Single‐cell transcriptomics of LepR‐positive skeletal cells reveals heterogeneous stress‐dependent stem and progenitor pools
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ABSTRACT:
PROVIDER: PRJNA576804 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10257243_1.fastq.gz | Fastqsanger.gz | |||
| SRR10257243_2.fastq.gz | Fastqsanger.gz | |||
| SRR10257244_1.fastq.gz | Fastqsanger.gz | |||
| SRR10257244_2.fastq.gz | Fastqsanger.gz | |||
| SRR10257245_1.fastq.gz | Fastqsanger.gz |
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Project description:Leptin receptor (LepR)-positive cells are key components of the bone marrow hematopoietic microenvironment, and highly enrich skeletal stem and progenitor cells that maintain homeostasis of the adult skeleton. However, the heterogeneity and lineage hierarchy within this population has been elusive. Using genetic lineage tracing and single-cell RNA sequencing, we found that Lepr-Cre labels most bone marrow stromal cells and osteogenic lineage cells in adult long bones. Integrated analysis of Lepr-Cre-traced cells under homeostatic and stress conditions revealed dynamic changes of the adipogenic, osteogenic, and periosteal lineages. Importantly, we discovered a Notch3+ bone marrow sub-population that is slow-cycling and closely associated with the vasculatures, as well as key transcriptional networks promoting osteo-chondrogenic differentiation. We also identified a Sca-1+ periosteal sub-population with high clonogenic activity but limited osteo-chondrogenic potential. Together, we mapped the transcriptomic landscape of adult LepR+ stem and progenitor cells and uncovered cellular and molecular mechanisms underlying their maintenance and lineage specification.
2021-11-17 | GSE138689 | GEO
Project description:Leptin receptor (LepR)-positive cells are key components of the bone marrow hematopoietic microenvironment, and highly enrich skeletal stem and progenitor cells that maintain homeostasis of the adult skeleton. However, the heterogeneity and lineage hierarchy within this population has been elusive. Using genetic lineage tracing and single-cell RNA-sequencing, we found that Lepr-Cre labels most bone marrow stromal cells and osteogenic lineage cells in adult long bones. Integrated analysis of Lepr-Cre-traced cells under homeostatic and stress conditions revealed dynamic changes of the adipogenic, osteogenic and periosteal lineages. Importantly, we discovered a Notch3+ bone marrow subpopulation that is slow-cycling and closely associated with the vasculatures, as well as key transcriptional networks promoting osteo-chondrogenic differentiation. We also identified a Sca-1+ periosteal subpopulation with high clonogenic activity but limited osteo-chondrogenic potential. Together, we mapped the transcriptomic landscape of adult LepR+ stem and progenitor cells, and uncovered cellular and molecular mechanisms underlying their maintenance and lineage specification.
| S-SCDT-EMBOJ-2021-108415 | biostudies-other
Project description:Leptin receptors (Lepr) are expressed by various types of stem cells including mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells, and induced pluripotent stem cells. Leptin/lepr signaling is also a central regulator of metabolism. However, the role of Lepr in pluripotency, metabolic disease progression and growth development is still controversial and poorly understood. In the present study, we explored the Lepr function in disease progression, pluripotency and metabolism using day 14.5 mouse embryonic fibroblasts (MEFs) and their reprogrammed induced pluripotent stem cells (iPSCs) as model system. We successfully reprogrammed mouse embryonic fibroblasts into iPSCs from control and db/db (Lepr deficient) mice. Using a global quantitative proteomic approach, we identified key pathways regulating pluripotency, metabolic homeostasis and protein synthesis during fetal growth and development. The Lepr MEFs show abnormal metabolic abnormalities and mitochondrial dysfunction as compared to control MEFs, while Lepr iPSCs show upregulated elongated factor 4 e (eIF4e) protein synthesis pathway and altered Oct4 and Stat3 pathways which are involved in normal fetal growth development. Furthermore, chip analysis revealed that higher Stat3 binding on the promoter of eIF4e in Lepr iPSCs leads to higher protein synthesis in these cell types as compared to control iPSCs. Finally, point mutation corrected Lepr iPSCs using CRISPR/Cas9 gene editing method showed recovered pluripotency, metabolic and protein synthesis pathways. In conclusion, we have shown that Lepr signaling is involved in the regulation of the metabolic properties and key developmental pathways in MEFs and stemness of pluripotent stem cells. Disruption of Lepr signaling has been shown to involve in the pathophysiology of various diseases including obesity and diabetes. The generated MEFs and iPSCs in this present study provide valuable tools to explore the role of Lepr in the progression of obesity, diabetes and metabolic abnormalities, and to find the putative targets of Lepr signaling during the development of these diseases.
2021-09-09 | PXD020959 | Pride
Project description:Leptin receptor (LEPR) identifies a subpopulation of hematopoietic stem cells (HSCs) with high repopulating potential. In this study, we demonstrated that LEPR-expressing HSCs while exhibiting significantly higher engrafting potential and self-renewing capacity in young mice showed early age-associated decline in these functions as compared to the LEPR- HSCs. LEPR+ HSCs have transcriptomic profiles significantly different from LEPR- HSCs in young mouse bone marrow, but middle-aged HSCs do not have distinct transcriptomic profiles based on LEPR status. The age-related phenotypes were associated with a proinflammatory transcriptomic profile at baseline in young LEPR+ HSCs, which was further exacerbated by age. In contrast, LEPR- HSCs did not show age-associated functional impairment at the ages tested. This suggested that subsets of HSCs are susceptible to age-related decline in function at varying ages and that LEPR+ HSCs are a potential target for early cellular therapeutic interventions in delaying the detrimental effects of aging in hematopoiesis.
2023-02-18 | GSE221126 | GEO
Project description:To study the regulation of Lepr on transcriptome in WT and Lepr KO AMs under resting state and after LPS stimulation, Lepr-sufficient (Lepr+/+, Lyz2-Cre) and Lepr-deficient (Leprfl/fl, Lyz2-Cre) alveolar macrophages (AMs) were isolated by collecting BALF. Lipopolysaccharide (LPS) was added in vitro for 1h or cells were left untreated. Total RNA was extracted for deep sequencing. Gene expression in WT and Lepr KO cells were analyzed.
2022-07-20 | GSE185218 | GEO
Project description:To identify transcripts enriched in ventomedial hypothalamus (VMH) Lepr neurons, we used translating affinity ribosome purification combined with RNA-seq (TRAP-seq) from Lepr-Cre mice.
2021-05-19 | GSE172200 | GEO
Project description:Peri-implant fibrosis is one of the most common reasons for implant failure and surgical revision after prosthetic joint replacement. This type of surgical revisionis associated with substantial additional morbidity and healthcare costs. However, the cellular and molecular mediators of peri-implant fibrosis remain unclear. Here, we show that peri-implant fibrotic tissue in mice and humans is largely composed of a specific population of leptin receptor-expressing(LEPR+) cells and that these LEPR+cells are necessary and sufficient to both generate and maintain peri-implant fibrotic tissue. Genetic ablation of LEPR+cells prevents peri-implant fibrosis, and implantation of LEPR+cells from peri-implant fibrotic tissue is sufficient to induce fibrosis in secondary hosts. We further identify adhesion G protein-coupled receptorF5 (ADGRF5) as a crucial mediator of the fibrotic response by LEPR+cells, as conditional deletion of ADGRF5 in LEPR+cells attenuates peri-implant fibrosis while augmenting peri-implant bone formation. Finally, we demonstrate that inhibition of ADGRF5 by intra articular or systemic administration of neutralizing anti-ADGRF5prevents and reverses peri-implant fibrosis. Thus, pharmaceutical agents that inhibit the ADGRF5 pathway inLEPR+cells may represent a new approach to prevent and treat peri-implant fibrosis.
2024-03-10 | GSE227128 | GEO
Project description:Heterogeneous Origins and Functions of Mouse Skeletal Muscle Resident Macrophages
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Project description:To identify transcripts enriched in ventomedial hypothalamus (VMH) neurons that contain both Lepr and Slc17a6, we used translating affinity ribosome purification combined with RNA-seq (TRAP-seq) from Lepr-Cre;Slc17a6-Flpo mice.
2021-05-19 | GSE172202 | GEO
Project description:To investigate the transcriptomic profile difference between LEPR cells in peri-implant fibrous tissue and peri-implant bone
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