Leptin Receptor, a Surface Marker for a Subset of Highly Engrafting Long-term Functional Hematopoietic Stem Cells
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ABSTRACT:
PROVIDER: PRJNA665066 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12694900_1.fastq.gz | Fastqsanger.gz | |||
| SRR12694900_2.fastq.gz | Fastqsanger.gz | |||
| SRR12694901_1.fastq.gz | Fastqsanger.gz | |||
| SRR12694901_2.fastq.gz | Fastqsanger.gz | |||
| SRR12694902_1.fastq.gz | Fastqsanger.gz |
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Project description:The hematopoietic system is sustained by a rare population of hematopoietic stem cells (HSCs), which emerge during early fetal development and then reside in the hypoxic niche of the adult bone marrow microenvironment. Although leptin receptor (Lepr)-expressing stromal cells are well-studied as critical regulators of murine hematopoiesis, the biological implications of Lepr expression on HSCs remain largely unexplored. We hypothesized that Lepr+HSCs are functionally different from other HSCs. Using in vitro and in vivo experimental approaches, we demonstrated that Lepr further differentiates SLAM HSCs into two distinct populations; Lepr+HSCs engrafted significantly higher than Lepr-HSCs and self-renewed more extensively as noted in secondary transplants. To determine how molecular pathways and gene expression profiles affect their functional differences, we performed bulk RNA-sequencing on purified Lepr+HSC/MPP and Lepr-HSC/MPP cells. Our results showed that Lepr+HSCs were characterized by a proinflammatory transcriptomic profile enriched for Type-I Interferon and Interferon-gamma (IFN-γ) response pathways, which are known to be critical for the emergence of HSCs in fetal life. Gene set analyses indicated that Lepr+HSCs were more highly enriched for genes associated with long-term HSCs whereas Lepr-HSCs’ expression profiles were more closely related to progenitors. We conclude that although Lepr+HSCs represent a minor subset of HSCs, they are highly engrafting cells that possess embryonic-like transcriptomic characteristics, and that Lepr can serve as a useful marker for functional long term HSCs, which may have potential clinical applicability.
2020-10-30 | GSE158393 | GEO
Project description:The hematopoietic system is sustained by a rare population of hematopoietic stem cells (HSCs), which emerge during early embryonic development and then reside in the hypoxic niche of the adult bone marrow microenvironment. Although leptin receptor (Lepr)-expressing stromal cells are well-studied as critical regulators of murine hematopoiesis, the biological implications of Lepr expression on HSCs remain largely unexplored. We hypothesized that Lepr+HSCs are functionally different from other HSCs. Using in vitro and in vivo experimental approaches, we demonstrated that Lepr further differentiates SLAM HSCs into two distinct populations; Lepr+HSCs engrafted better than Lepr-HSCs in primary transplant. Compared to Lepr-LSK cells, Lepr+LSK cells were highly enriched for extensively repopulating and self-renewing HSCs. Molecularly, Lepr+HSCs were characterized by a pro-inflammatory transcriptomic profile enriched for Type-I Interferon and Interferon-gamma (IFN-γ) response pathways, which are known to be critical for the emergence of HSCs in the embryo. We conclude that although Lepr+HSCs represent a minor subset of HSCs, they are highly engrafting cells that possess embryonic-like transcriptomic characteristics, and that Lepr can serve as a reliable marker for functional long-term HSCs, which may have potential clinical applicability.
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Project description:CD34+ monocyte subset is highly susceptible to HIV-1 infection
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Project description:HIV-1 persists in cellular reservoirs despite effective antiretroviral therapy (ART). CD4+ T cells are the well-known reservoir, but there is growing evidence that myeloid cells, including circulating monocytes, are also a clinically relevant reservoir. However, it is unclear what are preferentially infected monocyte subsets in vivo. Here, we show that a monocyte fraction expressing the stem cell marker CD34 is more susceptible to HIV-1 infection than the CD34-negative major subset. In ART-untreated viremic patients, CD34+ fraction increased in the percentage in total monocytes, and harbored more proviral DNA than the major subset. Consistent with this, when compared to the major subset, CD34+ fraction expressed HIV-1 receptors (CD4 and CCR5) at higher levels and HIV-1 restriction factors (MX2 and SAMHD1) at lower levels. Interestingly, proviral DNA was detected in CD34+ fraction of ART-treated virologically suppressed patients. CD34+ monocytes were also present in lymph nodes, and expressed CD4 and CCR5 at higher levels than the major subset, as observed for peripheral blood. Moreover, CD34+ monocytes present in peripheral blood and lymph nodes highly expressed CCR7 and sphingosine-1-phosphate receptor 1 (S1PR1), critical regulators of in vivo cellular trafficking. Our findings suggest that circulating CD34+ monocytes are infected with residual HIV-1 after migrating into tissues including lymph nodes and return to circulation, which explains the detection of proviral DNA in the cells even after long-term ART.
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Project description:Obesity induces profound transcriptome changes in adipocytes; recent evidence suggests that lncRNAs play key roles in this process. Here, we performed a comprehensive transcriptome study by RNA-Seq in adipocytes isolated from interscapular brown, inguinal and epididymal white adipose tissues in diet-induced obese mice. Our analysis reveals a set of obesity-dysregulated lncRNAs, many of which exhibit dynamic changes in fed vs. fasted state, potentially serving as novel molecular markers reflecting adipose energy status. Among the most prominent ones is Lnc-leptin, an lncRNA transcribed from an enhancer region upstream of Leptin. Expression of Lnc-leptin is sensitive to insulin and closely correlates to Leptin expression across diverse pathophysiological conditions. Functionally, induction of Lnc-leptin is essential for adipogenesis, and its presence is required for a loop formation between exon2 of Lnc-leptin and promoter of Leptin in mature adipocytes and the maintenance of Leptin expression in vitro and in vivo. Our study establishes Lnc-leptin as a new regulator of Leptin.
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