IGF-1

Abstract

Biomaterial-based skeletal muscle tissue engineering approaches have largely focused on mimicking the 3D aligned architecture of native muscle, which is critical for guiding myotube formation and force transmission. In contrast, fewer studies incorporate glycosaminoglycan (GAG)-mediated biochemical cues despite their known role in regulating myogenesis and growth factor sequestration. In this study, we develop aligned collagen-GAG (CG) scaffolds using directional freeze-drying and systematically vary GAG type by incorporating GAGs of increasing sulfation levels (hyaluronic acid, chondroitin sulfate, and heparin). While all scaffold variants support myoblast adhesion, metabolic activity, and myotube alignment, heparin-modified CG scaffolds significantly enhance myoblast metabolic activity and myogenic differentiation as measured by myosin heavy chain (MHC) expression and myotube size. We additionally show that heparin-modified scaffolds sequester and retain significantly higher levels of insulin-like growth factor-1 (IGF-1), a potent promoter of myogenesis, compared to other scaffold groups. Together, these results highlight the importance of tailoring GAG type in CG scaffolds for targeted applications and underscore the promise of heparin-modified CG scaffolds as a material platform for skeletal muscle tissue engineering.

Abstract

Solitary fibrous tumors are exceptionally rare mesenchymal tumors that can present with paraneoplastic syndromes, the most common being nonislet cell tumor hypoglycemia. We describe a case of refractory hypoglycemia that resolved following surgical resection of a large abdominal solitary fibrous tumor.

Abstract

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) regulate cell proliferation, differentiation, metabolic processes, and immune activities. Psoriasis is a systemic inflammatory disease with metabolic disorders as an important comorbidity in the pathogenesis of which members of the IGF family could also play a role. Therefore, we decided to evaluate the levels of members of the IGF signaling pathway in patients with psoriasis. Sixty-nine people were enrolled in our study: 34 patients with psoriasis and 35 controls. The following parameters were evaluated in serum obtained from peripheral blood: total cholesterol, triglycerides, high-density lipoprotein, fasting glucose, IGF-1, IGF-1R, IGF-2, IGF-2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP6, and insulin. The levels of several parameters differed between groups. The levels of fasting glucose, insulin, IGFBP3, and IGFBP6 were higher in patients with psoriasis, while the levels of IGF-1, IGF-1R, and IGBP4 were higher in controls. The results suggested that the IGF-1 signaling pathway can be involved in the pathogenesis of psoriasis and its comorbidities, especially metabolic disorders such as insulin resistance, diabetes, and metabolic syndrome. The novelty of our study is in its comprehensive assessment of the involvement of the IGF-1 signaling pathway in the pathogenesis of psoriasis and advances the understanding of the pathogenesis of psoriasis and its comorbidities.

Abstract

The role of insulin-like growth factor 1 (IGF-1) in preserving cardiovascular (CV) health, a well-established fact, cannot be overstated. IGF-1 affects inducible nitric oxide synthase (iNOS) activity, contributing to metabolic homeostasis by promoting insulin and glucose metabolism. Excessive iNOS production is involved in the occurrence and progression of insulin resistance and CV diseases (CVD). This study aimed to assess the in vivo impact of IGF-1 on the activity and gene expression of iNOS in the hearts of obese rats, through the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway.

Abstract

Thyroid-stimulating hormone pituitary adenomas (TSHomas) are a rare cause of central hyperthyroidism, characterized by abnormally high TSH levels, and typically respond to somatostatin analogue (SSA). We report a young patient with SSA-insensitive TSHoma where Lugol's solution facilitated surgical preparation.

Abstract

Glaucoma is a chronic neurodegenerative disease of the visual system, and treatment is targeted toward lowering intraocular pressure. However, some patients fail to respond to treatment and their intraocular pressure levels remain high, risking continuous vision loss. Explainable machine learning provides a mechanism for both individual prognostication and the identification of factors associated with treatment outcome. Here, we used explainable machine learning to predict intraocular pressure for glaucoma patients receiving medication treatment. We accessed the UK Biobank to obtain information on 290 eyes from 161 participants who reported a diagnosis of glaucoma and were receiving treatment. Features were divided into three distinct datasets containing demographic data only, physiometabolic parameters and medication prescription data, and all data combined. We evaluated five machine learning techniques for each feature set in terms of their ability to predict intraocular pressure at a follow-up visit in a classification task. We then calculated SHapley Additive exPlanation (SHAP) values for the best performing model to determine feature importance, stability, and interactions. We found that eXtreme Gradient Boosting (XGBoost) outperformed all other models when trained and tested on the combined feature set with an area under receiver operating characteristic curve (AUC) of 0.708. Insulin-like growth factor 1 (IGF-1), low-density lipoprotein (LDL), and lymphocyte count ranked as the three most important features for this model. LDL and IGF-1 exhibited a low degree of global variability in contribution to the model output across all cross-validation repeats. SHAP values demonstrated the strongest interactions being between LDL and IGF-1. In summary, our studies indicated the importance of blood LDL and IGF-1 in contributing to the outcomes of intraocular pressure lowering treatment and demonstrated the ability of XGBoost to predict these outcomes.

Abstract

Cancer cachexia, characterized by progressive skeletal muscle loss, is common in advanced malignancies and correlates with poor prognosis. Cisplatin, a widely used chemotherapeutic, is linked to muscle atrophy, but its mechanisms remain unclear. Recent studies implicate endoplasmic reticulum (ER) stress in muscle disorders; however, its role in chemotherapy-induced muscle atrophy is unknown. This study examined the effects of five anticancer agents-cisplatin, 5-fluorouracil, vincristine, irinotecan, and cyclophosphamide-on mouse skeletal muscle. Quadriceps muscle mass, gene expression related to protein synthesis (IGF-1), degradation (MuRF1, atrogin-1), ER stress (Ddit3/CHOP, Atf4, sXbp-1), and inflammation (TNF-α, IL-1β, COX2) were analyzed. Despite similar body weight loss, cisplatin-treated mice showed a significant reduction in muscle mass compared to dietary-restricted controls. Only cisplatin upregulated MuRF1 and atrogin-1 and downregulated IGF-1. Inflammatory markers were unaffected. Notably, cisplatin induced ER stress genes Ddit3, Atf4, and sXbp1. These findings suggest cisplatin promotes muscle atrophy via ER stress activation and protein degradation, independently of reduced food intake or inflammation. Targeting ER stress may help prevent chemotherapy-induced muscle wasting. Further studies are needed to clarify mechanisms and develop protective strategies.

Abstract

Age-related circulating factors are recognized as major contributors to the progression of sarcopenia. This network meta-analysis (NMA) aimed to compare the effects of various interventions on circulating factor responses among individuals with sarcopenia.

Abstract

Microplastics (MPs) are known to induce diverse toxic effects across biological systems; however, how environmentally photoaged MPs influence organismal aging and the underlying mechanisms remain poorly understood. Here, virgin polystyrene (PS-0) and 45-day photoaged polystyrene (PS-45) were evaluated at environmentally relevant concentrations (0-100 μg/L) to assess aging-related effects and molecular pathways in Caenorhabditis elegans. Photoaging markedly altered PS physicochemical properties, including surface morphology, crystallinity, and functional groups. Exposure to 100 μg/L PS-0 or PS-45 significantly shortened lifespan, impaired physiological behaviors, and increased lipofuscin accumulation, whereas PS-45 at 10-100 μg/L elicited substantially stronger pro-aging effects. These enhanced toxicities were driven by particle-associated processes, particularly elevated environmentally persistent free radical generation and increased particle accumulation in nematodes. Mechanistically, PS-45 inhibited DAF-16 nuclear translocation and dysregulated insulin/IGF-1 signaling genes (daf-2, age-1, pdk-1, akt-1, and daf-16). Concurrently, PS-45 induced ferroptosis, as evidenced by increased Fe2+ and malondialdehyde levels, glutathione depletion, and suppression of ftn-1; these effects were alleviated by the ferroptosis inhibitor ferrostatin-1. Mutations in daf-2, age-1, pdk-1, akt-1, daf-16, and ftn-1 significantly altered PS-45-induced aging phenotypes and ferroptotic stress, identifying the DAF-2-AGE-1-PDK-1-AKT-DAF-16-FTN-1 axis as a central regulatory pathway. Collectively, this study reveals a mechanistic link between insulin signaling and ferroptosis in MPs-induced aging and highlights the elevated environmental health risks posed by photoaged MPs.

Abstract

Evaluate long-term efficacy, safety, and tolerability of once-weekly somapacitan, a long-acting growth hormone (GH) derivative, in children born small for gestational age (SGA) with short stature, including after switching from daily GH.

Abstract

Dwarfism, a condition characterized by short stature, has been the focus of therapeutic advancements with the emergence of novel peptide drugs. Vosoritide, indicated for certain types of dwarfism, has shown therapeutic potential in clinical trials. However, a comprehensive safety profile is essential for its clinical application. The current literature lacks a detailed assessment of vosoritide's safety, indicating a significant gap that this study aims to address.

Abstract

Pituitary growth hormone (GH) secretion is primarily controlled by GH-releasing hormone (GHRH) and somatostatin (SST), peptides produced by hypothalamic neurons. Evidence indicates that dopamine also modulates GH secretion, potentially via D2 dopamine receptor (D2R). Additionally, a subset of GHRH neurons in the arcuate nucleus of the hypothalamus expresses tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine biosynthesis. However, the role of dopamine release from GHRH neurons and the neuronal population that expresses D2R to regulate GH secretion remain currently unknown.

Abstract

Growth factors (GF) fulfil essential functions during organ development and regeneration. In tissue regeneration, evidence suggests that the combined application of several GFs is more efficient compared to their individual application. Single or multiple GFs are often applied to animal models of organ regeneration through release by hydrogels. Such hydrogels are often formed by self-assembling peptides (SAPs) spontaneously polymerizing into peptide nanofiber (PNF) networks. In this study, we established PNFs by conjugating an SAP backbone (KIKIQIN) with bioactive peptide sequences derived from two GFs, FGF2 and IGF1. This resulted in the GF-mimicking fusion peptides FGF2-SAP and IGF1-SAP, respectively. In these PNFs, both GFs were stably incorporated rather than released as in the case of PNF-derived hydrogels. When individually added to culture medium, FGF1-SAP and IGF1-SAP stimulated the growth of mouse primary hippocampal neurons. Notably, their growth-stimulating potential exceeded neuronal growth achieved with the SAP backbone or the GF peptides alone. Finally, combinations of FGF2-SAP, IGF1-SAP, and the SAP backbone were tested, which formed FGF2 and IGF1 presenting PNFs. Indeed, specific GF-SAP combinations resulted in elevated numbers of surviving neurons compared to individual application. In summary, in this study, we identified novel GF-SAP hybrid nanofibers capable of stimulating cellular growth. Such nanofibers, enabling stable and simultaneous presentation of multiple GFs, might be well suited for tissue regeneration in vivo.

Abstract

Musculoskeletal crosstalk is essential for maintaining the balance of bone metabolism, with macrophage‑derived exosomes emerging as key regulators of this process. Exosomes, small extracellular vesicles secreted by cells, carry a variety of bioactive molecules; proteins, lipids, mRNAs and miRNAs and facilitate intercellular communication by transferring these cargos to recipient cells. Specifically, macrophage‑derived exosomes mediate muscle‑bone interactions by transferring key regulators such as insulin‑like growth factor‑1 (IGF‑1) and fibroblast growth factor‑2 (FGF‑2), thereby playing a pivotal role in bone metabolic homeostasis. Macrophages are classified into pro‑inflammatory M1 and anti‑inflammatory M2 phenotypes, each performing distinct functions in immune responses. Exosomes from M1 macrophages typically carry pro‑inflammatory factors that can activate osteoclastic bone resorption, disrupting bone metabolism in pathological conditions. By contrast, exosomes from M2 macrophages often contain anti‑inflammatory factors that promote tissue repair and bone formation. In the context of bone metabolism, exosomes from M1 and M2 macrophages modulate muscle‑bone signaling by delivering regulators that influence the expression of IGF‑1 and FGF‑2, affecting osteoblast proliferation, differentiation, and mineralization. M1 macrophage‑derived exosomes activate signaling pathways such as NF‑κB and MAPK through the transfer of pro‑inflammatory cargo, thereby enhancing bone resorption. By contrast, exosomes from M2 macrophages can suppress pro‑inflammatory signaling while activating pathways like TGF‑β and PI3K/Akt, promoting bone synthesis and repair. As critical myokines, IGF‑1 and FGF‑2 not only support muscle growth, repair, and maintenance but also directly influence bone remodeling through musculoskeletal crosstalk.

Abstract

This study aimed to investigate the effects of maternal supplementation with fish oil, flaxseed oil, and walnut oil rich in omega-3 fatty acids during lactation on mammary tissue structure and milk quality. Rats were randomly assigned to negative control, control, fish oil, walnut oil, and flaxseed oil groups. The supplements were administered by oral gavage from parturition (Day 0) to the end of lactation (Day 21). Mammary tissues were evaluated immunohistochemically, and blood samples were analyzed biochemically. The docosahexaenoic acid (DHA) level in the fish oil group was significantly higher than in other groups (p < 0.05). Fatty Acid Desaturase-2 (FADS2) levels also differed significantly between the negative control and all other groups (p < 0.05), while no significant change was observed in the walnut oil group (p > 0.05). Immunostaining intensities for insulin-like growth factor 1 (IGF-1), transforming growth factor beta 1 (TGF-β1), and vascular endothelial growth factor (VEGF) varied significantly among all groups (p < 0.05). These findings suggest that maternal fish oil supplementation during lactation more effectively enhances milk quality and mammary tissue function than flaxseed or walnut oil, indicating its potential as a dietary strategy to improve milk composition and support offspring nutrition. Trial Registration: Registered on the Clinical Trial Registry (www.clinicaltrials.gov; Clinical Trials identifier: NCT06111378 (26/10/2023).

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used to treat obesity and metabolic diseases, yet their early impact on body composition and circulating regulators of muscle and bone remain unclear. This study aimed to assess early effects of liraglutide on total and regional body composition and associated changes in circulating markers of muscle and bone metabolism.

Abstract

The aim of this study was to analyze the correlation between pituitary function and obstructive sleep apnea (OSA) in pituitary adenomas (PA) patients, and to investigate the effect of related hormone levels on the severity of OSA.

Abstract

Breast cancer (BC) continues to be one of the most commonly diagnosed cancers worldwide, predominantly affecting women. Insulin-like growth factor-1 (IGF-1) is vital for cellular growth and metabolism. Dysregulation of IGF-1 has been linked to an increased risk of cancer. We hypothesized that unhealthy lifestyle factors (e.g., poor diet, low physical activity) are associated with higher serum IGF-1 levels and an increased risk of BC. This research examines the relationship between lifestyle factors, IGF-1, and BC risk in Palestinian women in the Gaza Strip.

Abstract

The aim of the study is to determine the changes in insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) in the emergence of bipolar disorder and its treatment with olanzapine.

Abstract

Sarcomas are rare cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) is among the most commonly diagnosed sarcomas and provides insights into dysfunctional differentiation through its well- and dedifferentiated subtypes (WDLPS and DDLPS). Despite differences in histology and clinical behavior, the molecular pathways underlying each subtype remain poorly defined, leaving patients with DDLPS reliant on empiric chemotherapies. We applied single-nucleus multiome sequencing and spatial profiling to human normal adipose, WDLPS, and DDLPS tissues and identified lineage-specific blocks in differentiation within LPS. We found that DDLPS is characterized by loss of insulin-like growth factor 1 (IGF1) signaling and activation of early mesenchymal and glucagon-like peptide-1 (GLP-1)-associated programs. IGF1 signaling loss was restricted to the DDLPS component within mixed histology tumors and correlated with poor survival in patients with LPS. In normal adipocytes, IGF1 drives differentiation through peroxisome proliferator-activated receptor gamma 2 (PPARG2). We found that DDLPS cells lack PPARG2, causing a barrier to differentiation. This defect rendered DDLPS cells unresponsive to exogenous proadipogenic signals. Restoration of PPARG2 expression alone was sufficient to reenable adipogenesis, pinpointing PPARG2 as the key molecular determinant of lineage fate. Last, IGF1 deficiency in DDLPS was associated with up-regulation of the IGF1 receptor (IGF1R), creating a selective vulnerability to IGF1R-targeted antibody-drug conjugates. In summary, we identified lineage-specific defects in DDLPS, with PPARG2 as the molecular mediator of differentiation state in LPS. More broadly, our findings demonstrate how defining lineage-specific mechanisms of tumor state can inform the development of nonchemotherapeutic treatment approaches.

Abstract

The decidua, a dynamic and heterogeneous maternal tissue essential for pregnancy maintenance, has emerged as a key contributor to preeclampsia (PE) pathogenesis. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq), we profiled N6-methyladenosine (m6A) methylation patterns and mRNA expression in the decidua of early-onset PE (EPE), late-onset PE (LPE), and normal pregnancy (NP) samples. Integrated analysis revealed that differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were significantly enriched in pathways critical for decidualization, including HIF-1, PI3K-AKT, and Rap1 signaling. These pathways exhibited concurrent m6A methylation and expression changes, implicating their involvement in PE development. Notably, insulin-like growth factor (IGF1) was hypomethylated and downregulated in PE decidua compared to NP controls. Given IGF1's central role in stromal cell differentiation and decidualization, its dysregulation likely impairs normal decidual function. Validation using external datasets, quantitative PCR, and siRNA knockdown in human endometrial stromal cells confirmed reduced IGF1 expression and its impact on decidual markers like prolactin. Our findings demonstrate that disrupted m6A methylation impairs decidualization via IGF1 regulation, offering novel mechanistic insight into PE. This study highlights the importance of epitranscriptomic regulation at the maternal-fetal interface and identifies m6A-modified transcripts as potential therapeutic and diagnostic targets in PE.

Abstract

This study aimed to evaluate the efficacy of Morinda officinalis oligosaccharides (MOS) in improving sperm motility and quality in a gossypol-induced asthenozoospermia mouse model, and to explore the potential underlying mechanisms.

Abstract

Three-dimensional DNA nanomachine is an attractive tool in bioanalytical applications; however, the walking efficiency is still constrained by the inherent weak driving force. Herein, by utilizing the localized polymerization reaction of polyacrylamide (pAM) and DNA initiated on gallium-based liquid metal (LM), a near-infrared propelled LM-pAM-DNA nanobullet was designed to construct a colorimetric (CL), photothermal (PT), and electrochemical (EC) triple-mode sensing platform. The LM-pAM-DNA nanobullet held a good photothermal effect under near-infrared irradiation, which caused a temperature gradient between the nanobullet and the ambient solution to propel thermoelectrophoresis, resulting in a higher walking efficiency and shortened moving time. With the target-triggered walking process progressing, the DNA tracks on magnetic beads@mesoporous silica (MBs@SiO2) conjugates were cleaved, leading to the release of loaded tetramethylbenzidine (TMB). Taking full advantage of the supernatant and precipitate, a triple-mode biosensing platform was constructed with the readout of colorimetric signal (CL mode) and photothermal signal (PT mode) of oxTMB, and electrochemical signal of the remnant TMB in MBs@SiO2-DNA conjugates (EC mode). Using insulin-like growth factor-1 (IGF-1) as a model target, the proposed strategy achieved sensitive detection of IGF-1 with the detection limits of 83.73 pM, 447.73 pM, and 0.22 fM for CL, PT, and EC modes, respectively, providing a promising approach for early diagnosis and monitoring of disease.

Abstract

Studies have shown that sarcopenia and its related parameters are associated with cognition. Preclinical evidence suggests that myokines, such as irisin, Brain-Derived Neurotrophic Factor(BDNF), myostatin and Insulin-like Growth Factor-1(IGF-1) might explain this relationship. This study aimed to explore the associations between sarcopenia-related parameters and cognition, and whether myokines influence this association.

Abstract

Cancer-associated fibroblast (CAF)-derived extracellular vesicles (EVs) mediate lung adenocarcinoma (LUAD) progression, but the role of their protein cargo remains poorly defined. Through quantitative proteomic profiling of EVs from patient-derived CAFs, we identify the V-ATPase subunit ATP6V1C1 as a protein highly enriched in pro-migratory CAF-EVs that critically mediates LUAD metastasis. Mechanistically, EV-delivered ATP6V1C1 suppresses insulin-like growth factor binding protein 3 (IGFBP3) expression by downregulating the transcriptional regulator ID1. This suppression of IGFBP3 induces epithelial-mesenchymal transition in LUAD cells and amplifies the oncogenic IGF1/IGF1R/Akt/ERK signaling cascade initiated by CAF-secreted IGF1. This dual action establishes a feedforward loop that exacerbates metastatic progression. Our findings identify ATP6V1C1 as a dual regulator of LUAD metastasis and suggest a potential stroma-targeted therapeutic approach.

Abstract

HIV-associated lipodystrophy leads to visceral fat accumulation, metabolic complications, body image concerns, medication non-adherence, and increased cardiovascular risks. We thought to assess the effects of Tesamorelin, a synthetic growth hormone-releasing hormone analogue, that has been proposed as a targeted therapy.

Abstract

Galactose, a component of lactose, has nutritional programming power in mice. Lactose-free formulae contain maltodextrin, but no galactose. Here, partly replacing maltodextrin with galactose in the post-weaning diet was investigated for its metabolic and nutritional programming effects. Female and male mice were fed 39 energy% (en%) maltodextrin and 8 en% glucose (CON), or 31 en% maltodextrin with 16 en% galactose (GAL), or 15 en% maltodextrin and 16 en% galactose plus 16 en% glucose (lactose-mimic, LM) from postnatal week (PW) 3 to PW6. Body weight, fat mass, lean mass, energy expenditure (EE), and respiratory exchange ratio (RER) were lower at PW6 in female GAL and LM mice (p < 0.05). After receiving 9 weeks of the same obesogenic high-fat diet, the expression of hepatic insulin-like growth factor 1 (Igf1) appeared lower in both galactose-fed groups in females (p < 0.05). Partly replacing maltodextrin with galactose or galactose plus glucose in a post-weaning diet in mice resulted in significantly lower body weight, fat and lean mass, EE, and RER in early-life, and had no obvious nutritional programming effects except on liver Igf1 mRNA in females in later-life. The implications of this programming effect remain to be investigated further.

Abstract

Chronic arsenic exposure is a major environmental cause of neurotoxicity, linked to oxidative stress and apoptosis. While its toxicity is established, protective strategies are limited. Insulin-like growth factor-1 (IGF-1) is a key neurotrophic factor, but its potential to counteract arsenic-induced neuronal apoptosis and DNA fragmentation remains largely unexplored. The neuroprotective role of IGF-1 against sodium arsenite (NaAsO₂) was investigated in human SH-SY5Y neuroblastoma cells. Differentiated cells were employed to study IGF-1/AKT signaling, while undifferentiated cells were employed for apoptosis assays. Cells were exposed to NaAsO₂ with or without IGF-1 treatment. AKT phosphorylation status at Thr308 and Ser473 was assessed by Western blot. Apoptosis was evaluated via flow cytometric analysis of the sub-G1 population and by immunoblotting for key apoptotic markers, including cleaved caspase-3, cleaved PARP, p53, and Bcl-2. Arsenic exposure significantly suppressed AKT phosphorylation and induced concentration-dependent apoptosis, evidenced by increased p53, cleaved caspase-3, PARP cleavage, and a compensatory increase in Bcl-2. Treatment with IGF-1 significantly attenuated these effects. IGF-1 restored AKT signaling, reduced pro-apoptotic markers (p53, cleaved caspase-3), diminished PARP cleavage, and significantly decreased apoptotic cell death and DNA fragmentation (sub-G1 population). The observed reduction in Bcl-2 following IGF-1 treatment suggests a restoration of apoptotic equilibrium. The findings present novel evidence that IGF-1 confers protection against arsenic-induced neuroapoptosis and DNA fragmentation by reactivating the PI3K/AKT pathway. This reactivation rebalances apoptotic regulators and suppresses p53-mediated apoptosis. The findings highlight IGF-1 signaling as a promising therapeutic target for arsenic-related neuronal damage, warranting further investigation in vivo.

Abstract

In vitro oocyte maturation and embryo culture are critical for preserving and expanding genetic lines, and are necessary to produce genetically engineered pigs for biomedical and agricultural purposes. However, suboptimal in vitro conditions compromise oocyte and embryo viability. Recent improvements to in vitro maturation medium, including the addition of FGF2, LIF, and IGF1 (FLI), have increased the number of oocytes that reached the metaphase II stage, doubled the number of oocytes that reached the blastocyst stage, and quadrupled the number of piglets born after embryo transfer. Despite these benefits, the underlying cellular mechanisms remain not fully understood. Given the essential role of cumulus cells (CCs) in oocyte maturation, we investigated how FLI affects CCs gene expression. Cumulus-oocyte complexes were matured for 24 h in control or FLI media, and CCs from oocytes that reached the blastocyst stage underwent RNA sequencing. FLI altered 1257 transcripts (423 upregulated, 834 downregulated; adj-p < 0.05), with enrichment of junctional communication genes and downregulation of extracellular matrix organization. Immunofluorescence confirmed increased TJP1, TJP2, and GJA4 in FLI-treated complexes. Additionally, cortical granule localization suggested enhanced cytoplasmic maturation with FLI supplementation. These findings indicate that FLI promotes CC communication and supports improved oocyte competence in porcine in vitro maturation.

Abstract

The Itabaianinha cohort in Brazil carries a homozygous growth hormone-releasing hormone (GHRH) receptor (GHRH-R) gene mutation, causing congenital isolated GH deficiency (GHD). Affected individuals present with severe short stature, central obesity, hypercholesterolemia, and marked reductions in serum GH, IGF-I, and IGFBP 3 concentrations yet show no premature atherosclerosis and maintain a normal lifespan. IGF-I mostly circulates bound to IGFBPs and requires proteolytic cleavage for IGF-I receptor activation. Pregnancy-associated plasma protein A (PAPP-A) is an important IGF-dependent cleavage enzyme, binding to IGFBP 4 and releasing IGF-I. PAPP-A activity is inhibited by stanniocalcin-2 (STC2). The IGFBP 4-STC2-PAPP-A axis (ISPa) has emerged as a key regulator of IGF-I bioactivity.