RNAseq analysis of Angiotensin II perfused Apolipoprotein E deficient mice reconstituted with Wild Type or Netrin-1 deficient hematopoietic stem cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE118217 | GEO | 2018/11/01
REPOSITORIES: GEO
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Project description:We report the transcriptomic analysis of RNA-seq of aortas isolated from ApoE-/- mice exposed to Ang II or PBS to uncover the mechanisms underlying the undefined role ripk3 in AAA
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Project description:RNAseq analysis of Angiotensin II perfused Apolipoprotein E deficient mice reconstituted with Wild Type or Netrin-1 deficient hematopoietic stem cells
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Project description:The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. However, the relative flaws in the understanding of the molecular mechanisms promoting or limiting reprogramming still hinder the efficient generation of high quality iPS cells. Whereas modulation of the initial Oct4, Sox2, Klf4 and c-Myc (OSKM) cocktail with new transcription factors has been extensively documented, comparatively little is known about soluble molecules promoting the process, even if such recombinant factors could be highly valuable for therapeutic applications. In this study we developed a large-scale identification method to uncover novel programmed cell death (PCD)-related mechanisms limiting somatic cell reprogramming to pluripotency (SCRP). We identified Netrin-1 and its dependence receptor Dcc (Deleted in Colorectal Carcinoma), previously described for their respective survival/death functions both in normal and oncogenic contexts, as novel key SCRP modulators. We show that the early phase of SCRP is accompanied with a strong Netrin-1 deficiency, due to the improper epigenetic regulation of the Ntn1 promoter by OSKM. Mechanistically, we demonstrate that such Netrin-1 imbalance induces apoptosis mediated by the dependence receptor Dcc in a p53-independent manner. Correction of the Netrin-1/Dcc equilibrium by gain-of-ligand and loss-of-receptor experiments constrains apoptosis and improves reprogramming. As a consequence, we propose a novel iPS derivation protocol including a sequential treatment with recombinant Netrin1 that greatly facilitates the generation of mouse and human iPS cells. RNA-sequencing of mouse embryonic fibroblasts (passage 2 and passage 4), mouse pre-iPS cells (passage 5 and passage 25), 1 clone of control iPS (passage 5 and passage 25) and 2 independent clones of "Netrin-1 derived" iPS cells (passage 5 and passage 25). For this analysis, mouse iPS cell lines were grown in KSR+LIF media.
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Project description:The formation of vascular niche is pivotal during the early stage of peripheral nerve regeneration. This antecedent angiogenesis meets the nutrient requirements for subsequent rapid axon regeneration and remyelination. Nevertheless, the mechanisms of vascular niche in the regulation of peripheral nerve remain unclear. The axon guidance molecule Netrin-1 (NTN1) is widely expressed in peripheral nerves and particularly was found up-regulated in sciatic nerve stump after peripheral nerve injury (PNI). Herein, we demonstrated that NTN1-high endothelial cells (NTN1+ECs) were the critical component of vascular niche, fostering angiogenesis, axon regeneration and repair-related phenotypes. And we also found that NTN1+ECs derived exosomes (NTN1 EC-EXO) were involved in the formation of vascular niche as a critical role. Multi-omics analysis further verified that NTN1 EC-EXO carried a low-level expression of let7a-5p and activated key pathways associated with niche formation including focal adhesion, axon guidance, PI3K-AKT signaling pathway and mTOR signaling pathway. Taken together, our findings suggested the potential construction of a pre-regenerative niche induced by NTN1 EC-EXO, thereby establishing a conductive microenvironment for nerve repair and facilitating the functional recovery after PNI in the early injury phase.
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Project description:The formation of vascular niche is pivotal during the early stage of peripheral nerve regeneration. This antecedent angiogenesis meets the nutrient requirements for subsequent rapid axon regeneration and remyelination. Nevertheless, the mechanisms of vascular niche in the regulation of peripheral nerve remain unclear. The axon guidance molecule Netrin-1 (NTN1) is widely expressed in peripheral nerves and particularly was found up-regulated in sciatic nerve stump after peripheral nerve injury (PNI). Herein, we demonstrated that NTN1-high endothelial cells (NTN1+ECs) were the critical component of vascular niche, fostering angiogenesis, axon regeneration and repair-related phenotypes. And we also found that NTN1+ECs derived exosomes (NTN1 EC-EXO) were involved in the formation of vascular niche as a critical role. Multi-omics analysis further verified that NTN1 EC-EXO carried a low-level expression of let7a-5p and activated key pathways associated with niche formation including focal adhesion, axon guidance, PI3K-AKT signaling pathway and mTOR signaling pathway. Taken together, our findings suggested the potential construction of a pre-regenerative niche induced by NTN1 EC-EXO, thereby establishing a conductive microenvironment for nerve repair and facilitating the functional recovery after PNI in the early injury phase.
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Project description:The formation of vascular niche is pivotal during the early stage of peripheral nerve regeneration. This antecedent angiogenesis meets the nutrient requirements for subsequent rapid axon regeneration and remyelination. Nevertheless, the mechanisms of vascular niche in the regulation of peripheral nerve remain unclear. The axon guidance molecule Netrin-1 (NTN1) is widely expressed in peripheral nerves and particularly was found up-regulated in sciatic nerve stump after peripheral nerve injury (PNI). Herein, we demonstrated that NTN1-high endothelial cells (NTN1+ECs) were the critical component of vascular niche, fostering angiogenesis, axon regeneration and repair-related phenotypes. And we also found that NTN1+ECs derived exosomes (NTN1 EC-EXO) were involved in the formation of vascular niche as a critical role. Multi-omics analysis further verified that NTN1 EC-EXO carried a low-level expression of let7a-5p and activated key pathways associated with niche formation including focal adhesion, axon guidance, PI3K-AKT signaling pathway and mTOR signaling pathway. Taken together, our findings suggested the potential construction of a pre-regenerative niche induced by NTN1 EC-EXO, thereby establishing a conductive microenvironment for nerve repair and facilitating the functional recovery after PNI in the early injury phase.
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Project description:The kidneys intricate vascular system supports body fluid and organ homeostasis. However, little is known about how vascular architecture is established during kidney development. More specifically, how signals from the kidney influence vessel maturity and patterning remains poorly understood. Netrin-1 (Ntn1) is a secreted ligand critical for vessel and neuronal guidance. Here, we demonstrate that Ntn1 is expressed by Foxd1+ stromal progenitors in the developing kidney and conditional deletion (Foxd1GC/+;Ntn1fl/fl) results in hypoplastic kidneys with extended nephrogenesis. Wholemount 3D analyses additionally revealed the loss of a predictable vascular pattern in Foxd1GC/+;Ntn1fl/fl kidneys. As vascular patterning has been linked to vessel maturity, we investigated arterialization. Quantification of the CD31+ endothelium at E15.5 revealed no differences in metrics such as the number of branches or branch points, whereas the arterial vascular smooth muscle metrics were significantly reduced at both E15.5 and P0. In support of our observed phenotypes, whole kidney RNA-seq revealed disruptions to genes and programs associated with stromal cells, vasculature, and differentiating nephrons. Together, our findings highlight the significance of netrin-1 to proper vascularization and kidney development.
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Project description:The formation of vascular niche is pivotal during the early stage of peripheral nerve regeneration. This antecedent angiogenesis meets the nutrient requirements for subsequent rapid axon regeneration and remyelination. Nevertheless, the mechanisms of vascular niche in the regulation of peripheral nerve remain unclear. The axon guidance molecule Netrin-1 (NTN1) is widely expressed in peripheral nerves and particularly was found up-regulated in sciatic nerve stump after peripheral nerve injury (PNI). Herein, we demonstrated that NTN1-high endothelial cells (NTN1+ECs) were the critical component of vascular niche, fostering angiogenesis, axon regeneration and repair-related phenotypes. And we also found that NTN1+ECs derived exosomes (NTN1 EC-EXO) were involved in the formation of vascular niche as a critical role. Multi-omics analysis further verified that NTN1 EC-EXO carried a low-level expression of let7a-5p and activated key pathways associated with niche formation including focal adhesion, axon guidance, PI3K-AKT signaling pathway and mTOR signaling pathway. Taken together, our findings suggested the potential construction of a pre-regenerative niche induced by NTN1 EC-EXO, thereby establishing a conductive microenvironment for nerve repair and facilitating the functional recovery after PNI in the early injury phase.
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