Regulation of spermatogenesis by paracrine/autocrine testicular factors

Spermatogenesis is a complex process regulated by endocrine and testicular paracrine/autocrine factors. Gonadotropins are involved in the regulation of several testicular paracrine factors, mainly of the IL-1 family and testicular hormones. Testicular cytokines and growth factors (such as IL-1, IL-6, TNF, IFN-γ, LIF and SCF) were shown to affect both the germ cell proliferation and the Leydig and Sertoli cells functions and secretion. Cytokines and growth factors are produced by immune cells and in the interstitial and seminiferous tubular compartments by various testicular cells, including Sertoli, Leydig, peritubular cells, spermatogonia, differentiated spermatogonia and even spermatozoa. Corresponding cytokine and growth factor receptors were demonstrated on some of the testicular cells. These cytokines also control the secretion of the gonadotropins and testosterone in the testis. Under pathological conditions the levels of pro-inflammatory cytokines are increased and negatively affected spermatogenesis. Thus, the expression levels and the mechanisms involved in the regulation of testicular paracrine/autocrine factors should be considered in future therapeutic strategies for male infertility.

SF/HGF-c-Met autocrine and paracrine promote metastasis of hepatocellular carcinoma

AIM: To explore the role of SF/HGF-Met autocrine and paracrine in metastasis of hepatocellular carcinoma (HCC). METHODS: SF/HGF and c-met transcription and protein expression in HCC were examined by RT-PCR and Western Blot in 4 HCC cell lines, including HepG2, Hep3B, SMMC7721 and MHCC-1, the last cell line had a higher potential of metastasis. sf/hgf cDNA was transfected by the method of Lipofectin into SMMC7721. SF/HGF and c-met antibody were used to stimulate and block SF/HGF-c-met signal transduction. Cell morphology, mobility, and proliferation were respectively compared by microscopic observation, wound healing assay and cell growth curve. RESULTS: HCC malignancy appeared to be relative to its met-SF/HGF expression. In MHCC-1, c-met expression was much stronger than that in other cell lines with lower potential of metastasis and only SF/HGF autocrine existed in MHCC-1. After sf/hgf cDNA transfection or conditioned medium of MHCC-1 stimulation, SMMC7721 changed into elongated morphology, and the abilities of proliferation (P 【 0.05) and mobility increased. Such bio-activity could be blocked by c-met antibody (P 【 0.05). CONCLUSION: The system of SF/HGF-c-met autocrine and paracrine played an important role in development and metastasis potential of HCC. Inhibition of SF/HGF-c-met signal transduction system may reduce the growth and metastasis of HCC.

SIMULTANEOUS OVER-EXPRESSION OF INSULIN-LIKE GROWTH FACTOR- Ⅱ (IGF- Ⅱ ) AND IGF- Ⅱ RECEPTOR(IGF- Ⅱ R) GENES IN HUMAN PRIMARY CANCER-IMPLICATION OF AUTOCRINE AND PARACRINE MECHANISM IN AUTONOMOUS GROWTH OF HEPATIC CANCER

This is first report about the simultaneous over-expression of both Insulin-like growth factor (IGF- I ) and its receptor (IGF- I R) at mRNA level in human primary hepatic Cancer (PHC). In 10 PHC samples from China, IGF-I and IGF- I R were both over-expressed, whereas only a background signal was detected in normal liver. In 5 pairs of PHC and its non- tumorous adjacent liver tissues from South Africa, IGF- I and IGF- I R were also over-expressed in PHC. mRNA expression of IGF- I in all 5 cases and IGF- I R in 4 of 5 cases were higher in cancer than non- tumorous adjacent liver tissues. These results strongly implicate that an autocrine and/ or paracrine mechanism might be Involved in formation and progression of PHC.

A Polyvinyl Alcohol/Acrylamide Hydrogel with Enhanced Mechanical Properties Promotes Full-Thickness Skin Defect Healing by Regulating Immunomodulation and Angiogenesis Through Paracrine Secretion

Hydrogel-based tissue-engineered skin has attracted increased attention due to its potential to restore the structural integrity and functionality of skin.However,the mechanical properties of hydrogel scaffolds and natural skin are substantially different.Here,we developed a polyvinyl alcohol(PVA)/acrylamide based interpenetrating network(IPN)hydrogel that was surface modified with polydopamine(PDA)and termed Dopa-gel.The Dopa-gel exhibited mechanical properties similar to native skin tissue and a superior ability to modulate paracrine functions.Furthermore,a tough scaffold with tensile resistance was fabricated using this hydrogel by three-dimensional printing.The results showed that the interpenetration of PVA,alginate,and polyacrylamide networks notably enhanced the mechanical properties of the hydrogel.Surface modification with PDA endowed the hydrogels with increased secretion of immunomodulatory and proangiogenic factors.In an in vivo model,Dopa-gel treatment accelerated wound closure,increased vascularization,and promoted a shift in macrophages from a proinflammatory M1 phenotype to a prohealing and anti-inflammatory M2 phenotype within the wound area.Mechanistically,the focal adhesion kinase(FAK)/extracellular signal-related kinase(ERK)signaling pathway may mediate the promotion of skin defect healing by increasing paracrine secretion via the Dopa-gel.Additionally,proangiogenic factors can be induced through Rho-associated kinase-2(ROCK-2)/vascular endothelial growth factor(VEGF)-mediated paracrine secretion under tensile stress conditions.Taken together,these findings suggest that the multifunctional Dopa-gel,which has good mechanical properties similar to those of native skin tissue and enhanced immunomodulatory and angiogenic properties,is a promising scaffold for skin tissue regeneration.

Paracrine and endocrine actions of bone——the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts

The skeleton is a dynamic organ that is constantly remodeled. Proteins secreted from bone cells, namely osteoblasts, osteocytes,and osteoclasts exert regulation on osteoblastogenesis, osteclastogenesis, and angiogenesis in a paracrine manner. Osteoblasts secrete a range of different molecules including RANKL/OPG, M-CSF, SEMA3A, WNT5A, and WNT16 that regulate osteoclastogenesis. Osteoblasts also produce VEGFA that stimulates osteoblastogenesis and angiogenesis. Osteocytes produce sclerostin（SOST） that inhibits osteoblast differentiation and promotes osteoclast differentiation. Osteoclasts secrete factors including BMP6, CTHRC1, EFNB2, S1P, WNT10B, SEMA4D, and CT-1 that act on osteoblasts and osteocytes, and thereby influencea A osteogenesis. Osteoclast precursors produce the angiogenic factor PDGF-BB to promote the formation of Type H vessels, which then stimulate osteoblastogenesis. Besides, the evidences over the past decades show that at least three hormones or ＂osteokines＂from bone cells have endocrine functions. FGF23 is produced by osteoblasts and osteocytes and can regulate phosphate metabolism. Osteocalcin（OCN） secreted by osteoblasts regulates systemic glucose and energy metabolism, reproduction, and cognition. Lipocalin-2（LCN2） is secreted by osteoblasts and can influence energy metabolism by suppressing appetite in the brain.We review the recent progresses in the paracrine and endocrine functions of the secretory proteins of osteoblasts, osteocytes, and osteoclasts, revealing connections of the skeleton with other tissues and providing added insights into the pathogenesis of degenerative diseases affecting multiple organs and the drug discovery process.

Gastrin as an autocrine growth factor in colorectal carcinoma:implications for therapy

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Adipose-derived stem cells enhance myogenic differentiation in the mdx mouse model of muscular dystrophy via paracrine signaling

Adipose-derived stem cells have been shown to promote peripheral nerve regeneration through the paracrine secretion of neurotrophic factors. However, it is unclear whether these cells can promote myogenic differentiation in muscular dystrophy. Adipose-derived stem cells （6 × 106） were injected into the gastrocnemius muscle of mdx mice at various sites. Dystrophin expression was found in the muscle fibers. Phosphorylation levels of Akt, mammalian target of rapamycin （mTOR）, eIF-4E binding protein 1 and $6 kinase 1 were increased, and the Akt/mTOR pathway was activated. Simultaneously, myogenin levels were increased, whereas cleaved caspase 3 and vimentin levels were decreased. Necrosis and fibrosis were reduced in the muscle fibers. These findings suggest that adipose-derived stem cells promote the re- generation and survival of muscle cells by inhibiting apoptosis and fibrosis, thereby alleviating muscle damage in muscular dystrophy.

Intravitreal stem cell paracrine properties as a potential neuroprotective therapy for retinal photoreceptor neurodegenerative diseases

Retinal degenerations are the leading causes of irreversible visual loss worldwide. Many pathologies included under this umbrella involve progressive degeneration and ultimate loss of the photoreceptor cells, with age-related macular degeneration and inherited and ischemic retinal diseases the most relevant. These diseases greatly impact patients' daily lives, with accompanying marked social and economic consequences. However, the currently available treatments only delay the onset or slow progression of visual impairment, and there are no cures for these photoreceptor diseases. Therefore, new therapeutic strategies are being investigated, such as gene therapy, optogenetics, cell replacement, or cell-based neuroprotection. Specifically, stem cells can secrete neurotrophic, immunomodulatory, and anti-angiogenic factors that potentially protect and preserve retinal cells from neurodegeneration. Further, neuroprotection can be used in different types of retinal degenerative diseases and at different disease stages, unlike other potential therapies. This review summarizes stem cell-based paracrine neuroprotective strategies for photoreceptor degeneration, which are under study in clinical trials, and the latest preclinical studies. Effective retinal neuroprotection could be the next frontier in photoreceptor diseases, and the development of novel neuroprotective strategies will address the unmet therapeutic needs.

A paracrine role for white thermogenic adipocytes in innervation: an evidence-based hypothesis

White adipose tissue(WAT) stores energy and also plays an important endocrine role in producing adipokines for communication with the peripheral and central nervous system. WAT consists of the major lipogenic unilocular adipocytes and the minor populations of beige and brite multilocular adipocytes. These multilocular adipocytes express thermogenic genes and have phenotypic similarity with thermogenic brown adipose tissue. According to a current paradigm, multilocular adipocytes have a thermogenic function in WAT. In this mini review, we discuss data revealing heterogeneity among multilocular cell subsets in WAT and their functions beyond thermogenesis. We propose a hypothetical neuroendocrine role for multilocular adipocytes subsets in the formation of adaptive sensory-sympathetic circuits between the central nervous system and adipose tissue, which activate lipolysis and thermogenesis in WAT in high energy demand situations.

Autocrine Production of Interleukin-6: A Mechanism of Interleukin-6 Independence in Dexamethasone-Resistant 7TD1 Murine Myeloma Cells

Several factors could contribute to proliferation of multiple myeloma (MM) cells independent of interleukin-6 (IL6) in the later stages of the disease. Our previous studies established a dexamethasone-resistant 7TD1 cell line (7TD1-Dxm) and have shown that one mechanism of resistance to dexamethasone is due to inhibition of cytochrome c release. We have also observed that 7TD1-Dxm cells proliferate independently of externally-added IL6. This study therefore aimed to elucidate the mechanisms responsible for IL6-independent proliferation in 7TD1-Dxm cells. Our results indicated that 7TD1-Dxm cells produced IL6 in an autocrine fashion. We have observed that dexamethasone-resistant 7TD1 cells become dexamethasone-resistant and IL6-independent for proliferation concomitantly. This strongly suggests that production of IL6 by 7TD1-Dxm cells may play an important role in the development of dexamethasone resistance. Consequently, further investigation of the molecular mechanisms responsible for IL6 production may be helpful in delineating the mechanisms leading to dexamethasone resistance.

Paracrine factors for neurodegenerative disorders:special emphasis on Parkinson's disease

The progressive loss of dopaminergic neurons in the ventral mesencephalon is the main pathological hallmark of Parkinson’s disease（PD）.Drugs currently available only alleviate the principal symptomatic motor-related disturbances and their benefit is counteracted by side effects in the long time.

EFFECTS OF TGF β1 AUTOCRINE BLOCKAGE ONOSTEOSARCOMA CELLS

Objective To evaluate the effects of transforming growth factor β1 (TGF β1) autocrine blockage on proliferation activity and drug sensitivity of osteosarcoma. Methods Northern blot, MTT determination, and 3H thymidine incorporation were used to investigate the effects of antisense TGF β1 gene on osteosarcoma. Results The proliferation of osteosarcoma cells transfected by antisense TGF β1 gene was suppressed markedly, and adriamycin sensitivity was significantly increased. Conclusion Blockage of osteosarcoma cells TGF β1 autocrine loop inhibits cell proliferation and enhances chemother-apy sensitivity.

Differential expression of autocrine motility factor receptor (AMFR) mRNA in normal and cancer cells detected by in situ hybridization

The receptor for autocrine motility factor (AMFR) is known to be involved in the process of AMF-mediated cell migration and metastasis. This paper describes the procedures of non-radioactive in situ hybridization (ISH) detection of AMFR mRNA in both paraffin-embedded surgical sections and cultured cells using either biotinylated oligonucleotide probes or digoxigenin-labeled RNA probes. The results showed that the AMFR mRNA was expressed at an enhanced level in hyperplaJstic and malignant tissues of breast and prostate cancer patient surgical specimens, indicating that the elevated AMFR expression was associated with the tissue malignancy Moreover, AMFR mRNA was detected in both normal and earcinoma cells when cultured at a subconfluent density. However, AMFR expression was inhibited in confluent normal (3T3-A31 murine fibroblast and FHs738BL human bladder) cells while it continued to express in carcinoma (J82 human bladder)and metastatic (3T3-M murine fibroblast) cells irrespective of cell density This suggested a cell-cell contact downregulation of AMFR mRNA expression in normal but not in cancer cells. The ISH data obtained in this study are closely consistent with the AMFR protein expression pattern previously reported, implying that the differential expression of AMFR gene may be regulated and controlled at the transcriptional level.

Activin-Directed Differentiation of Human Embryonic Stem Cells Differentially Modulates Alveolar Epithelial Wound Repair via Paracrine Mechanism

Differentiated embryonic stem cells (ESC) can ameliorate lung inflammation and fibrosis in animal lung injury models;therefore, ESC, or their products, could be candidates for regenerative therapy for incurable lung diseases, such as idiopathic pulmonary fibrosis (IPF). In this study, we have investigated the paracrine effect of differentiated and undifferentiated human ESC on alveolar epithelial cell (AEC) wound repair. hESC line, SHEF-2 cells were differentiated with Activin treatment for 22 days in an embryoid body (EB) suspension culture. Conditioned media (CM) which contain cell secretory factors were collected at different time points of differentiation. CM were then tested onin vitro?wound repair model with human type II AEC line, A549 cells (AEC). Our study demonstrated that CM originated from undifferentiated hESC significantly inhibited AEC wound repair when compared to the control. Whereas, CM originated from Activin-directed hESC differentiated cell population demonstrated a differential reparative effect on AEC wound repair model. CM obtained from Day-11 of differentiation significantly enhanced AEC wound repair in comparison to CM collected from pre- and post-Day-11 of differentiation. Day-11 CM enhanced AEC wound repair through significant stimulation of cell migration and cell proliferation. RT-PCR and immunocytochemistry confirmed that Day-11 CM was originated form a mixed population of endodermal/mesodermal differentiated hESC. This report suggests a putative paracrine-mediated epithelial injury healing mechanism by hESC secreted products, which is valuable in the development of novel stem cell-based therapeutic strategies.

PARTIAL PURIFICATION AND CHARACTERIZATION OF AN AUTOCRINE T SUPPRESSOR FACTOR FROM MURINE LEUKEMIA

The leukemia-associated autoinhibitor (LAI-615) derived from murine leukemia L7811 has been investigated intensively in our laboratory. In the following experiments, the partial purification of LA I-615 has been carried out in addition to the observation of phenotype variations of L7811 leuke-mic cells. The factor was purified over 1306-fold by sequential fractionation with Sephadex G-150 gel filtration, DEAE-cellulose ion exchange chromato-graphy, and Mono Q-fast protein liquid chromato-graphy. The molecular weight of LAI-615 was 68,000 as estimated by gel filtration. LAI-615 was a protein but not glycosylated, and it was suggested LAI-615 be secreted in an autocrine manner. Im-munocytochemical staining showed that the expression of Lyt2 phenotype of L7811 leukemic cells was often coincident with the secretion of LAI-615. Moreover, the physicochemical characteristics of LAI-615 was similar to that of T suppressor factor. Thus it is concluded that LAI-615 may be one of TsF-like factors.

巨噬细胞迁移抑制因子对人胚胎干细胞存活、增殖和分化的影响

背景:巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)是一种具有多效性作用的细胞因子,可以在不同类型干细胞中自分泌并且能调控细胞的增殖、分化和迁移。课题组前期研究证实人胚胎干细胞自分泌MIF,且在培养液中浓度基本固定。然而,MIF是否参与了人胚胎干细胞的存活、增殖和分化尚不清楚。目的:探究MIF对人胚胎干细胞存活、增殖和分化的作用。方法:(1)培养人胚胎干细胞H9,CCK-8法检测并绘制细胞生长曲线,采用酶联免疫吸附法定量检测培养基中MIF水平。(2)为了明确外源性MIF对人胚胎干细胞存活、增殖的影响,分为:对照组,细胞在干细胞培养基中正常培养;外源性MIF组,在干细胞培养基中分别添加30,100,300 ng/m L的MIF;MIF抑制剂ISO-1组,在干细胞培养基中分别添加2,7,21μmol/L的ISO-1;MIF+ISO-1组,在不同浓度ISO-1组中分别添加100 ng/m L MIF,采用CCK-8法检测上述各组细胞活力。(3)为进一步阐明MIF基因对人胚胎干细胞存活、增殖的影响,采用CRISPRCas9技术构建MIF敲除的H9细胞系,观察建系情况。(4)为了明确高浓度MIF对人胚胎干细胞初步分化是否有影响,在培养基中分别添加100 ng/m L MIF和100 ng/m L CXCR4中和抗体,采用实时荧光定量聚合酶链式反应(RT-q PCR)、免疫细胞荧光、蛋白质印迹法(Western blot)检测干细胞自我更新因子(KLF4、c-MYC、NANOG、OCT4、SOX2)及分化转录因子(FOXA2、OTX2)的表达水平。结果与结论:(1)人胚胎干细胞H9的对数生长期为3-6 d,正常生长的情况下自分泌MIF水平约为20 ng/m L,与细胞量无关;(2)与对照组相比,添加不同质量浓度MIF对人胚胎干细胞的增殖无影响(P>0.05);ISO-1明显抑制人胚胎干细胞的增殖,ISO-1浓度越大,抑制越明显(P<0.05);ISO-1中添加MIF可以减少ISO-1的抑制作用(P<0.05);(3)RT-q PCR检测MIF基因敲除约50%后,人胚胎干细胞生长活力显著降低并且无法建系成功;(4)在培养基中添加100 ng/m L外源性MIF,自我更新转录因子KLF4的m RNA、蛋白及荧光表达水平均下降;分化因子FOXA2的m RNA、蛋白及荧光表达水平均上升;(5)在培养基中添加100 ng/m L CXCR4中和抗体,KLF4的m RNA及蛋白表达水平均上升;FOXA2的m RNA及蛋白表达水平均下降,与MIF组表达趋势相反。综上所述,人胚胎干细胞自分泌的MIF是其存活所必需的;培养基中额外添加MIF并不能促进人胚胎干细胞增殖,但可以使自我更新因子KLF4表达下降,转录因子FOXA2表达上升,为下一步探明MIF对人胚胎干细胞分化的影响及机制提供了线索,MIF-CXCR4轴在其中起到一定的调控作用。

Effects of microenvironment and biological behavior on the paracrine function of stem cells

Mesenchymal stem cells(MSCs),the most well-studied cell type in the field of stem cell therapy,have multi-lineage differentiation and self-renewal potential.MsC-based thera-pies have been used to treat diverse diseases because of their ability to potently repair tissue and locally restore function.An increasing body of evidence demonstrates that paracrine func-tion is central to the effects of MsC-based therapy.Growth factors,cytokines,chemokines,extracellular matrix components,and extracellular vehicles all contribute to the beneficial ef-fects of MSCs on tissue regeneration and repair.The paracrine substances secreted by MSCs change depending on the tissue microenvironment and biological behavior.In this review,we discuss the bioactive substances secreted by MsCs depending on the microenvironment and biological behavior and their regulatory mechanisms,which explain their potential to treat human diseases,to provide new ideas for further research and clinical cell-free therapy.

人肝癌Huh7细胞上皮间充质转化与VEGFa/VEGFR2自分泌途径的相关性及华蟾素的调控作用

目的探究华蟾素(cinobufagin,CBG)注射液对人肝癌Huh7细胞血管内皮生长因子a(vascular endothelial growth factor a,VEGFa)/血管内皮生长因子受体2(vascular endothelial growth factor receptor 2,VEGFR2)自分泌信号通路及上皮间充质转化进程的影响。方法通过CCK-8实验、细胞划痕实验、Transwell侵袭实验和成球实验检测人肝癌Huh7细胞增殖、迁移、侵袭和成球能力;免疫荧光双标实验对人肝癌Huh7细胞VEGFa/VEGFR2进行共定位分析,ELISA法检测人肝癌Huh7细胞上清液中VEGFa水平,Western blot法检测人肝癌Huh7细胞中VEGFa/VEGFR2通路及上皮间充质转化相关蛋白表达水平。结果CBG注射液能显著抑制人肝癌Huh7细胞的增殖、迁移、侵袭和成球能力;人肝癌Huh7细胞可能存在VEGFa/VEGFR2自分泌途径;CBG注射液能抑制VEGFa的分泌,降低下游p-VEGFR2、p-PI3K、p-AKT及间充质标志物N-Cadherin、Vimentin、Snail蛋白的表达水平,升高上皮标志物E-Cadherin蛋白的表达水平。结论CBG注射液可能通过VEGFa/VEGFR2自分泌途径调控人肝癌Huh7细胞上皮间充质转化。

γ-氨基丁酸在肿瘤微环境中的研究进展

氨基丁酸是神经系统中经典的抑制性神经递质,由γ-氨基丁酸能神经元合成并释放至突触间隙,作用于突触后膜,引起抑制性突触后电位。近年来研究发现,肿瘤微环境中γ-氨基丁酸代谢通路的相关代谢酶存在异常表达,γ-氨基丁酸得以过度累积,相关受体也存在异常亚基组成或表达。γ-氨基丁酸一方面可作为额外的碳源回补进入TCA循环,另一方面可分泌至胞外,与各细胞成分的膜受体结合,启动下游信号转导。γ-氨基丁酸通过代谢燃料补给、自分泌及旁分泌作用,影响肿瘤细胞增殖、侵袭和转移,并存在着调节肿瘤免疫微环境的潜力。

低氧和氧化应激对不同来源间充质干细胞旁分泌的差异性影响

背景:间充质干细胞的生物学行为受所处生存微环境的影响,微环境条件预处理是调控间充质干细胞功能的重要手段。目的:对比氧化应激和低氧条件下脐带间充质干细胞、脂肪间充质干细胞旁分泌功能的差异,为治疗不同疾病选择适当的间充质干细胞预处理方式提供理论依据。方法:培养脐带间充质干细胞和脂肪间充质干细胞,分别加入不同浓度的H_(2)O_(2)或不同体积分数的O_(2)干预,检测细胞形态、增殖、活力和旁分泌因子表达。结果与结论:①普通培养环境下,脐带间充质干细胞中脑源性神经营养因子和转化生长因子β的表达水平显著高于脂肪间充质干细胞,而脂肪间充质干细胞中基质细胞衍生因子1α和肿瘤坏死因子刺激因子6的表达水平显著高于脐带间充质干细胞;②中低浓度水平(≤100μmol/L)H_(2)O_(2)对2种间充质干细胞活力的影响无显著差异,但H_(2)O_(2)浓度从50μmol/L增至100μmol/L使脐带间充质干细胞中血管内皮生长因子表达水平显著增高,脂肪间充质干细胞中碱性成纤维细胞生长因子、血管内皮生长因子、基质细胞衍生因子1α和白细胞介素10表达水平均显著升高;③体积分数1%O_(2)促进2种间充质干细胞增殖;体积分数1%O_(2)干预24 h后,2种间充质干细胞中基因表达水平均有升高,但脂肪间充质干细胞中血管内皮生长因子、白细胞介素10和肿瘤坏死因子刺激因子6的表达水平显著高于脐带间充质干细胞;④结果提示:低氧和氧化应激预处理可提高间充质干细胞旁分泌功能,但2种间充质干细胞对低氧和氧化应激的响应不同,治疗疾病可选择适合的间充质干细胞预处理方式进一步提升其治疗潜力。