The study aims to investigate the effects of cardiac fibroblast (CF) paracrine factors on murine embryonic stem cells (ESCs). Conditioned mediums from either neonatal cardiac fibroblasts (ConM-NCF) or adult cardiac fibroblasts (ConM-ACF) were diluted by 1:50 and 1:5, respectively, to investigate whether these conditioned mediums impact murine ESCs distinctly with RT-real time PCR techniques, cell proliferation essay, ELISA and by counting percentage of beating embryoid bodies (EBs) during ESCs differentiation. The data showed that the paracrine ability of CFs changed dramatically during development, in which interleukin 6 (IL6) increased with maturation. ConM-NCF 1:50 and ConM-NCF 1:5 had opposite effects on the pluripotent markers, although they both reduced mouse ESC proliferation. ConM-ACF 1:50 promoted ESCs pluripotent markers and proliferation, while ConM-ACF 1:5 exerted negative effects. All CF-derived conditioned mediums inhibited cardiac differentiation, but with distinguishable features: ConM-NCF 1:50 slightly decreased the early cardiac differentiation without altering the maturation tendency or cardiac specific markers in EBs at differentiation of day 17; ConM-ACF 1:50 had more significant inhibitory effects on early cardiac differentiation than ConM-NCF 1:50 and impeded cardiac maturation with upregulation of cardiac specific markers. In addition, IL6 neutralization antibody attenuated positive effect of ConM-ACF 1:50 on ESCs proliferation, but had no effects on ConM-NCF 1:50. Long-term IL6 neutralization reduced the percentage of beating EBs at early developmental stage, but did not alter the late cardiac differentiation. Taken together, both the quality and quantity of factors and cytokines secreted by CFs are critical for the ESC fate. IL6 could be a favorable cytokine for ESC pluripotency and the early cardiac differentiation.
Animals ; Embryonic Stem Cells ; Fibroblasts ; Heart ; Mice ; Mouse Embryonic Stem Cells ; Paracrine Communication

Bone marrow derived mesenchymal stem cell (BMSC) is one of the crucial cell types which plays roles in wound healing of tissues. In the last decades, it was believed that BMSCs promoted wound healing by differentiating into multiple lineages and placing the wounded tissues. In recent years, a new viewpoint arose from evidences that the paracrine effect of BMSCs might play a more important role in the process of wound healing than differentiation. Understanding the role of BMSCs paracrine in wound healing would be vital to clarify the mechanism how BMSCs take part into the process of wound healing. In this paper, we review the new research processes of BMSCs paracrine in wound healing of tissues.
Animals ; Bone Marrow Cells ; cytology ; physiology ; Cell Differentiation ; physiology ; Cells, Cultured ; Humans ; Mesenchymal Stromal Cells ; cytology ; physiology ; Paracrine Communication ; physiology ; Wound Healing ; physiology

PURPOSE: Breast carcinomas are highly malignant tumor that the angiogenesis factor, vascular endothelial growth factor and its receptors are overexpressed. To elucidate the role of Angiopoietin-2 (ANG2) and ANG2 receptor Tie-2 in invasive ductal carcinoma, we examined the expression of ANG2, and Tie-2 at the mRNA and protein levels in human breast cancer cell lines and samples. METHODS: Total RNA from 22 breast cancer patient biopsies were extracted. ANG2 and Tie-2 mRNA expression was measured by means of reverse transcription-PCR assay. RESULTS: RT-PCR indicated that the ANG2 and Tie-2 mRNA levels in carcinoma samples were significantly higher than those of the adjacent non-neoplastic breast tissues. For ANG2 and Tie-2, 41 of 71 invasive ductal carcinomass (58%) showed high expressions in Immunohistochemistry. Immunohistochemical analysis demonstrated that ANG2 and Tie-2 were expressed by both tumor cells and endothelial elements. Expression in tumor cells were confirmed by studying a panel of human breast carcinoma cell lines cultured by RT-PCR. Our study showed that the ANG2 positivity was correlated with axillary lymph node metastasis among the clinicopathological parameter and confirmed that high expressions of ANG2 correlated highly with the axillary lymph node metastases, histological grade, positive PR status, and age, and Tie-2 expression correlated significantly with the p53 status. Moreover, ANG2 and Tie-2 co-expression correlated significantly with the axillary lymph node metastases, compared with ANG2(-)/Tie-2 (-) and ANG2 (+)/Tie-2 (-) or ANG2 (-)/Tie-2 (+) cases. CONCLUSION: These findings suggested that ANG2 and Tie-2 might be involved in the progression of invasive ductal carcinomas through autocrine and paracrine signaling and that it may be clinically useful in selecting patients who could benefit from adjuvant treatment by further study.
Angiogenesis Inducing Agents ; Angiopoietin-2* ; Biopsy ; Breast Neoplasms* ; Breast* ; Carcinoma, Ductal ; Cell Line ; Humans ; Immunohistochemistry ; Lymph Nodes ; Neoplasm Metastasis ; Paracrine Communication ; RNA ; RNA, Messenger ; Vascular Endothelial Growth Factor A

Linear growth occurs at the growth plate. Therefore, genetic defects that interfere with the normal function of the growth plate can cause linear growth disorders. Many genetic causes of growth disorders have already been identified in humans. However, recent genome-wide approaches have broadened our knowledge of the mechanisms of linear growth, not only providing novel monogenic causes of growth disorders but also revealing single nucleotide polymorphisms in genes that affect height in the general population. The genes identified as causative of linear growth disorders are heterogeneous, playing a role in various growth-regulating mechanisms including those involving the extracellular matrix, intracellular signaling, paracrine signaling, endocrine signaling, and epigenetic regulation. Understanding the underlying genetic defects in linear growth is important for clinicians and researchers in order to provide proper diagnoses, management, and genetic counseling, as well as to develop better treatment approaches for children with growth disorders.
Child ; Diagnosis ; Epigenomics ; Extracellular Matrix ; Genetic Counseling ; Genome-Wide Association Study ; Growth Disorders ; Growth Plate ; Humans ; Paracrine Communication ; Polymorphism, Single Nucleotide

Obesity results in an inflammatory microenvironment in adipose tissue, leading to the deterioration of tissue protective mechanisms. Although recent studies suggested the importance of type 2 immunity in an anti-inflammatory microenvironment in adipose tissue, the regulatory effects of T helper 2 (Th2) cytokines on systemic metabolic regulation are not fully understood. Recently, we identified the roles of the Th2 cytokine (interleukin 4 [IL-4] and IL-13)-induced adipokine, growth differentiation factor 15 (GDF15), in adipose tissue in regulating systemic glucose metabolism via signal transducer and activator of transcription 6 (STAT6) activation. Moreover, we showed that mitochondrial oxidative phosphorylation is required to maintain these macrophage-regulating autocrine and paracrine signaling pathways via Th2 cytokine-induced secretion of GDF15. In this review, we discuss how the type 2 immune response and Th2 cytokines regulate metabolism in adipose tissue. Specifically, we review the systemic regulatory roles of Th2 cytokines in metabolic disease and the role of mitochondria in maintenance of type 2 responses in adipose tissue homeostasis.
Adipokines ; Adipose Tissue ; Cytokines ; Glucose ; Growth Differentiation Factor 15 ; Homeostasis ; Metabolic Diseases ; Metabolism ; Mitochondria ; Obesity ; Oxidative Phosphorylation ; Paracrine Communication ; STAT6 Transcription Factor

Serglycin belongs to a family of small proteoglycans with Ser-Gly dipeptide repeats, and it is modified with different types of glycosaminoglycan side chains. Intracellular serglycin affects the retention and secretion of proteases, chemokines, or other cytokines by physically binding to these factors in secretory granules. Extracellular serglycin has been found to be released by several types of human cancer cells, and it is able to promote the metastasis of nasopharyngeal carcinoma cells. Serglycin can bind to CD44, which is another glycoprotein located in cellular membrane. Serglycin's function of promoting cancer cell metastasis depends on glycosylation of its core protein, which can be achieved by autocrine as well as paracrine secretion mechanisms. Further investigations are warranted to elucidate serglycin signaling mechanisms with the goal of targeting them to prevent cancer cell metastasis.
Autocrine Communication ; Glycosylation ; Hematologic Neoplasms ; metabolism ; pathology ; Humans ; Hyaluronan Receptors ; metabolism ; Nasopharyngeal Neoplasms ; metabolism ; pathology ; Neoplasm Metastasis ; Paracrine Communication ; Protein Binding ; Proteoglycans ; biosynthesis ; physiology ; secretion ; RNA, Messenger ; metabolism ; Vesicular Transport Proteins ; biosynthesis ; physiology ; secretion

Platelet-derived growth factors (PDGFs) and their receptors were identified and purified decades ago. PDGFs are important during normal development and in human cancers. In particular, autocrine PDGF signaling has been implicated in various types of malignancies such as gliomas and leukemia. In contrast, paracrine signaling was found in cancers that originate from epithelial cells, where it may be involved in stromal cell recruitment, metastasis, and epithelial-mesenchymal transition. This editorial briefly discusses autocrine and paracrine PDGF signaling and their roles in human cancers, and introduces a series of review articles in this issue that address the possible roles of PDGFs in various processes involved in different types of cancers.
Animals ; Autocrine Communication ; Epithelial-Mesenchymal Transition ; Humans ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Neoplasms ; pathology ; physiopathology ; Paracrine Communication ; Platelet-Derived Growth Factor ; genetics ; metabolism ; physiology ; Receptors, Platelet-Derived Growth Factor ; genetics ; metabolism ; physiology

BACKGROUND AND OBJECTIVES: An increase in intracellular calcium concentration due to loss of Ca2+ homeostasis triggers arrhythmia or cardiac cell death in the heart. Paracrine factors released from stem cells have beneficial cardioprotective effects. However, the mechanism of modulation of Ca2+ homeostasis by paracrine factors in ischemic myocardium remains unclear. MATERIALS AND METHODS: We isolated rat bone marrow-derived mesenchymal stem cells (MSCs), and prepared paracrine media (PM) from MSCs under hypoxic or normoxic conditions (hypoxic PM and normoxic PM). We induced rat myocardial infarction by left anterior descending ligation for 1 hour, and treated PM into the border region of infarcted myocardium (n=6/group) to identify the alteration in calcium-regulated proteins. We isolated and stained the heart tissue with specific calcium-related antibodies after 11 days. RESULTS: The hypoxic PM treatment increased Ca2+-related proteins such as L-type Ca2+ channel, sarcoplasmic reticulum Ca2+ ATPase, Na+/K+ ATPase, and calmodulin, whereas the normoxic PM treatment increased those proteins only slightly. The sodium-calcium exchanger was significantly reduced by hypoxic PM treatment, compared to moderate suppression by the normoxic PM treatment. CONCLUSION: Our results suggest that hypoxic PM was significantly associated with the positive regulation of Ca2+ homeostasis in infarcted myocardium.
Adenosine Triphosphatases ; Animals ; Antibodies ; Arrhythmias, Cardiac ; Calcium ; Calcium-Transporting ATPases ; Calmodulin ; Cell Death ; Heart ; Homeostasis ; Ligation ; Mesenchymal Stromal Cells ; Myocardial Infarction ; Myocardium* ; Paracrine Communication ; Rats* ; Sarcoplasmic Reticulum ; Sodium-Calcium Exchanger ; Stem Cells

A better understanding of the underlying mechanisms by which signals from the fetus initiate human parturition is required. Our recent findings support the core hypothesis that oxidative stress (OS) and cellular senescence of the fetal membranes (amnion and chorion) trigger human parturition. Fetal membrane cell senescence at term is a natural physiological response to OS that occurs as a result of increased metabolic demands by the maturing fetus. Fetal membrane senescence is affected by the activation of the p38 mitogen activated kinase-mediated pathway. Similarly, various risk factors of preterm labor and premature rupture of the membranes also cause OS-induced senescence. Data suggest that fetal cell senescence causes inflammatory senescence-associated secretory phenotype (SASP) release. Besides SASP, high mobility group box 1 and cell-free fetal telomere fragments translocate from the nucleus to the cytosol in senescent cells, where they represent damage-associated molecular pattern markers (DAMPs). In fetal membranes, both SASPs and DAMPs augment fetal cell senescence and an associated ‘sterile’ inflammatory reaction. In senescent cells, DAMPs are encapsulated in extracellular vesicles, specifically exosomes, which are 30–150 nm particles, and propagated to distant sites. Exosomes traffic from the fetus to the maternal side and cause labor-associated inflammatory changes in maternal uterine tissues. Thus, fetal membrane senescence and the inflammation generated from this process functions as a paracrine signaling system during parturition. A better understanding of the premature activation of these signals can provide insights into the mechanisms by which fetal signals initiate preterm parturition.
Aging ; Cell Aging ; Cytosol ; Exosomes ; Extracellular Vesicles ; Extraembryonic Membranes ; Female ; Fetus ; Humans ; Inflammation ; Membranes ; Obstetric Labor, Premature ; Oxidative Stress ; Paracrine Communication ; Parturition ; Phenotype ; Pregnancy ; Premature Birth ; Risk Factors ; Rupture ; Telomere

Aberrant activation of hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, Met, is involved in the development and progression of many human cancers. In the cell-based screening assay, (-)epigallocatechin-3-gallate (EGCG) inhibited HGF/SF-Met signaling as indicated by its inhibitory activity on HGF/SF-induced cell scattering and uPA activation (IC50 = 15.8 microg/ml). Further analysis revealed that EGCG at low doses specifically inhibited HGF/SF-induced tyrosine phosphorylation of Met but not epidermal growth factor (EGF)-induced phosphorylation of EGF receptor (EGFR). On the other hand, high-dose EGCG decreased both Met and EGFR proteins. We also found that EGCG did not act on the intracellular portion of Met receptor tyrosine kinase, i.e., it inhibited InlB-dependent activation of Met but not NGF-induced activation of Trk-Met hybrid receptor. This inhibition decreased HGF-induced migration and invasion by parental or HGF/SF-transfected B16F10 melanoma cells in vitro in either a paracrine or autocrine manner. Furthermore, EGCG inhibited the invasion/metastasis of HGF/SF-transfected B16F10 melanoma cells in mice. Our data suggest the possible use of EGCG in human cancers associated with dysregulated paracrine or autocrine HGF/SF-Met signaling.
Animals ; Autocrine Communication/*drug effects ; Catechin/*analogs & derivatives/metabolism/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Female ; *Hepatocyte Growth Factor ; Humans ; Mice ; Mice, Inbred BALB C ; Neoplasms, Experimental/*metabolism/pathology ; Paracrine Communication/*drug effects ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-met/antagonists & inhibitors/metabolism ; Receptors, Growth Factor/antagonists & inhibitors/metabolism ; Signal Transduction