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Single cell analysis of the Common Lymphoid Progenitor compartment reveals functional and molecular heterogeneity

ABSTRACT: In order to investigate molecular events involved in the regulation of lymphoid lineage commitment, we crossed lamda5 reporter transgenic mice to mice where the GFP gene is inserted into the Rag1 locus. This allowed us to sub-fractionate common lymphoid progenitors (CLPs) and pre-pro-B cells into lamda5-Rag1low, lamda5-Rag1high and lamda5+Rag1high cells. Clonal in vitro differentiation analysis demonstrated that Rag1low cells gave rise to B/T and NK cells. Rag1high cells displayed reduced NK-cell potential with preserved capacity to generate B- and T-lineage cells while the lamda5+ cells were B-lineage restricted. Ebf1 and Pax5 expression was largely confined to the Rag1high populations. These cells also expressed a higher level of the surface protein LY6D providing an additional tool for the analysis of early lymphoid development. These data suggest that the classical CLP compartment composes a mixture of cells with more or less restricted lineage potentials opening new possibilities to investigate early hematopoiesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE19142 | GEO | 2009/11/24

SECONDARY ACCESSION(S): PRJNA120689

REPOSITORIES: GEO

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Single cell analysis of the Common Lymphoid Progenitor compartment reveals functional and molecular heterogeneity

Project description:In order to investigate molecular events involved in the regulation of lymphoid lineage commitment, we crossed lamda5 reporter transgenic mice to mice where the GFP gene is inserted into the Rag1 locus. This allowed us to sub-fractionate common lymphoid progenitors (CLPs) and pre-pro-B cells into lamda5-Rag1low, lamda5-Rag1high and lamda5+Rag1high cells. Clonal in vitro differentiation analysis demonstrated that Rag1low cells gave rise to B/T and NK cells. Rag1high cells displayed reduced NK-cell potential with preserved capacity to generate B- and T-lineage cells while the lamda5+ cells were B-lineage restricted. Ebf1 and Pax5 expression was largely confined to the Rag1high populations. These cells also expressed a higher level of the surface protein LY6D providing an additional tool for the analysis of early lymphoid development. These data suggest that the classical CLP compartment composes a mixture of cells with more or less restricted lineage potentials opening new possibilities to investigate early hematopoiesis. Two newly identified subpopulations of common lymphoid progenitors (CLP), hereafter called CLP_RAGhigh and CLP_RAGlow, have been sorted in 2 replicates. RNA was extracted from 2,000 purified adult BM cells using the RNAeasy microkit. RNA was labeled and amplified by dual amplification and hybridized to Affymetrix microarray MOE430_2, according to AffymetrixTM GeneChip Expression Analysis Technical Manual. Probe level expression values were calculated using the RMA algorithm.

2009-11-24 | E-GEOD-19142 | biostudies-arrayexpress

Expression profiling of early lymphoid progenitors deficient for Ebf1 and Foxo1

Project description:Foxo1 and Ebf1 deficiency leads to a similar disruption of normal B-cell development at the level of the common lymphoid progenitor (CLP). Both mouse strains display the existance of LY6D+ CLPs but a marked/complete lack of proB cells. To investigate similarities of the developmental defects observed we generated gene expression profiles from both genotypes (with corresponding WT controls). This illustrated a shared gene expression signature in Ebf1/Foxo1 deficient CLPs. Gene expression profiling was done using highly purified (FACS sorted) progenitor cells. Cells were purified from bone marrow of wild-type, Foxo1 deficient and Ebf1 deficient mice. Ebf1 deficient bone marrow was aquired by transplantation of Ebf1 deficient progenitors into irradiated hosts. Populations analysed were CLP LY6D-, CLP LY6D+ and proB cells.

2012-11-01 | E-GEOD-41931 | biostudies-arrayexpress

Common lymphoid progenitor-independent pathways of innate and T lymphocyte development

Project description:All lymphocytes are thought to develop from common lymphoid progenitors (CLPs). However, lymphoid-primed multi-potent progenitors (LMPPs) are more efficient than CLPs in differentiating into T cells and group 2 innate lymphoid cells (ILC2s). Here, we have divided LMPPs into CD127− (LMPP-s) and CD127+ (LMPP+s) subsets and compared them with Ly6D− and Ly6D+ CLPs. Adult LMPP+s differentiated into T cells and ILCs more rapidly and efficiently than other progenitors in transplantation assays. The development of T cells and ILC2s is highly active in the neonatal period. Neonatal CLPs are rare and, unlike prominent neonatal LMPP+s, do not efficiently differentiate into T cells and ILC2s. ILC2s generated in the neonatal period are long-lived and persist in adult tissues. These results suggest that some ILCs and T cells may develop from LMPP+s via CLP-independent pathways.

2016-02-17 | GSE67034 | GEO

Comparison of Ly6D- common lymphoid progenitors (CLPs) from OcnCre;iDTR control and mutant mice.

Project description:We performed gene expression microarray comparing Ly6D- CLPs isolated from OcnCre;iDTR control and mutant mice by flow cytometry. Ly6D- CLPs were isolated from the bone marrow of OcnCre;iDTR control or mutant mice by flow cytometry and subjected to Affymetrix microarray comparison of gene expression. Markers used to define Ly6D- CLP by flow cytometry was: LineageLo, cKit+, Sca+, CD127+, Thy1.2-, Ly6D-

2015-04-10 | E-GEOD-66102 | biostudies-arrayexpress

Expression profiling of early lymphoid progenitors deficient for Ebf1 and Foxo1

2012-11-01 | GSE41931 | GEO

Comparison of gene expression profiles of ex vivo sorted Common Lymphoid Progenitors (CLPs) and in vitro cultured cCLPs.

Project description:A common lymphoid progenitor cell culture system was established, maintaining a multipotent, proliferating state of CLPs. Cells can be cultured and expanded in vitro for several months, maintaining their in vitro and in vivo lymphoid differentiation potential. We were interested, whether cCLP are changing, with regards to their gene expression program, compared to in vivo CLPs, during their expansion in culture. Therefore we compared the gene expression profile of cultured cCLPs and their counterparts in vivo, by NextGenSeq. CLPs were sorted from bone marrow of 6-10 weeks old C57BL/6 mice (n=4). Cells were sorted for Lin-, IL7R+, Flk2+, CD27+, Ly6d- marker expressing CLPs by Flow Cytometry for gene expression analysis. In parallel the same cell population was sorted and cultured under cCLP culture conditions. After two months culture the cells sorted again for Lin-, CD27+, Ly6d- cells by Flow Cytometry for gene expression analysis (n=4). The analysis shows that cCLPs maintain a very similar transcription profile to ex vivo sorted common lymphoid progenitors.

2018-04-01 | GSE109805 | GEO

The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program

Project description:Mature lymphoid cells express the transcriptional repressor Bach2, which imposes regulation on humoral and cellular immunity. Here we found critical roles for Bach2 in the development of cells of the B lineage, commencing from the common lymphoid progenitor (CLP) stage, with Bach1 as an auxiliary. Overexpression of Bach2 in pre-pro-B cells deficient in the transcription factor EBF1 and single-cell analysis of CLPs revealed that Bach2 and Bach1 repressed the expression of genes important for myeloid cells (‘myeloid genes’). Bach2 and Bach1 bound to presumptive regulatory regions of the myeloid genes. Bach2hi CLPs showed resistance to myeloid differentiation even when cultured under myeloid conditions. Our results suggest that Bach2 functions with Bach1 and EBF1 to promote B cell development by repressing myeloid genes in CLPs.

2014-10-26 | GSE61409 | GEO

The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program

Project description:Mature lymphoid cells express the transcriptional repressor Bach2, which imposes regulation on humoral and cellular immunity. Here we found critical roles for Bach2 in the development of cells of the B lineage, commencing from the common lymphoid progenitor (CLP) stage, with Bach1 as an auxiliary. Overexpression of Bach2 in pre-pro-B cells deficient in the transcription factor EBF1 and single-cell analysis of CLPs revealed that Bach2 and Bach1 repressed the expression of genes important for myeloid cells (M-bM-^@M-^Xmyeloid genesM-bM-^@M-^Y). Bach2 and Bach1 bound to presumptive regulatory regions of the myeloid genes. Bach2hi CLPs showed resistance to myeloid differentiation even when cultured under myeloid conditions. Our results suggest that Bach2 functions with Bach1 and EBF1 to promote B cell development by repressing myeloid genes in CLPs. WT and Bach1 and Bach2 double deficient (DD) CLPs. Multipotent progenitors (MPPs) infected with control-GFP and Bach2-GFP and cultured several condition. Follicular B cells (Fo B) stimulated with IgM. Three expreriments was performed in this paper.

2014-10-26 | E-GEOD-61409 | biostudies-arrayexpress

The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor

Project description:Innate lymphoid cells (ILCs) are recently identified lymphocytes that limit infection and promote tissue repair at mucosal surfaces. However, the pathways underlying ILC development remain unclear. Here we show that the transcription factor NFIL3 directs the development of a committed bone marrow precursor that differentiates into all known ILC lineages. NFIL3 was required in the common lymphoid progenitor (CLP), and was essential for the differentiation of CLP, a bone marrow cell population that gives rise to all known ILC lineages. Clonal differentiation studies revealed that CXCR6+ cells within the CLP population differentiate into all ILC lineages but not T- and B-cells. We further show that NFIL3 governs ILC development by directly regulating expression of the transcription factor TOX. These findings establish that NFIL3 directs the differentiation of a committed ILC precursor that gives rise to all ILC lineages and provide insight into the defining role of NFIL3 in ILC development. This experiment is to compare gene expression profiles between wild-type and Nfil3-/- common lymphoid progenitor (CLP) cells to identify genes regulated by NFIL3. There are 6 samples in this experiment, including 3 biological replicates for wild-type CLPs and 3 biological replicates for Nfil3-/- CLPs. All mice used are on the C57BL/6 background.

2014-10-16 | E-GEOD-62337 | biostudies-arrayexpress

Expression data from WT, HEB-KO and E2A-KO LY6D- CLP cells

Project description:The E-protein transcription factors E2A and HEB play important roles at several stages of hematopoiesis. However, the exact mechanism for theire action and the main targets in the LY6D negative common lymphoid progentior (CLP) compartment remains unknown. By adressing this question, we will gain important infromation regarding the early events leading to B-cell specification. FACS sorted LY6D negative common lymphoid progenitors from WT, HEB-KO and E2A-KO mice were subjected to RNA extraction and hybridization on Affymetrix microarrays. At least two independent sorts were performed per genotype. During each sort, cells were pooled from several bone marrows.

2011-11-22 | E-GEOD-27402 | biostudies-arrayexpress

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