The role of GDF11 in aging and skeletal muscle,cardiac and bone homeostasis

GDF11 is a secreted factor in the TGFß family of cytokines. Its nearest neighbor evolutionarily is myostatin, a factor discovered as being a negative regulator of skeletal muscle growth. High profile studies several years ago suggested that GDF11 declines with age, and that restoration of systemic GDF11 to ‘youthful’ levels is beneficial for several age-related conditions. Particularly surprising was a report that supplementation of GDF11 aided skeletal muscle regeneration, as its homolog, myostatin, has the opposite role. Given this apparent contradiction in functionality, multiple independent labs sought to discern differences between the two factors and better elucidate age-related changes in circulating GDF11, with most failing to reproduce the initial finding of declining GDF11 levels, and, importantly, all subsequent studies examining the effects of GDF11 on skeletal muscle described an inhibitory effect on regeneration – and that higher doses induce skeletal muscle atrophy and cachexia. There have also been several studies examining the effect of GDF11 and/or the downstream ActRII pathway on cardiac function, along with several interesting reports on bone. A review of the GDF11 literature, as it relates in particular to aging and skeletal muscle, cardiac and bone biology, is presented.     

A targeted proteomic assay for the measurement of plasma proteoforms related to human aging phenotypes

Circulating polypeptides and proteins have been implicated in reversing or accelerating aging phenotypes, including growth/differentiation factor 8 (GDF8), GDF11, eotaxin, and oxytocin. These proteoforms, which are defined as the protein products arising from a single gene due to alternative splicing and PTMs, have been challenging to study. Both GDF8 and GDF11 have known antagonists such as follistatin (FST), and WAP, Kazal, immunoglobulin, Kunitz, and NTR domain‐containing proteins 1 and 2 (WFIKKN1, WFIKKN2). We developed a novel multiplexed SRM assay using LC‐MS/MS to measure five proteins related to GDF8 and GDF11 signaling, and in addition, eotaxin, and oxytocin. Eighteen peptides consisting of 54 transitions were monitored and validated in pooled human plasma. In 24 adults, the mean (SD) concentrations (ng/mL) were as follows: GDF8 propeptide, 11.0 (2.4); GDF8 mature protein, 25.7 (8.0); GDF11 propeptide, 21.3 (10.9); GDF11 mature protein, 16.5 (12.4); FST, 29.8 (7.1); FST cleavage form FST303, 96.4 (69.2); WFIKKN1, 38.3 (8.3); WFIKKN2, 32.2 (10.5); oxytocin, 1.9 (0.9); and eotaxin, 2.3 (0.5). This novel multiplexed SRM assay should facilitate the study of the relationships of these proteoforms with major aging phenotypes.     

血清VEGF、miR-122、GDF15及TK1在乙肝相关性肝病表达水平及其临床意义

摘要 目的：分析不同类型乙肝相关性肝病患者血清血管内皮生长因子（VEGF）、microRNA-122（miR-122）、生长分化因子15（GDF-15）及胸苷激酶1（TK1）的表达差异变化及其临床意义。方法：随机选取2020年1月-2022年6月在我院消化内科收治的不同类型乙肝相关性肝病患者135例作为研究组。其中根据乙型肝炎诊断标准分为慢性乙型肝炎组（CHB）76例,乙型肝炎肝硬化组（LC）57例,乙型肝炎肝癌组（HCC）78例,选取同时期在本院进行体检的健康受检者96例作为健康组。比较各组的基本资料、检测研究对象血清VEGF、miR-122、GDF15、TK1、HBV DNA载量水平和AFP表达水平。采用Pearson相关性检验分析乙肝相关性肝病患者血清VEGF、miR-122、GDF15及TK1表达水平与HBV DNA载量水平的相关性,采用受试者工作特征曲线（ROC）诊断LC和HCC的价值。结果：CHB 组、LC 组 和HCC组VEGF、TK1表达水平显著高于健康组,差异具有统计学意义（P<0.01）,CHB 组、LC 组 和HCC组组间两两比较,差异具有统计学意义（P<0.01）。CHB 组、LC 组 和HCC组miR-122表达水平显著低于健康组,差异具有统计学意义（P<0.01）,CHB 组、LC 组 和HCC组组间两两比较,差异具有统计学意义（P<0.01）。LC 组 和HCC组GDF15表达水平显著高于 CHB 组和健康组,差异具有统计学意义（P<0.01）,CHB 组和健康组组间比较差异无统计学意义（P>0.05）。CHB 组、LC 组 和HCC组HBV DNA载量水平显著高于健康组,差异具有统计学意义（P<0.01）,LC 组 和HCC组组间比较,差异无统计学意义（P>0.05）。LC 组 和HCC组AFP表达水平显著高于 CHB 组和健康组,差异具有统计学意义（P<0.01）,LC 组 和HCC组、CHB 组和健康组组间比较差异无统计学意义（P>0.05）。CHB组、LC+HCC组血清VEGF、miR-122、GDF15及TK1水平与HBV DNA载量水平具有相关性（P<0.01或P<0.05）。血清VEGF、miR-122、GDF15及TK1单独检测诊断LC和HCC的曲线下面积（AUC）为0.695、0.783、0.743及0.7687,四项指标联合检测诊断LC和HCC的AUC为0.839,敏感度为84.21,特异度为83.25。结论：血清VEGF、miR-122、GDF15及TK1在各类型乙肝相关性肝病中表达水平存在差异,血清VEGF、miR-122、GDF15及TK1联合检测诊断LC和HCC具有临床价值。     

Serum levels of GDF15 are reduced in preeclampsia and the reduction is more profound in late-onset than early-onset cases

BackgroundPreeclampsia is a pregnancy specific disorder affecting 3–5% of pregnancies worldwide. It is clinically divided into early-onset and late-onset subtypes. Placental factors are involved in the pathogenesis of preeclampsia. Growth differentiation factor 15 (GDF15), a protein of the transforming growth factor beta superfamily, is highly expressed in the placenta. However, it is unclear whether the circulating levels of GDF15 are altered in preeclampsia at the time of or prior to disease presentation.MethodsSerum samples across three trimesters from 29 healthy pregnancies, third trimester sera from 34 women presenting with preeclampsia (early-onset n = 16, late-onset n = 18) and 66 gestation-age-matched controls, and sera at 11–13 weeks of pregnancy from women who later did (n = 36) or did not (n = 33) develop late-onset preeclampsia, were examined for GDF15 by ELISA.ResultsSerum GDF15 levels increased significantly with gestation in normal pregnancy. Serum GDF15 was significantly reduced in the third trimester in women presenting with preeclampsia compared to their gestation-age-matched controls. This reduction was apparent in both early-onset and late-onset subtypes, but it was more profound in late-onset cases. At 11–13 weeks of gestation, however, serum levels of GDF15 were similar between women who subsequently did and did not develop late-onset preeclampsia.ConclusionSerum GDF15 increased with gestation age, reaching the highest level in the third trimester. Serum GDF15 was significantly reduced in the third trimester in women presenting with preeclampsia, especially in late-onset cases. However, serum GDF15 was not altered in the first trimester in women destined to develop late-onset preeclampsia.     

生长分化因子11对甲醛诱导的海马神经细胞凋亡的影响

目的探讨生长分化因子11（GDF11）对甲醛诱导的海马神经（HT22）细胞毒性的影响。 方法把HT22细胞分为对照组（细胞未做任何处理）、甲醛组（50、100、200 μmol/ L甲醛处理细胞）和GDF11+甲醛组（GDF11转染细胞后用100 μmol/L甲醛处理）。细胞计数试剂盒（CCK8）法检测HT22细胞的活力;蛋白免疫印迹法检测HT22细胞凋亡相关蛋白Bax以及Bcl-2的变化;caspase-3活性检测试剂盒检测HT22细胞内caspase-3活性;DCFDA染色流式细胞仪检测HT22细胞中活性氧（ROS）水平。三组间比较采用单因素方差分析,组间两两比较采用LSD-t检验。 结果与对照组比较,甲醛组HT22细胞活力（92.23±0.20比56.12±0.61）和Bcl-2蛋白表达（220.32±2.21比150.25±0.31）水平均降低,差异具有统计学意义（P均< 0.05）;而caspase-3活性（95.36±1.74比190.17±2.14）、Bax蛋白表达（132.19±1.21比150.17±1.06）和ROS水平（1099.32±75.47比2802.17±126.49）均升高,差异具有统计学意义（P均< 0.05）。GDF11转染HT22细胞后,与甲醛组比较,GDF11+甲醛组HT22细胞活力升高（56.12±0.61比83.11±1.64）,Bax蛋白表达（270.03±0.17比150.17±1.06）降低,Bcl-2蛋白表达（150.25±0.31比187.34±1.52）升高,caspase-3活性降低（190.17±2.14比105.31±4.12）和ROS水平降低（2802.17±126.49比1305.36±68.45）,差异具有统计学意义（P均< 0.05）。 结论GDF11能够逆转甲醛对HT22细胞凋亡的诱导作用以及降低甲醛对HT22细胞ROS水平的增加作用,此机制对防治甲醛的神经毒性具有重要意义。     

Growth differentiation factor 11 promotes differentiation of MSCs into endothelial‐like cells for angiogenesis

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor‐β super family. It has multiple effects on development, physiology and diseases. However, the role of GDF11 in the development of mesenchymal stem cells (MSCs) is not clear. To explore the effects of GDF11 on the differentiation and pro‐angiogenic activities of MSCs, mouse bone marrow–derived MSCs were engineered to overexpress GDF11 (MSC^GDF11) and their capacity for differentiation and paracrine actions were examined both in vitro and in vivo. Expression of endothelial markers CD31 and VEGFR2 at the levels of both mRNA and protein was significantly higher in MSC^GDF11 than control MSCs (MSC^Vector) during differentiation. More tube formation was observed in MSC^GDF11 as compared with controls. In an in vivo angiogenesis assay with Matrigel plug, MSC^GDF11 showed more differentiation into CD31⁺ endothelial‐like cells and better pro‐angiogenic activity as compared with MSC^Vector. Mechanistically, the enhanced differentiation by GDF11 involved activation of extracellular‐signal‐related kinase (ERK) and eukaryotic translation initiation factor 4E (EIF4E). Inhibition of either TGF‐β receptor or ERK diminished the effect of GDF11 on MSC differentiation. In summary, our study unveils the function of GDF11 in the pro‐angiogenic activities of MSCs by enhancing endothelial differentiation via the TGFβ‐R/ERK/EIF4E pathway.     

GDF1 is a novel mediator of macrophage infiltration in brown adipose tissue of obese mice

We previously demonstrated a marked upregulation in the bone morphogenic protein (BMP)/growth differentiation factor (GDF) family member, GDF5, which is capable of promoting brown adipogenesis, in brown adipose tissue (BAT) of obese mice. In this study, we identified other GDF family members, besides GDF5 that are responsive to different obesogenic signals in BAT using inborn and acquired obesity animal models. In BAT from leptin-deficient ob/ob mice, GDF1 expression was preferentially downregulated, whereas the expression of several other genes in the BMP/GDF family, including GDF5, was upregulated. Moreover, in cultured brown adipocytes exposed to tunicamycin and hydrogen peroxide, at concentrations not affecting cellular viability, GDF1 expression was significantly downregulated. Recombinant GDF1 failed to significantly alter brown adipogenesis, despite the promoted phosphorylation of Smad1/5/8 in cultured brown adipocytes, but accelerated Smad1/5/8 phosphorylation with a concomitant increase in the number of migrating cells during exposure in a manner sensitive to activin-like kinase inhibitors in macrophagic RAW264.7 cells. Similarly, accelerated migration was observed in murine peritoneal macrophages exposed to GDF1. These results indicate that obesity could lead to predominant downregulation of GDF1 expression in BAT, which can modulate cellular migration through a mechanism relevant to activation of the downstream Smad signaling pathway in adjacent macrophages.     

Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction‐like phenotype in aged mice

Aging is a negative regulator of general homeostasis, tissue function, and regeneration. Changes in organismal energy levels and physiology, through systemic manipulations such as calorie restriction and young blood infusion, can regenerate tissue activity and increase lifespan in aged mice. However, whether these two systemic manipulations could be linked has never been investigated. Here, we report that systemic GDF11 triggers a calorie restriction‐like phenotype without affecting appetite or GDF15 levels in the blood, restores the insulin/IGF‐1 signaling pathway, and stimulates adiponectin secretion from white adipose tissue by direct action on adipocytes, while repairing neurogenesis in the aged brain. These findings suggest that GDF11 has a pleiotropic effect on an organismal level and that it could be a linking mechanism of rejuvenation between heterochronic parabiosis and calorie restriction. As such, GDF11 could be considered as an important therapeutic candidate for age‐related neurodegenerative and metabolic disorders.     

GDF15基因在卵巢上皮性癌组织中的表达及其临床意义

目的:探讨生长分化因子GDF15(Growth Differentiation Factor 15)基因在卵巢上皮性癌组织中的表达及其与铂类耐药的相关性。方法:应用免疫组化、western blot、RT-PCR等方法对80例原发性卵巢癌组织和卵巢癌顺铂敏感/耐药株A2780和CP70、SKOV3和SKOV3/DDP中生长分化因子GDF15表达水平进行测定。结果:生长分化因子GDF15的表达强度与卵巢癌铂类耐药性显著相关。在卵巢癌顺铂耐药株CP70、SKOV3/DDP中GDF15表达水平较顺铂敏感株A2780、SKOV3明显增高。结论:GDF15表达水平与卵巢癌发生发展及铂类耐药相关,对于卵巢癌患者早期筛选、预测预后具有一定的临床指导价值。     

GDF11 prevents the formation of thoracic aortic dissection in mice: Promotion of contractile transition of aortic SMCs

Thoracic aortic dissection (TAD) is an aortic disease associated with dysregulated extracellular matrix composition and de-differentiation of vascular smooth muscle cells (SMCs). Growth Differentiation Factor 11 (GDF11) is a member of transforming growth factor β (TGF-β) superfamily associated with cardiovascular diseases. The present study attempted to investigate the expression of GDF11 in TAD and its effects on aortic SMC phenotype transition. GDF11 level was found lower in the ascending thoracic aortas of TAD patients than healthy aortas. The mouse model of TAD was established by β-aminopropionitrile monofumarate (BAPN) combined with angiotensin II (Ang II). The expression of GDF11 was also decreased in thoracic aortic tissues accompanied with increased inflammation, arteriectasis and elastin degradation in TAD mice. Administration of GDF11 mitigated these aortic lesions and improved the survival rate of mice. Exogenous GDF11 and adeno-associated virus type 2 (AAV-2)-mediated GDF11 overexpression increased the expression of contractile proteins including ACTA2, SM22α and myosin heavy chain 11 (MYH11) and decreased synthetic markers including osteopontin and fibronectin 1 (FN1), indicating that GDF11 might inhibit SMC phenotype transition and maintain its contractile state. Moreover, GDF11 inhibited the production of matrix metalloproteinase (MMP)-2, 3, 9 in aortic SMCs. The canonical TGF-β (Smad2/3) signalling was enhanced by GDF11, while its inhibition suppressed the inhibitory effects of GDF11 on SMC de-differentiation and MMP production in vitro. Therefore, we demonstrate that GDF11 may contribute to TAD alleviation via inhibiting inflammation and MMP activity, and promoting the transition of aortic SMCs towards a contractile phenotype, which provides a therapeutic target for TAD.     

卵巢癌患者血清HB-EGF、TK1、GDF15水平与临床病理特征和预后的关系

摘要 目的：研究卵巢癌患者血清肝素结合性表皮生长因子（HB-EGF）、胸苷激酶1(TK1)、生长分化因子15(GDF15)水平与临床病理特征和预后的关系。方法：利用酶联免疫吸附试验（ELISA）检测94例卵巢癌患者和60例健康体检志愿者的血清HB-EGF、TK1、GDF15水平。Pearson相关分析卵巢癌患者血清HB-EGF、TK1、GDF15三者的相关性。分析卵巢癌患者血清HB-EGF、TK1、GDF15水平与临床病理特征的关系。Kaplan-Meier生存分析不同血清HB-EGF、TK1、GDF15水平的卵巢癌患者的生存率差异。单因素及多因素COX回归分析影响卵巢癌患者生存预后的因素。结果：与健康对照组相比,卵巢癌组患者血清HB-EGF、TK1、GDF15水平明显较高（均P<0.05）。卵巢癌组患者血清HB-EGF与TK1、GDF15水平呈正相关,TK1与GDF15水平呈正相关（均P<0.05）。卵巢癌患者血清HB-EGF、TK1、GDF15水平与FIGO分期、分化程度有关（均P<0.05）。血清HB-EGF、TK1、GDF15高水平的卵巢癌患者3年总体生存率分别低于低水平患者（P<0.05）。血清HB-EGF、TK1、GDF15高水平、FIGO分期为Ⅲ期及低分化程度是影响卵巢癌患者预后的独立危险因素。结论：卵巢癌患者血清中HB-EGF、TK1、GDF15水平升高,三者水平与卵巢癌肿瘤FIGO分期、肿瘤分化程度有关,检测血清HB-EGF、TK1、GDF15水平有助于评估卵巢癌患者的预后。     

Macrophage inhibitory cytokine‐1 (MIC‐1/GDF15): a new marker of all‐cause mortality

Macrophage inhibitory cytokine‐1 (MIC‐1/GDF15) is a member of the TGF‐b superfamily, previously studied in cancer and inflammation. In addition to regulating body weight, MIC‐1/GDF15 may be used to predict mortality and/or disease course in cancer, cardiovascular disease (CVD), chronic renal and heart failure, as well as pulmonary embolism. These data suggested that MIC‐1/GDF15 may be a marker of all‐cause mortality. To determine whether serum MIC‐1/GDF15 estimation is a predictor of all‐cause mortality, we examined a cohort of 876 male subjects aged 35–80 years, selected from the Swedish Population Registry, and followed them for overall mortality. Serum MIC‐1/GDF15 levels were determined for all subjects from samples taken at study entry. A second (independent) cohort of 324 same‐sex twins (69% female) from the Swedish Twin Registry was similarly examined. All the twins had telomere length measured and 183 had serum levels of interleukin 6 (IL‐6) and C‐reactive protein (CRP) available. Patients were followed for up to 14 years and had cause‐specific and all‐cause mortality determined. Serum MIC‐1/GDF15 levels predicted mortality in the all‐male cohort with an adjusted odds ratio (OR) of death of 3.38 (95%CI 1.38–8.26). This finding was validated in the twin cohort. Serum MIC‐1/GDF15 remained an independent predictor of mortality when further adjusted for telomere length, IL‐6 and CRP. Additionally, serum MIC‐1/GDF15 levels were directly correlated with survival time independently of genetic background. Serum MIC‐1/GDF15 is a novel predictor of all‐cause mortality.     

Senescence‐associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15

The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence‐associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence‐associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation.     

Pathophysiological role of growth differentiation factor 15 (GDF15) in obesity,cancer, and cachexia

Growth differentiation factor 15 or macrophage inhibitory cytokine-1 (GDF15/MIC-1) is a divergent member of the transforming growth factor β superfamily and has a diverse pathophysiological roles in cancers, cardiometabolic disorders, and other diseases. GDF15 controls hematopoietic growth, energy homeostasis, adipose tissue metabolism, body growth, bone remodeling, and response to stress signals. The role of GDF15 in cancer development and progression is complicated and depends on the specific cancer type, stage, and tumor microenvironment. Recently, research on GDF15 and GDF15-associated signaling has accelerated due to the identification of the GDF15 receptor: glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL). Therapeutic interventions to target GDF15 and/or GFRAL revealed the mechanisms that drive its activity and might improve overall outcomes of patients with metabolic disorders and cancer. This review highlights the structure and functions of GDF15 and its receptor, emphasizing the pleiotropic role of GDF15 in obesity, tumorigenesis, metastasis, immunomodulation, and cachexia.     

Depletion of growth differentiation factor 15 (GDF15) leads to mitochondrial dysfunction and premature senescence in human dermal fibroblasts

Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine also known as a mitokine; however, its role in mitochondrial homeostasis and cellular senescence remained elusive. We show here that knocking down GDF15 expression in human dermal fibroblasts induced mitochondrial dysfunction and premature senescence, associated with a distinct senescence-associated secretory phenotype. Fibroblast-specific loss of GDF15 expression in a model of 3D reconstructed human skin induced epidermal thinning, a hallmark of skin aging. Our results suggest GDF15 to play a so far undisclosed role in mitochondrial homeostasis to delay both the onset of cellular senescence and the appearance of age-related changes in a 3D human skin model.     

Autoregulation of neurogenesis by GDF11

In the olfactory epithelium (OE), generation of new neurons by neuronal progenitors is inhibited by a signal from neurons themselves. Here we provide evidence that this feedback inhibitory signal is growth and differentiation factor 11 (GDF11). Both GDF11 and its receptors are expressed by OE neurons and progenitors, and GDF11 inhibits OE neurogenesis in vitro by inducing p27(Kip1) and reversible cell cycle arrest in progenitors. Mice lacking functional GDF11 have more progenitors and neurons in the OE, whereas mice lacking follistatin, a GDF11 antagonist, show dramatically decreased neurogenesis. This negative autoregulatory action of GDF11 is strikingly like that of its homolog, GDF8/myostatin, in skeletal muscle, suggesting that similar strategies establish and maintain proper cell number during neural and muscular development.     

Absolute quantification of DcR3 and GDF15 from human serum by LC‐ESI MS

Biomarkers are widely used in clinical diagnosis, prognosis and therapy monitoring. Here, we developed a protocol for the efficient and selective enrichment of small and low concentrated biomarkers from human serum, involving a 95% effective depletion of high‐abundant serum proteins by partial denaturation and enrichment of low‐abundant biomarkers by size exclusion chromatography. The recovery of low‐abundance biomarkers was above 97%. Using this protocol, we quantified the tumour markers DcR3 and growth/differentiation factor (GDF)15 from 100 μl human serum by isotope dilution mass spectrometry, using ¹⁵N metabolically labelled and concatamerized fingerprint peptides for the both proteins. Analysis of three different fingerprint peptides for each protein by liquid chromatography electrospray ionization mass spectrometry resulted in comparable concentrations in three healthy human serum samples (DcR3: 27.23 ± 2.49 fmol/ml; GDF15: 98.11 ± 0.49 fmol/ml). In contrast, serum levels were significantly elevated in tumour patients for DcR3 (116.94 ± 57.37 fmol/ml) and GDF15 (164.44 ± 79.31 fmol/ml). Obtained data were in good agreement with ELISA and qPCR measurements, as well as with literature data. In summary, our protocol allows the reliable quantification of biomarkers, shows a higher resolution at low biomarker concentrations than antibody‐based strategies, and offers the possibility of multiplexing. Our proof‐of‐principle studies in patient sera encourage the future analysis of the prognostic value of DcR3 and GDF15 for colon cancer patients in larger patient cohorts.     

GDF11 exhibits tumor suppressive properties in hepatocellular carcinoma cells by restricting clonal expansion and invasion

Growth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features, despite some controversies in age-related studies. GDF11 has been poorly investigated in cancer, particularly in those with stemness capacity, such as hepatocellular carcinoma (HCC), one of the most aggressive cancers worldwide. Here, we focused on investigating the effects of GDF11 in liver cancer cells. GDF11 treatment significantly reduced proliferation, colony and spheroid formation in HCC cell lines. Consistently, down-regulation of CDK6, cyclin D1, cyclin A, and concomitant upregulation of p27 was observed after 24 h of treatment. Interestingly, cell viability was unchanged, but cell functionality was compromised. These effects were potentially induced by the expression of E-cadherin and occludin, as well as Snail and N-cadherin repression, in a time-dependent manner. Furthermore, GDF11 treatment for 72 h induced that cells were incapable of sustaining colony and sphere capacity in the absent of GDF11, up to 5 days, indicating that the effect of GDF11 on self-renewal capacity is not transient. Finally, in vivo invasion studies revealed a significant decrease in cell migration of hepatocellular carcinoma cells treated with GDF11 associated to a decreased proliferation judged by Ki67 staining. Data show that exogenous GDF11 displays tumor suppressor properties in HCC cells.     

抗衰老的GDF11生物学特征与功能表现

生长分化因子11（growth differentiation factor-11, GDF11）是转化生长因子β(transforming growth factor-β, TGF-β) 超家族中骨形态发生蛋白（bone morphogenetic proteins,BMPs）亚家族中的一个重要成员,在哺乳动物的骨骼、肾等多种器官组织上均有表达,且在胚胎发育、骨骼和肌肉形成等方面起着重要作用。近年研究发现,GDF11与哺乳动物的抗衰老作用联系越来越紧密。本文整理国内外关于GDF11与衰老关系的研究,对 GDF11生物学基础以及对动物心脏的衰老、认知能力以及骨骼肌肉等方面的影响进行了综述。我们认为,GDF11作为一种新的细胞因子,可以调控多种下游信号通路,其作用的方式及影响还有待研究。GDF11研究可为在抗衰老以及与衰老相关疾病的治疗提供一定的理论基础。