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BMP signalling differentially regulates distinct haematopoietic stem cell types.

Crisan M, Kartalaei PS, Vink C, Yamada-Inagawa T, Bollerot K, van IJcken W, van der Linden R, de Sousa Lopes SM, Monteiro R, Mummery C, Dzierzak E - Nat Commun (2015)

Bottom Line: Adult haematopoiesis is the outcome of distinct haematopoietic stem cell (HSC) subtypes with self-renewable repopulating ability, but with different haematopoietic cell lineage outputs.Clonal transplantation demonstrates that they have distinct haematopoietic lineage outputs.Our findings provide insight into the molecular control mechanisms that define HSC types and have important implications for reprogramming cells to HSC fate and treatments targeting distinct HSC types.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands [2] University of Edinburgh, Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.

ABSTRACT
Adult haematopoiesis is the outcome of distinct haematopoietic stem cell (HSC) subtypes with self-renewable repopulating ability, but with different haematopoietic cell lineage outputs. The molecular basis for this heterogeneity is largely unknown. BMP signalling regulates HSCs as they are first generated in the aorta-gonad-mesonephros region, but at later developmental stages, its role in HSCs is controversial. Here we show that HSCs in murine fetal liver and the bone marrow are of two types that can be prospectively isolated--BMP activated and non-BMP activated. Clonal transplantation demonstrates that they have distinct haematopoietic lineage outputs. Moreover, the two HSC types differ in intrinsic genetic programs, thus supporting a role for the BMP signalling axis in the regulation of HSC heterogeneity and lineage output. Our findings provide insight into the molecular control mechanisms that define HSC types and have important implications for reprogramming cells to HSC fate and treatments targeting distinct HSC types.

No MeSH data available.


Related in: MedlinePlus

Transcriptome differences between BMP-activated and non-BMP-activated FL and BM HSCs.(a) FPKM values for BMP receptor and Smad genes expressed by GFP+ and GFP− LSK SLAM sorted HSCs from E14 FL and adult BM. ND, not detected. (b–d) Gene list enrichment analysis on genes with more than two fold difference in expression level between GFP+ and GFP− LSK SLAM sorted cells from FL and BM using Enrichr web-application (threshold false discovery rate (FDR)=0.01). GFP+ high genes are enriched in (b) BMPR2 gene targets (FDR<1.0e−13; Gene Expression Omnibus (GEO) Kinase perturbation gene sets). Gene lists available on request. (c) Also, overrepresented in GFP+ high genes are genes involved in homoeostasis (FDR=9.8e−4; Mouse Genome Informatics (MGI) mammalian phenotype term MP0001764), metabolism (FDR=5.4e−4; MGI mammalian phenotype term MP0005266), MYC (FDR=2.7e−4; TRANSFAC and JASPAR Position Weight Matrix (PWM) genesets), and STAT5B (FDR=2.7e−4; TRANSFAC and JASPAR PWM gene sets); (d) GFP− high genes are enriched for NFE2 (FDR=9.6e−3; TRANSFAC and JASPAR PWM gene sets), NFKB1 (FDR=2.7e−3; TRANSFAC and JASPAR PWM gene sets), SP1 (FDR=2.7e−3; TRANSFAC and JASPAR PWM gene sets), and haematopoietic system (FDR=5.2e−7; MGI mammalian phenotype term MP0002396)-related genes.
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f3: Transcriptome differences between BMP-activated and non-BMP-activated FL and BM HSCs.(a) FPKM values for BMP receptor and Smad genes expressed by GFP+ and GFP− LSK SLAM sorted HSCs from E14 FL and adult BM. ND, not detected. (b–d) Gene list enrichment analysis on genes with more than two fold difference in expression level between GFP+ and GFP− LSK SLAM sorted cells from FL and BM using Enrichr web-application (threshold false discovery rate (FDR)=0.01). GFP+ high genes are enriched in (b) BMPR2 gene targets (FDR<1.0e−13; Gene Expression Omnibus (GEO) Kinase perturbation gene sets). Gene lists available on request. (c) Also, overrepresented in GFP+ high genes are genes involved in homoeostasis (FDR=9.8e−4; Mouse Genome Informatics (MGI) mammalian phenotype term MP0001764), metabolism (FDR=5.4e−4; MGI mammalian phenotype term MP0005266), MYC (FDR=2.7e−4; TRANSFAC and JASPAR Position Weight Matrix (PWM) genesets), and STAT5B (FDR=2.7e−4; TRANSFAC and JASPAR PWM gene sets); (d) GFP− high genes are enriched for NFE2 (FDR=9.6e−3; TRANSFAC and JASPAR PWM gene sets), NFKB1 (FDR=2.7e−3; TRANSFAC and JASPAR PWM gene sets), SP1 (FDR=2.7e−3; TRANSFAC and JASPAR PWM gene sets), and haematopoietic system (FDR=5.2e−7; MGI mammalian phenotype term MP0002396)-related genes.

Mentions: The expression profiles of the BMP-activated and non-activated HSCs as examined by RNA sequencing show distinct genetic programs (Fig. 3). FL and BM LSK-SLAM GFP+ HSCs express Bmpr genes, whereas GFP− LSK-SLAM HSCs do not (Fig. 3a). Smad genes are expressed in both fractions. Genes upregulated in the GFP+ FL and BM HSC fractions are significantly enriched in BMPR2 downstream targets, confirming BMP signalling activation (Fig. 3b). Moreover, other categories/gene sets were found to be differentially expressed between the two HSC types. For example, sets common to FL and BM upregulated in the BMP-activated HSCs are significantly enriched for genes involved in homoeostasis and metabolism, and MYC and STAT5B target genes (Fig. 3c). Upregulated sets in the non-BMP-activated HSCs are significantly enriched for genes involved in haematopoietic system development, NFKB1, SP1 and NFE2 target genes (Fig. 3d; see figure legend for false discovery rate corrected Fisher exact test P values). As some of these transcription factors affect normal and malignant haematopoietic cells and specific haematopoietic lineages, the distinct programs may influence the functional characteristics of the two HSC types.


BMP signalling differentially regulates distinct haematopoietic stem cell types.

Crisan M, Kartalaei PS, Vink C, Yamada-Inagawa T, Bollerot K, van IJcken W, van der Linden R, de Sousa Lopes SM, Monteiro R, Mummery C, Dzierzak E - Nat Commun (2015)

Transcriptome differences between BMP-activated and non-BMP-activated FL and BM HSCs.(a) FPKM values for BMP receptor and Smad genes expressed by GFP+ and GFP− LSK SLAM sorted HSCs from E14 FL and adult BM. ND, not detected. (b–d) Gene list enrichment analysis on genes with more than two fold difference in expression level between GFP+ and GFP− LSK SLAM sorted cells from FL and BM using Enrichr web-application (threshold false discovery rate (FDR)=0.01). GFP+ high genes are enriched in (b) BMPR2 gene targets (FDR<1.0e−13; Gene Expression Omnibus (GEO) Kinase perturbation gene sets). Gene lists available on request. (c) Also, overrepresented in GFP+ high genes are genes involved in homoeostasis (FDR=9.8e−4; Mouse Genome Informatics (MGI) mammalian phenotype term MP0001764), metabolism (FDR=5.4e−4; MGI mammalian phenotype term MP0005266), MYC (FDR=2.7e−4; TRANSFAC and JASPAR Position Weight Matrix (PWM) genesets), and STAT5B (FDR=2.7e−4; TRANSFAC and JASPAR PWM gene sets); (d) GFP− high genes are enriched for NFE2 (FDR=9.6e−3; TRANSFAC and JASPAR PWM gene sets), NFKB1 (FDR=2.7e−3; TRANSFAC and JASPAR PWM gene sets), SP1 (FDR=2.7e−3; TRANSFAC and JASPAR PWM gene sets), and haematopoietic system (FDR=5.2e−7; MGI mammalian phenotype term MP0002396)-related genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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f3: Transcriptome differences between BMP-activated and non-BMP-activated FL and BM HSCs.(a) FPKM values for BMP receptor and Smad genes expressed by GFP+ and GFP− LSK SLAM sorted HSCs from E14 FL and adult BM. ND, not detected. (b–d) Gene list enrichment analysis on genes with more than two fold difference in expression level between GFP+ and GFP− LSK SLAM sorted cells from FL and BM using Enrichr web-application (threshold false discovery rate (FDR)=0.01). GFP+ high genes are enriched in (b) BMPR2 gene targets (FDR<1.0e−13; Gene Expression Omnibus (GEO) Kinase perturbation gene sets). Gene lists available on request. (c) Also, overrepresented in GFP+ high genes are genes involved in homoeostasis (FDR=9.8e−4; Mouse Genome Informatics (MGI) mammalian phenotype term MP0001764), metabolism (FDR=5.4e−4; MGI mammalian phenotype term MP0005266), MYC (FDR=2.7e−4; TRANSFAC and JASPAR Position Weight Matrix (PWM) genesets), and STAT5B (FDR=2.7e−4; TRANSFAC and JASPAR PWM gene sets); (d) GFP− high genes are enriched for NFE2 (FDR=9.6e−3; TRANSFAC and JASPAR PWM gene sets), NFKB1 (FDR=2.7e−3; TRANSFAC and JASPAR PWM gene sets), SP1 (FDR=2.7e−3; TRANSFAC and JASPAR PWM gene sets), and haematopoietic system (FDR=5.2e−7; MGI mammalian phenotype term MP0002396)-related genes.
Mentions: The expression profiles of the BMP-activated and non-activated HSCs as examined by RNA sequencing show distinct genetic programs (Fig. 3). FL and BM LSK-SLAM GFP+ HSCs express Bmpr genes, whereas GFP− LSK-SLAM HSCs do not (Fig. 3a). Smad genes are expressed in both fractions. Genes upregulated in the GFP+ FL and BM HSC fractions are significantly enriched in BMPR2 downstream targets, confirming BMP signalling activation (Fig. 3b). Moreover, other categories/gene sets were found to be differentially expressed between the two HSC types. For example, sets common to FL and BM upregulated in the BMP-activated HSCs are significantly enriched for genes involved in homoeostasis and metabolism, and MYC and STAT5B target genes (Fig. 3c). Upregulated sets in the non-BMP-activated HSCs are significantly enriched for genes involved in haematopoietic system development, NFKB1, SP1 and NFE2 target genes (Fig. 3d; see figure legend for false discovery rate corrected Fisher exact test P values). As some of these transcription factors affect normal and malignant haematopoietic cells and specific haematopoietic lineages, the distinct programs may influence the functional characteristics of the two HSC types.

Bottom Line: Adult haematopoiesis is the outcome of distinct haematopoietic stem cell (HSC) subtypes with self-renewable repopulating ability, but with different haematopoietic cell lineage outputs.Clonal transplantation demonstrates that they have distinct haematopoietic lineage outputs.Our findings provide insight into the molecular control mechanisms that define HSC types and have important implications for reprogramming cells to HSC fate and treatments targeting distinct HSC types.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Cell Biology, Erasmus MC Stem Cell Institute, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands [2] University of Edinburgh, Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.

ABSTRACT
Adult haematopoiesis is the outcome of distinct haematopoietic stem cell (HSC) subtypes with self-renewable repopulating ability, but with different haematopoietic cell lineage outputs. The molecular basis for this heterogeneity is largely unknown. BMP signalling regulates HSCs as they are first generated in the aorta-gonad-mesonephros region, but at later developmental stages, its role in HSCs is controversial. Here we show that HSCs in murine fetal liver and the bone marrow are of two types that can be prospectively isolated--BMP activated and non-BMP activated. Clonal transplantation demonstrates that they have distinct haematopoietic lineage outputs. Moreover, the two HSC types differ in intrinsic genetic programs, thus supporting a role for the BMP signalling axis in the regulation of HSC heterogeneity and lineage output. Our findings provide insight into the molecular control mechanisms that define HSC types and have important implications for reprogramming cells to HSC fate and treatments targeting distinct HSC types.

No MeSH data available.


Related in: MedlinePlus