COL1A1-Enhanced CD44/SLC7A11 Interaction and Cystine Uptake Result in CD34+ Foam-Like Macrophage Accumulation in Transplant Arteriosclerosis-Spatial Transcriptomic dataset
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE328244 | GEO | 2026/09/10
REPOSITORIES: GEO
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Project description:Chronic transplant arteriosclerosis is the primary cause of long-term graft failure. Selectively targeting specific inflammatory macrophage subpopulations is essential for inhibiting the primary triggers of inflammatory and immune responses. Therefore, elucidating the origins and regulatory mechanisms of these macrophages in allograft arteriosclerosis is critical for the development of targeted therapies. We performed scRNA-seq and spatial transcriptomics or integrated transcriptomic data from human chronic allograft vasculopathy specimens and mouse vascular allograft models. Flow cytometry and immunofluorescence staining were employed to characterize macrophage subpopulations within remodeled allograft arteries. To determine cellular origins, CD34+ lineage-tracing and depletion strategies were used. The interactions between COL1A1, CD44, and SLC7A11 were analyzed using proximity ligation assays and co-immunoprecipitation. Furthermore, metabolic profiles were investigated via ultra-performance liquid chromatography coupled with high-resolution mass spectrometry. To validate the role of cystine transport in macrophage differentiation, we employed pharmacological inhibitors and a genetic approach using myeloid-specific SLC7A11 knockout mice (Lysm-Slc7a11-KO). The mechanisms identified in vivo were further corroborated through in vitro experiments.
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Project description:Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFα associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFα in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFα-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis. RNA was extracted by RNAeasy kits (Qiagen) from the RCC4 Vec and VHL-reconstituted cells which were exposed to the control full DMEM or cystine deprived DMEM media for 6 hours (three replicates in each condition).
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Project description:Endothelial metabolic reprogramming is essential for vascular growth and critical for organ (re)generation, health and life span. Here, we identify a nuclear oxidative catabolic pathway that links cystine metabolism to endothelial gene regulation and angiogenesis. Endothelial cells preparing to proliferate, increase the translation of the transporter (SLC)7A11 to import cystine, which is further oxidatively catabolized by cystathionine gamma lyase (CSE) within the nuclear compartment. This process, preserved in young but not aged tissues, generates acetyl moieties in a pyruvate dehydrogenase dependent manner and initiates specific histone H3 lysine acetylation, leading to chromatin reorganization. Such changes solidify endothelial cell transcriptional programmes and maintain cell proliferation. Combined deletion of the SLC7A11 and CSE causes embryonic lethality and abrogates vascular growth. While SLC7A11 deficiency triggers compensatory de novo cysteine synthesis from methionine, partially preserving angiogenesis; CSE deletion disrupts nuclear cystine oxidative catabolism, endothelial transcription, and vessel formation. Therapeutically, oral cystine supplementation in models of retinopathy of prematurity, acute myocardial infraction and vascular injury in aging promotes vascular growth and repair. Together, our study highlights the role of cyst(e)ine nuclear oxidative catabolism in robust control of endothelial gene transcription, vessel growth and repair.
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Project description:Endothelial metabolic reprogramming is essential for vascular growth and critical for organ (re)generation, health and life span. Here, we identify a nuclear oxidative catabolic pathway that links cystine metabolism to endothelial gene regulation and angiogenesis. Endothelial cells preparing to proliferate, increase the translation of the transporter (SLC)7A11 to import cystine, which is further oxidatively catabolized by cystathionine gamma lyase (CSE) within the nuclear compartment. This process, preserved in young but not aged tissues, generates acetyl moieties in a pyruvate dehydrogenase dependent manner and initiates specific histone H3 lysine acetylation, leading to chromatin reorganization. Such changes solidify endothelial cell transcriptional programmes and maintain cell proliferation. Combined deletion of the SLC7A11 and CSE causes embryonic lethality and abrogates vascular growth. While SLC7A11 deficiency triggers compensatory de novo cysteine synthesis from methionine, partially preserving angiogenesis; CSE deletion disrupts nuclear cystine oxidative catabolism, endothelial transcription, and vessel formation. Therapeutically, oral cystine supplementation in models of retinopathy of prematurity, acute myocardial infraction and vascular injury in aging promotes vascular growth and repair. Together, our study highlights the role of cyst(e)ine nuclear oxidative catabolism in robust control of endothelial gene transcription, vessel growth and repair.
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Project description:Endothelial metabolic reprogramming is essential for vascular growth and critical for organ (re)generation, health and life span. Here, we identify a nuclear oxidative catabolic pathway that links cystine metabolism to endothelial gene regulation and angiogenesis. Endothelial cells preparing to proliferate, increase the translation of the transporter (SLC)7A11 to import cystine, which is further oxidatively catabolized by cystathionine gamma lyase (CSE) within the nuclear compartment. This process, preserved in young but not aged tissues, generates acetyl moieties in a pyruvate dehydrogenase dependent manner and initiates specific histone H3 lysine acetylation, leading to chromatin reorganization. Such changes solidify endothelial cell transcriptional programmes and maintain cell proliferation. Combined deletion of the SLC7A11 and CSE causes embryonic lethality and abrogates vascular growth. While SLC7A11 deficiency triggers compensatory de novo cysteine synthesis from methionine, partially preserving angiogenesis; CSE deletion disrupts nuclear cystine oxidative catabolism, endothelial transcription, and vessel formation. Therapeutically, oral cystine supplementation in models of retinopathy of prematurity, acute myocardial infraction and vascular injury in aging promotes vascular growth and repair. Together, our study highlights the role of cyst(e)ine nuclear oxidative catabolism in robust control of endothelial gene transcription, vessel growth and repair.
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