpress

cis-regulation of Grem1 during limb development [ChIP-seq]

Project description:Chromatin immunoprecipitation in combination with sequencing (ChIP-seq) was used to identify the interactions of CRMs with key regulators of Grem1 expression, namely SMAD4 (mediating response to BMP signal transduction) and GLI3 (SHH signal transduction). This analysis revealed the presence of a single significantly enriched SMAD4 ChIP-seq peak in CRM2 during initiation of forelimb bud development, when BMP4 is required to initiate/upregulate the Grem1 transcription. During progression of limb development, GLI3 chromatin complexes interact with all enhancers except CRM5. which agrees with the predominant role of SHH-mediated Grem1 regulation during outgrowth and/or GLI3R-mediated repression during termination. Thus, the Grem1 TAD encodes an array of CRM enhancers that integrate inputs from BMP and SHH signaling into the dynamic regulation of Grem1 during limb bud outgrowth.

2021-07-31 | GSE151646 | GEO

Loss of Grem1-lineage chondrogenic progenitor 1 cells causes osteoarthritis

Project description:Osteoarthritis (OA) is characterised by an irreversible degeneration of articular cartilage. Here we show that the BMP-antagonist Gremlin 1 (Grem1) marks a bipotent chondrogenic and osteogenic progenitor cell population within the articular surface. Notably, these progenitors are depleted by injury-induced OA and increasing age. OA is also caused by ablation of Grem1 cells in mice. Transcriptomic and functional analysis in mice found that articular surface Grem1-lineage cells are dependent on Foxo1 and ablation of Foxo1 in Grem1-lineage cells caused OA. FGFR3 signalling was confirmed as a promising therapeutic pathway by administration of pathway activator, FGF18, resulting in Grem1-lineage chondrocyte progenitor cell proliferation, increased cartilage thickness and reduced OA. These findings suggest that OA, in part, is caused by mechanical, developmental or age-related attrition of Grem1 expressing articular cartilage progenitor cells. These cells, and the FGFR3 signalling pathway that sustains them, may be effective future targets for biological management of OA.

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cis-regulation of Grem1 expression during limb development [ATAC HH24]

Project description:Spatiotemporal gene expression programs are orchestrated by transcriptional enhancers which interact with target-gene promoters to regulate gene expression. The BMP antagonist Gremlin1 (Grem1) is an important node in the gene regulatory network that controls vertebrate limb development. In this study, we used a combination of open chromatin profiling (ATAC-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) in mouse and chick to identify putative cis-regulatory modules (CRMs) that regulate Grem1 in limb buds. Using CRISPR/Cas genome editing we generated different Grem1 regulatory alleles lacking either individual CRMs, combinations or entire enhancer clusters. To study potential interactions of these CRMs with the Grem1 promoter, we generated 4C-seq profiles of specific regulatory alleles. Taken together our results revealed that the spatio-temporal changes in Grem1 expression are caused by cis-regulatory alterations due to the deletions of enhancer clusters rather than global changes in chromatin architecture.

2021-07-30 | GSE151467 | GEO

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cis-regulation of Grem1 expression during limb development [E10.5 H3K27Ac ChIP-Seq]

Project description:Spatiotemporal gene expression programs are orchestrated by transcriptional enhancers which interact with target-gene promoters to regulate gene expression. The BMP antagonist Gremlin1 (Grem1) is an important node in the gene regulatory network that controls vertebrate limb development. In this study, we used a combination of open chromatin profiling (ATAC-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) in mouse and chick to identify putative cis-regulatory modules (CRMs) that regulate Grem1 in limb buds. Using CRISPR/Cas genome editing we generated different Grem1 regulatory alleles lacking either individual CRMs, combinations or entire enhancer clusters. To study potential interactions of these CRMs with the Grem1 promoter, we generated 4C-seq profiles of specific regulatory alleles. Taken together our results revealed that the spatio-temporal changes in Grem1 expression are caused by cis-regulatory alterations due to the deletions of enhancer clusters rather than global changes in chromatin architecture.

2021-07-30 | GSE164905 | GEO

cis-regulation of Grem1 expression during limb development [ATAC mouse forelimb buds]

Project description:Spatiotemporal gene expression programs are orchestrated by transcriptional enhancers which interact with target-gene promoters to regulate gene expression. The BMP antagonist Gremlin1 (Grem1) is an important node in the gene regulatory network that controls vertebrate limb development. In this study, we used a combination of open chromatin profiling (ATAC-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) in mouse and chick to identify putative cis-regulatory modules (CRMs) that regulate Grem1 in limb buds. Using CRISPR/Cas genome editing we generated different Grem1 regulatory alleles lacking either individual CRMs, combinations or entire enhancer clusters. To study potential interactions of these CRMs with the Grem1 promoter, we generated 4C-seq profiles of specific regulatory alleles. Taken together our results revealed that the spatio-temporal changes in Grem1 expression are caused by cis-regulatory alterations due to the deletions of enhancer clusters rather than global changes in chromatin architecture.

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Project description:Spatiotemporal gene expression programs are orchestrated by transcriptional enhancers which interact with target-gene promoters to regulate gene expression. The BMP antagonist Gremlin1 (Grem1) is an important node in the gene regulatory network that controls vertebrate limb development. In this study, we used a combination of open chromatin profiling (ATAC-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) in mouse and chick to identify putative cis-regulatory modules (CRMs) that regulate Grem1 in limb buds. Using CRISPR/Cas genome editing we generated different Grem1 regulatory alleles lacking either individual CRMs, combinations or entire enhancer clusters. To study potential interactions of these CRMs with the Grem1 promoter, we generated 4C-seq profiles of specific regulatory alleles. Taken together our results revealed that the spatio-temporal changes in Grem1 expression are caused by cis-regulatory alterations due to the deletions of enhancer clusters rather than global changes in chromatin architecture.

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