Cellular Factors Research Articles

Sheng Xue Ning as a Novel Agent that Promotes SCF-Driven Hematopoietic Stem/Progenitor Cell Proliferation to Promote Erythropoiesis.

Stimulating erythropoiesis is essential in the treatment of various types of anemia. Sheng Xue Ning (SXN) is commonly used in China as an iron supplement to treat iron deficiency anemia, renal anemia, and anemia in pregnancy. This research reports a novel effect of SXN in enhancing the proliferation of hematopoietic stem/progenitor cell (HSPC) to promote erythropoiesis in the bone marrow, which is distinct from conventional iron supplements that primarily aid in the maturation of red blood cells. Employing a model of hematopoietic dysfunction induced by X-ray exposure, we evaluated the efficacy of SXN in restoring hematopoietic function. SXN significantly promoted the recovery of peripheral erythroid cells and enhanced the proliferation and differentiation of Lin-/c-KIT+/Sca-1+ HSPC in mice exposed to X-ray irradiation. Our results showed that SXN elevated the expression of stem cell factor (SCF) and activated the SCF/c-KIT/PI3K/AKT signaling pathway, facilitating the proliferation and differentiation of HSPC. In vitro, SXN markedly enhanced the proliferation of bone marrow nucleated cell (BMNC) and the colony-forming capacity of BFU-E, CFU-E, and CFU-GM, while also elevating the expression of proteins involved in the SCF/c-KIT/PI3K/AKT pathway in BMNC. Additionally, SXN enhanced the proliferation and differentiation of mesenchymal stem cell (MSC) and increased SCF secretion. In conclusion, SXN demonstrates the capacity to enhance erythropoiesis by upregulating SCF expression, thereby promoting HSPC proliferation and differentiation via the SCF/c-KIT/PI3K/AKT pathway. SXN may offer a new strategy for improving the activity of HSPC and promoting erythropoiesis in the treatment of hematopoiesis disorders.

Assembly of a stem cell-derived human postimplantation embryo model.

The embryonic and extraembryonic tissue interactions underlying human embryogenesis at implantation stages are not currently understood. We have generated a pluripotent stem cell-derived model that mimics aspects of peri-implantation development, allowing tractable experimentation otherwise impossible in the human embryo. Activation of the extraembryonic lineage-specific transcription factors GATA6 and SOX17 (hypoblast factors) or GATA3 and TFAP2C (encoding AP2γ; trophoblast factors) in human embryonic stem (ES) cells drive conversion to extraembryonic-like cells. When combined with wild-type ES cells, self-organized embryo-like structures form in the absence of exogenous factors, termed human inducible embryoids (hiEmbryoids). The epiblast-like domain of hiEmbryoids polarizes and differentiates in response to extraembryonic-secreted extracellular matrix and morphogen cues. Extraembryonic mesenchyme, amnion and primordial germ cells are specified in hiEmbryoids in a stepwise fashion. After establishing stable inducible ES lines and converting ES cells to RSeT culture media, the protocol takes 7-10 d to generate hiEmbryoids. Generation of hiEmbryoids can be performed by researchers with basic expertise in stem cell culture.

Role of Interleukins in Pancreatic Cancer: A Literature Review.

This review article summarizes the pathophysiological aspects of interleukins (ILs) including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, and IL-10 in pancreatic cancer (PC). Science Direct, PubMed, and Google Scholar were used for the literature review. The search was conducted until August 12, 2024, and particular keywords such as "Pancreatic Cancer," "Interleukins," "Pathophysiological Aspects," "Immunosuppression," "Invasiveness," and "Metastasis" were used. Focusing on interleukins related to pancreatic cancer, 61 original studies were included: 32 studies for human patients, 16 studies for animal models, and 13 studies for both animal models and human patients. All types of PC were considered. The timeframe of 1991 to 2024 was chosen for clinical studies. In epithelial pancreatic tumors, IL-1 is a major inflammation factor. Serum concentrations of soluble interleukin-2-receptor were considerably greater in patients with PC and chronic pancreatitis than in healthy individuals. In comparison to controls, pancreatic cancer patients had considerably greater levels of macrophage colony-stimulating factor and significantly lower levels of stem cell factor and IL-3. The tissues and cells of pancreatic cancer have higher concentrations of IL-4 receptors. IL-5 has a role in the accumulation of pancreatic fibrosis. For individuals with pancreatic ductal adenocarcinoma (PDAC), a high serum level of IL-6 may be a separate risk factor for the development of widespread liver metastases. PDAC patients' peripheral blood mononuclear cells exhibit a substantial upregulation of IL-7 receptor. The role of IL-8 in the growth and spread of PC in humans. The miR-200a/β-catenin axis may be the mechanism by which IL-9 stimulates the proliferation and metastasis of PC cells. Blocking IL-10 in the local microenvironment appears to result in a significant reversal of tumor-induced immunosuppression. The article concludes that interleukins 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 played significant roles in the pathogenesis of PC.

Freeze-Dried Dentin Derivative Signal as a Factor for Differentiation of Human Dental Pulp Stem Cells: An In Vitro Study

: Tissue engineering is an emerging field in dentistry, and stem cell research has shown promise in regenerating new tissue. The three essential components for tissue engineering are stem cells, scaffolds, and growth/differentiation factors. Numerous studies have been conducted in regenerative medicine, and more recently in regenerative dentistry, utilizing different signals. In a pioneering study, dentin derivative signal (DDS), which was self-administered, was used as a differentiation factor for dental pulp stem cells to promote dentinogenesis in vitro. The study demonstrated that DDS can stimulate dental pulp stem cells to differentiate into other dental tissues, such as dentin.

A vascular endothelial growth factor-loaded chitosanhyaluronic acid hydrogel scaffold enhances the therapeutic effect of adipose-derived stem cells in the context of stroke.

Adipose-derived stem cell, one type of mesenchymal stem cells, is a promising approach in treating ischemia-reperfusion injury caused by occlusion of the middle cerebral artery. However, its application has been limited by the complexities of the ischemic microenvironment. Hydrogel scaffolds, which are composed of hyaluronic acid and chitosan, exhibit excellent biocompatibility and biodegradability, making them promising candidates as cell carriers. Vascular endothelial growth factor is a crucial regulatory factor for stem cells. Both hyaluronic acid and chitosan have the potential to make the microenvironment more hospitable to transplanted stem cells, thereby enhancing the therapeutic effect of mesenchymal stem cell transplantation in the context of stroke. Here, we found that vascular endothelial growth factor significantly improved the activity and paracrine function of adipose-derived stem cells. Subsequently, we developed a chitosan-hyaluronic acid hydrogel scaffold that incorporated vascular endothelial growth factor and first injected the scaffold into an animal model of cerebral ischemia-reperfusion injury. When loaded with adipose-derived stem cells, this vascular endothelial growth factor-loaded scaffold markedly reduced neuronal apoptosis caused by oxygen-glucose deprivation/reoxygenation and substantially restored mitochondrial membrane potential and axon morphology. Further in vivo experiments revealed that this vascular endothelial growth factor-loaded hydrogel scaffold facilitated the transplantation of adipose-derived stem cells, leading to a reduction in infarct volume and neuronal apoptosis in a rat model of stroke induced by transient middle cerebral artery occlusion. It also helped maintain mitochondrial integrity and axonal morphology, greatly improving rat motor function and angiogenesis. Therefore, utilizing a hydrogel scaffold loaded with vascular endothelial growth factor as a stem cell delivery system can mitigate the adverse effects of ischemic microenvironment on transplanted stem cells and enhance the therapeutic effect of stem cells in the context of stroke.

Ccn2 Deletion Reduces Cardiac Dysfunction, Oxidative Markers, and Fibrosis Induced by Doxorubicin Administration in Mice.

Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in cell communication and microenvironmental signaling. Overexpression of CCN2 has been documented in various cardiovascular pathologies, wherein it may exert either deleterious or protective effects depending on the pathological context, thereby suggesting that its role in the cardiovascular system is not yet fully elucidated. In this study, we aimed to investigate the effects of Ccn2 gene deletion on the progression of acute cardiac injury induced by doxorubicin (DOX), a widely utilized chemotherapeutic agent. To this end, we employed conditional knockout (KO) mice for the Ccn2 gene (CCN2-KO), which were administered DOX and compared to DOX-treated wild-type (WT) control mice. Our findings demonstrated that the ablation of CCN2 ameliorated DOX-induced cardiac dysfunction, as evidenced by improvements in ejection fraction (EF) and fractional shortening (FS) of the left ventricle. Furthermore, DOX-treated CCN2-KO mice exhibited a significant reduction in the gene expression and activation of oxidative stress markers (Hmox1 and Nfe2l2/NRF2) relative to DOX-treated WT controls. Additionally, the deletion of Ccn2 markedly attenuated DOX-induced cardiac fibrosis. Collectively, these results suggest that CCN2 plays a pivotal role in the pathogenesis of DOX-mediated cardiotoxicity by modulating oxidative stress and fibrotic pathways. These findings provide a novel avenue for future investigations to explore the therapeutic potential of targeting CCN2 in the prevention of DOX-induced cardiac dysfunction.

Sleep Deprivation Triggers the Excessive Activation of Ovarian Primordial Follicles via β2 Adrenergic Receptor Signaling.

Sleep deprivation (SD) is observed to adversely affect the reproductive health of women. However, its precise physiological mechanisms remain largely elusive. In this study, using a mouse model of SD, it is demonstrated that SD induces the depletion of ovarian primordial follicles, a phenomenon not attributed to immune-mediated attacks or sympathetic nervous system activation. Rather, the excessive secretion of stress hormones, namely norepinephrine (NE) and epinephrine (E), by overactive adrenal glands, has emerged as a key mediator. The communication pathway mediated by the KIT ligand (KITL)-KIT between granulosa cells and oocytes plays a pivotal role in primordial follicle activation. SD heightened the levels of NE/E that stimulates the activation of the KITL-KIT/PI3K and mTOR signaling cascade in an β2 adrenergic receptor (ADRB2)-dependent manner, thereby promoting primordial follicle activation and consequent primordial follicle loss in vivo. In vitro experiments further corroborate these observations, revealing that ADRB2 upregulates KITL expression in granulosa cells via the activation of the downstream cAMP/PKA pathway. Together, these results reveal the significant involvement of ADRB2 signaling in the depletion of ovarian primordial follicles under sleep-deprived conditions. Additionally, ADRB2 antagonists are proposed for the treatment or prevention of excessive activation of primordial follicles induced by SD.

Amphiphilic cytokine traps remodel marrow adipose tissue for hematopoietic microenvironment amelioration

Hematopoietic stem cell transplantation (HSCT) is extensively employed in the treatment of hematological malignancies but is markedly constrained by the paucity of hematopoietic stem/progenitor cells (HSPCs). Recent studies have found that marrow adipose tissue (MAT) acts on hematopoiesis through complicated mechanisms. Therefore, the osteo-organoids fabricated in vivo using biomaterials loaded with recombinant human bone morphogenetic protein 2 (rhBMP-2) have been used as models of MAT for our research. To obtain sufficient amounts of therapeutic HSPCs and healthy MAT, we have developed amphiphilic chitosan (AC)-gelatin as carriers of rhBMP-2 to the regulate type conversion of adipose tissue and trap hematopoietic growth factors. Unlike medicine interventions or cell therapies, the traps based on AC not only attenuate the occupancy of adipocytes within the hematopoietic microenvironment while preserving stem cell factor concentrations, but also improve marrow metabolism by promoting MAT browning. In conclusion, this approach increases the proportion of HSPCs in osteo-organoids, and optimizes the composition and metabolic status of MAT. These findings furnish an experimental basis for regulating hematopoiesis in vivo through materials that promote the development of autologous HSPCs. Additionally, this approach presents a theoretical model of rapid adipogenesis for the study of adipose-related pathologies and potential pharmacological targets.

Poly-ADP-ribosylation dynamics, signaling, and analysis.

ADP-ribosylation is a reversible post-translational modification that plays a role as a signaling mechanism in various cellular processes. This modification is characterized by its structural diversity, highly dynamic nature, and short half-life. Hence, it is tightly regulated at many levels by cellular factors that fine-tune its formation, downstream signaling, and degradation that together impacts cellular outcomes. Poly-ADP-ribosylation is an essential signaling mechanism in the DNA damage response that mediates the recruitment of DNA repair factors to sites of DNA damage via their poly-ADP-ribose (PAR)-binding domains (PBDs). PAR readers, encoding PBDs, convey the PAR signal to mediate cellular outcomes that in some cases can be dictated by PAR structural diversity. Several PBD families have been identified, each with variable PAR-binding affinity and specificity, that also recognize and bind to distinct parts of the PAR chain. PARylation signaling has emerged as an attractive target for the treatment of specific cancer types, as the inhibition of PAR formation or degradation can selectively eliminate cancer cells with specific DNA repair defects and can enhance radiation or chemotherapy response. In this review, we summarize the key players of poly-ADP-ribosylation and its regulation and highlight PBDs as tools for studying PARylation dynamics and the expanding potential to target PARylation signaling in cancer treatment.

Obesidad y sobrepeso

Obesity is a chronic, recurrent, heterogeneous, complex disease. It arises from an energy imbalance due to a sedentary lifestyle, excess calorie intake, or both, to which various genetic, social, behavioral, psychological, metabolic, cellular, and molecular factors must be added. This condition is characterized by an abnormal accumulation of adipose tissue. This increases the risk of chronic diseases such as type 2 diabetes, cardiovascular disease, and cancer, with important biological, psychological, and social implications. Its prevalence has increased globally, affecting all demographic groups. Multidisciplinary treatment focuses on lifestyle changes and is sometimes supplemented with medication. In extreme cases, bariatric surgery can improve the metabolic profile. This update will also focus in general on how excess weight behaves in pregnant patients, older adult patients, and patients with type 1 diabetes.

Quinoin, type 1 ribosome inactivating protein alters SARS-CoV-2 viral replication organelle restricting viral replication and spread

SARS-CoV-2 pandemic clearly demonstrated the lack of preparation against novel and emerging viral diseases. This prompted an enormous effort to identify antivirals to curb viral spread and counteract future pandemics. Ribosome Inactivating Proteins (RIPs) and Ribotoxin-Like Proteins (RL-Ps) are toxin enzymes isolated from edible plants and mushrooms, both able to inactivate protein biosynthesis. In the present study, we combined imaging analyses, transcriptomic and proteomic profiling to deeper investigate the spectrum of antiviral activity of quinoin, type 1 RIP from quinoa seeds. Here, we show that RIPs, but not RL-Ps, act on a post-entry step and impair SARS-CoV-2 replication, potentially by direct degradation of viral RNA. Interestingly, the inhibitory activity of quinoin was conserved also against other members of the Coronaviridae family suggesting a broader antiviral effect. The integration of mass spectrometry (MS)-based proteomics with transcriptomics, provided a comprehensive picture of the quinoin dependent remodeling of crucial biological processes, highlighting an unexpected impact on lipid metabolism. Thus, direct and indirect mechanisms can contribute to the inhibitory mechanism of quinoin, making RIPs family a promising candidate not only for their antiviral activity, but also as an effective tool to better understand the cellular functions and factors required during SARS-CoV-2 replication.

Genetic modifications of EGLN1 reactivate HbF production in β0-thalassemia/HbE

Reactivation of fetal hemoglobin (HbF, α2γ2) potentially alleviates clinical presentation in β-thalassemia. Prolyl hydroxylase domain enzymes (PHDs) play roles in the canonical oxygen-sensing pathway and maintain the stability of cellular hypoxia-inducible factor α (HIF-α) in response to low oxygen levels or hypoxia. Pharmacological inhibition of PHDs has been shown to increase HbF production in erythroid progenitors derived from healthy donors. Here, we demonstrated the relationship between PHD2, the main PHD isoform, and clinical phenotypes in β0-thalassemia/HbE disease. Although the targeted sequencing annotated several common variants within EGLN1, the gene encoding PHD2, none of these variants were located in the functional domains of PHD2 and were irrelevant to the clinical phenotypes. CRISPR-mediated EGLN1 modifications at the functional regions; however, led to significantly reduce PHD2 expression and increase HbF expression levels in severe β-thalassemia erythroblasts. Moreover, these beneficial phenotypes were independent to the two well-known HbF regulators including BCL11A and GATA1. Our findings introduce an additional mechanism for HbF regulation in β-thalassemia and propose that targeting the canonical oxygen-sensing pathway, particularly PHD2 functional domains, might offer a promising therapeutic strategy to β-thalassemia diseases.

SON controls mouse early embryonic development by regulating RNA splicing and histone methylation.

Thousands of genes are activated in late 2-cell embryos, which means that numerous pre-mRNAs are generated during this time. These pre-mRNAs must be accurately spliced to ensure that the mature mRNAs are translated to functional proteins. However, little is known about the roles of pre-mRNA splicing and cellular factors modulating pre-mRNA splicing during early embryonic development. Here, we report that downregulation of SON, a large Ser/Arg (SR)-related protein, reduced embryonic development and caused deficient blastomere cleavage. These embryonic developmental defects result from dysregulated nuclear speckle organization and pre-mRNA splicing of a set of cell cycle-related genes. Furthermore, SON downregulation disrupted the transcriptome (2128 upregulated and 1399 downregulated) in 4-cell embryos. Increased H3K4me3, H3K9me3 and H3K27me3 levels were detected in 4-cell embryos after SON downregulation. Taken together, these results demonstrate that accurate pre-mRNA splicing is essential for early embryonic development and that SON plays important roles in nuclear speckle organization, pre-mRNA splicing, transcriptome establishment and histone methylation reprogramming during early embryonic development.

Experimental study for the decontamination of various surfaces from 99Mo using PVA/Borax/Al(OH)3 strippable hydrogel

Polyvinyl alcohol (PVA) is a beneficial polymer capable of forming hydrogels helpful in a wide range of applications. Hydrogels based on cross-linking of PVA with borax, and able to incorporate with a decontaminating agent have been used in the decontamination of 99Mo from contaminated surfaces. Aluminum hydroxide has been introduced in the formulations of PVA-borax, to increase the gel efficiency for 99Mo decontamination from surfaces. The formulations were investigated with glass, stainless steel, and wood as examples of different surfaces. When the hydrogel is sprayed on different surfaces, it forms rapidly and adheres well. Moreover, the hydrogel was shown to efficiently decontaminate surfaces contaminated with 99Mo by a maximum value of decontamination factor (D.F) for glass, stainless steel, and wood to be 43.5, 31.3, and 19.6 respectively.

Tobacco smoking and other exposures shut off cancer-fighting genes

DNA mutations causing cancer occur in cells through aging, environmental exposures, and cellular factors. By analysing thousands of cancer genomes, we found that tobacco smoking, APOBEC enzymes, and oxidative stress often introduce harmful “stop-gain” mutations that disable genes. This study highlights how some lifestyle choices and cellular processes can modify genes that protect us from cancer.

Assessing Drug Uptake and Response Differences in 2D and 3D Cellular Environments Using Stimulated Raman Scattering Microscopy.

The architecture of cell culture, two-dimensional (2D) versus three-dimensional (3D), significantly impacts various cellular factors, including cell-cell interactions, nutrient and oxygen gradients, metabolic activity, and gene expression profiles. This can result in different cellular responses during cancer drug treatment, with 3D-cultured cells often exhibiting higher resistance to chemotherapeutic drugs. While various genetic and proteomic analyses have been employed to investigate the underlying mechanisms of this increased resistance, complementary techniques that provide experimental evidence of spatial molecular profiling data are limited. Stimulated Raman scattering (SRS) microscopy has demonstrated its capability to measure both intracellular drug uptake and growth inhibition. In this work, we applied three-band (C-D, C-H, and fingerprint regions) SRS imaging to 2D and 3D cell cultures and performed a comparative analysis of drug uptake and response with the goal of understanding whether the difference in drug uptake explains the drug resistance in 3D culture compared to 2D. Our investigations revealed that despite similar intracellular drug levels in 2D and 3D A549 cells during lapatinib treatment, the growth of 3D spheroids was less impacted, supporting an enhanced drug tolerance in the 3D microenvironment. We further elucidated drug penetration patterns and the resulting heterogeneous cellular responses across different spheroid layers. Additionally, we investigated the role of the extracellular matrix in modulating drug delivery and cell response and discovered that limited drug penetration in 3D could also contribute to lower drug response. Our study provides valuable insights into the intricate mechanisms of increased drug resistance in 3D tumor models during cancer drug treatments.

Time-of-day effects of cancer drugs revealed by high-throughput deep phenotyping

The circadian clock, a fundamental biological regulator, governs essential cellular processes in health and disease. Circadian-based therapeutic strategies are increasingly gaining recognition as promising avenues. Aligning drug administration with the circadian rhythm can enhance treatment efficacy and minimize side effects. Yet, uncovering the optimal treatment timings remains challenging, limiting their widespread adoption. In this work, we introduce a high-throughput approach integrating live-imaging and data analysis techniques to deep-phenotype cancer cell models, evaluating their circadian rhythms, growth, and drug responses. We devise a streamlined process for profiling drug sensitivities across different times of the day, identifying optimal treatment windows and responsive cell types and drug combinations. Finally, we implement multiple computational tools to uncover cellular and genetic factors shaping time-of-day drug sensitivity. Our versatile approach is adaptable to various biological models, facilitating its broad application and relevance. Ultimately, this research leverages circadian rhythms to optimize anti-cancer drug treatments, promising improved outcomes and transformative treatment strategies.

Correlation between inflammatory cytokines and the likelihood of developing multiple types of digestive system cancers: A Mendelian randomization study

ObjectiveInflammatory cytokines have been linked to digestive system cancers, yet their exact causal connection remains uncertain. Consequently, we conducted a Mendelian randomization (MR) analysis to gauge how inflammatory cytokines are linked to the risk of five prevalent digestive system cancers (DSCs). MethodsWe collected genetic variation data for 41 inflammatory cytokines from genome-wide association studies (GWAS), and the results data for five common diseases from the Finnish database. Our primary analytical approach involved employing the inverse-variance weighted, residual sum (IVW) method, complemented by the MR-Egger method, the weighted median method, simple mode analysis, and weighted mode analysis as supplementary analytical techniques. Furthermore, we conducted multiple sensitivity analyses. ResultsTumor necrosis factor-related apoptosis-inducing ligand (TRAIL), macrophage colony-stimulating factor (M-CSF), and interleukin (IL)-18 showed a negative association with the risk of hepatocellular carcinoma. Conversely, TRAIL was inversely linked to the risk of gastric cancer, while IL-16 exhibited a positive correlation with gastric cancer risk. Stem cell factor (SCF) acted as a protective factor against pancreatic cancer. For colorectal cancer, IL-7, IL-9, IL-13, and vascular endothelial growth factor (VEGF) were identified as risk factors. Notably, our results did not indicate a significant correlation between inflammatory cytokines and the risk of esophageal cancer. ConclusionOur research unveils potential connections between 41 inflammatory cytokines and the risk of five common DSCs through a MR analysis. These associations offer valuable insights that could aid in the development of diagnostic biomarkers and the identification of novel therapeutic targets for DSCs.

Cyprinid herpesvirus 3 replication is inhibited via decreased ORF3 promoter activity mediated by multiple cellular transcription factors

Cyprinid herpesvirus 3 (CyHV-3) is an enveloped and double-stranded DNA virus that primarily infects common carp and its variants. The transcriptional regulation program of the viral immediate early (IE) genes plays a crucial role in virus replication. However, the transcriptional regulatory mechanism of CyHV-3 IE genes remains largely unclear. In this study, we found that the IE gene ORF3 promoter, which exhibited the highest activity among the eight CyHV-3 IE genes, was inhibited in the host common carp brain (CCB) cells. Deletions of the ORF3 promoter revealed the presence of multiple regulatory elements. Site-directed deletions of multiple transcription factors binding sites (TFBS), including Yin Yang-1(YY1), TATA-binding protein (TBP), sex-determining region Y-box2 (SOX2), and cyclin-dependent kinase 8 (CDK8) binding sites, markedly inhibited the ORF3 promoter activity. Moreover, overexpression of these transcription factors in CCB cells also led to a noticeable reduction in ORF3 promoter activity. Importantly, YY1, TBP, SOX2, and CDK8 played antiviral roles against CyHV-3 infection, as evidenced by decreased viral transcripts (ORF55, ORF81, and ORF92) and genome copies after overexpression of these TFs followed by CyHV-3 infection. Collectively, CyHV-3 replication was markedly inhibited by reducing the promoter activity of ORF3 mediated by multiple cellular TFs. These findings enhance our understanding of the role of IE gene promoters in CyHV-3 and lays a foundation for in-depth studies on viral gene transcriptional regulation mechanisms.

Smooth muscle-specific deletion of Ccn2 causes severe aorta malformation and atherosclerosis.

Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in fibrotic diseases, with ongoing clinical trials evaluating anti-CCN2-based therapies. By uncovering CCN2 as abundantly expressed in non-diseased artery tissue, this study aimed to investigate the hypothesis that CCN2 plays a pivotal role in maintaining smooth muscle cell (SMC) phenotype and protection against atherosclerosis. Global- and SMC-specific Ccn2 knockout mouse models were employed to demonstrate that Ccn2 deficiency leads to SMC de-differentiation, medial thickening, and aorta elongation under normolipidemic conditions. Inducing hyperlipidemia in both models resulted in severe aorta malformation and a 17-fold increase in atherosclerosis formation. Lipid-rich lesions developed at sites of the vasculature typically protected from atherosclerosis-development by laminar blood flow, covering 90% of aortas, and extending to other vessels, including coronary arteries. Evaluation at earlier time points revealed medial lipid accumulation as a lesion-initiating event. Fluorescently labelled LDL injection followed by confocal microscopy showed increased LDL retention in the medial layer of Ccn2 knockout aortas, likely attributed to marked proteoglycan enrichment of the medial extracellular matrix. Analyses leveraging data from the Athero-Express study cohort indicated relevance of CCN2 in established human lesions, as CCN2 correlated with SMC marker transcripts across 654 transcriptomically profiled carotid plaques. These findings were substantiated through in situ hybridization showing CCN2 expression predominantly in the fibrous cap. This study identifies CCN2 as a major constituent of the normal artery wall, critical in regulating SMC differentiation and aorta integrity, and possessing a protective role against atherosclerosis development. These findings underscore the need for further investigation into the potential effects of anti-CCN2-based therapies on the vasculature.