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Myocardial infarction (MI) causes excessive damage to the myocardium, including the epicardium. However, whether pluripotent stem cell‐derived epicardial cells (EPs) can be a therapeutic approach for infarcted hearts remains unclear. Here, the authors report that intramyocardial injection of human embryonic stem cell‐derived EPs (hEPs) at the acute phase of MI ameliorates functional worsening and scar formation in mouse hearts, concomitantly with enhanced cardiomyocyte survival, angiogenesis, and lymphangiogenesis. Mechanistically, hEPs suppress MI‐induced infiltration and cytokine‐release of inflammatory cells and promote reparative macrophage polarization. These effects are blocked by a type I interferon (IFN‐I) receptor agonist RO8191. Moreover, intelectin 1 (ITLN1), abundantly secreted by hEPs, interacts with IFN‐β and mimics the effects of hEP‐conditioned medium in suppression of IFN‐β‐stimulated responses in macrophages and promotion of reparative macrophage polarization, whereas ITLN1 downregulation in hEPs cancels beneficial effects of hEPs in anti‐inflammation, IFN‐I response inhibition, and cardiac repair. Further, similar beneficial effects of hEPs are observed in a clinically relevant porcine model of reperfused MI, with no increases in the risk of hepatic, renal, and cardiac toxicity. Collectively, this study reveals hEPs as an inflammatory modulator in promoting infarct healing via a paracrine mechanism and provides a new therapeutic approach for infarcted hearts. [ABSTRACT FROM AUTHOR]

Summary: This study evaluated the effect of fibroblast growth factor-2 (FGF-2) on the morphology, primordial follicle activation and growth after in vitro culture of domestic cat ovarian tissue. Ovaries (n = 12) from prepubertal domestic cats were collected and fragmented. One fragment was fixed for histological analysis (fresh control). The remaining fragments were incubated in control medium alone or with 10, 50 or 100 ng/ml FGF-2 for 7 days. After in vitro culture, the following endpoints were analyzed: morphology, activation by counting primordial and developing follicles, and growth (follicle and oocyte diameters). Treatment with 100 ng/ml FGF-2 maintained (P > 0.05) the percentage of normal follicles similar to fresh control. Follicle survival was greater (P < 0.05) after culture in 100 ng/ml FGF-2 than in 50 ng/ml FGF-2. The percentage of primordial follicles decreased (P < 0.05) and the percentage of developing follicles increased (P < 0.05) in all treatments compared with fresh tissue. The proportion of developing follicles increased (P < 0.05) in tissues incubated with 100 ng/ml FGF-2 compared with control medium and other FGF-2 concentrations. Furthermore, culture in 10 or 100 ng/ml FGF-2 resulted in increased (P < 0.05) follicle and oocyte diameters compared with fresh tissues and MEM+. In conclusion, FGF-2 at 100 ng/ml maintains follicle survival and promotes the in vitro activation and growth of cat primordial follicles. [ABSTRACT FROM AUTHOR]

Melasma is a pigmentation disorder characterized by common clinical findings. However, the pathogenic mechanisms involved are heterogeneous in different individuals and ethnic groups. We have reviewed the pathophysiological mechanisms involved in melasma. Although the pathogenesis has not entirely been elucidated thus far, new findings are being identified by research groups. Epidemiologic studies may provide clues on the involvement of genetic factor(s), UV irradiation, or hormones in melasma. Some of the mechanisms of altered skin pigmentation, such as UV-induced pigmentation, may also be applicable to the pathogenesis of melasma. In fact, an increase in similar keratinocyte-derived melanogenic factors and their receptors occur in both UV-induced melanogenesis and melasma. Increased expression of female sex hormone receptors and the identification of the PDZ domain containing 1 (PDZK1) signaling mechanism provide insights to further our understanding of melasma. In addition to keratinocyte-derived paracrine factors, the role of paracrine factors from dermal fibroblasts, such as stem cell factor (SCF) and Wnt inhibitory factor-1 (WIF-1), is elucidated in melasma. Furthermore, the involvement of ion exchangers and microRNAs (miRNAs), such as H19 miRNA (miR-675), are also suggested.

Des-γ-carboxy prothrombin (DCP) is a prothrombin precursor produced in hepatocellular carcinoma (HCC). Because of deficiency of vitamin K or γ-glutamyl carboxylase in HCC cells, the 10 glutamic acid (Glu) residues in prothrombin precursor did not completely carboxylate to γ-carboxylated glutamic acid (Gla) residues, leaving some Glu residues remained in N-terminal domain. These prothrombin precursors with Glu residues are called DCPs. DCP displays insufficient coagulation activity. Since Liebman reported an elevated plasma DCP in patients with HCC, DCP has been used in the diagnosis of HCC. Recently, its biological malignant potential has been specified to describe DCP as an autologous growth factor to stimulate HCC growth and a paracrine factor to integrate HCC with vascular endothelial cells. DCP was found to stimulate HCC growth through activation of the DCP-Met-JAK1-STAT3 signaling pathway. DCP might increase HCC invasion and metastasis through activation of matrix metalloproteinase (MMPs) and the ERK1/2 MAPK signaling pathway. DCP has also been found to play a crucial role in the formation of angiogenesis. DCP could increase the angiogenic factors released from HCC and vascular endothelial cells. These effects of DCP in angiogenesis might be related to activation of the DCP-KDR-PLC-γ-MAPK signaling pathway. In this article, we summarized recent studies on DCP in biological roles related to cancer progression and angiogenesis in HCC.

Paracrine factors, including growth factors and cytokines, released from cardiac myocytes following β-adrenergic receptor (β-AR) stimulation regulate cardiac fibroblasts. Activated cardiac fibroblasts have the ability to increase collagen synthesis, cell proliferation and myofibroblast differentiation, leading to cardiac fibrosis. However, it is unknown which β-AR subtypes and signaling pathways mediate the upregulation of paracrine factors in cardiac myocytes. In this study, we demonstrated that sustained stimulation of β-ARs significantly induced synthesis and secretion of growth factors, including connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF), via the cAMP-dependent and protein kinase A (PKA)-dependent pathways. In addition, isoproterenol (ISO)-mediated synthesis and secretion of CTGF and VEGF through the β 1 -AR and β 2 -AR subtypes. Paracrine factors released by cardiac myocytes following sustained β-AR stimulation are necessary for the induction of cell proliferation and synthesis of collagen I, collagen III and α-smooth muscle actin (α-SMA) in cardiac fibroblasts, confirming that β-AR overstimulation of cardiac myocytes induces cardiac fibrosis by releasing several paracrine factors. These effects can be antagonized by β-blockers, including atenolol, metoprolol, and propranolol. Thus, the use of β-blockers may have beneficial effects on the treatment of myocardial fibrosis in patients with heart failure. [ABSTRACT FROM AUTHOR]

Recent evidence has indicated that overweight/obese children may experience cognitive and immune dysfunction, but the underlying mechanisms responsible for the association between overweight/obesity, immune dysfunction, and cognition have yet to be established. The present study aimed to identify a novel link between obesity-induced immune system dysregulation and cognition in preadolescent children. A total of 27 male children (age: 8–10 years) were recruited and separated by body mass index (BMI) into healthy weight (HW: 5th–84.9th percentile, n = 16) and overweight/obese (OW: ⩾85th percentile, n = 11) groups. Adiposity was assessed using dual energy X-ray absorptiometry (DXA), and aspects of executive function were assessed using the Woodcock-Johnson III Tests of Cognitive Abilities. Monocyte populations (CD14 + CD16 − , CD14 + CD16 + ) with and without expression of chemokine receptor type 2 (CCR2), and circulating progenitor cells (CPCs: CD34 + CD45 dim ), in peripheral blood were quantified by flow cytometry. CPCs were isolated by flow sorting and cultured for 24 h for collection of conditioned media (CM) that was applied to SH-SY5Y neuroblastomas to examine the paracrine effects of CPCs on neurogenesis. OW had significantly higher quantities of both populations of monocytes (CD14 + CD16 − : 57% increase; CD14 + CD16 + : 95% increase, both p < 0.01), monocytes expressing CCR2 (CD14 + CD16 − CCR2 + : 66% increase; CD14 + CD16 + CCR2 + : 168% increase, both p < 0.01), and CPCs (47% increase, p < 0.05) than HW. CPCs were positively correlated with abdominal adiposity in OW, and negatively correlated in HW with a significant difference between correlations (p < 0.05). CPC content was positively correlated with executive processes in OW, and negatively correlated in HW with a significant difference in the strength of the correlations between groups (p < 0.05 for correlation between OW and HW). Finally, CPC-CM from OW trended to increase neuroblast viability in vitro relative to HW (1.79 fold, p = 0.07). These novel findings indicate that increased content of CPCs among OW children may play a role in preventing decrements in cognitive function via paracrine mechanisms. [ABSTRACT FROM AUTHOR]

Stem cell therapies for atherosclerotic diseases are promising, but benefits remain modest with present cell delivery devices in part due to cell washout and immune attack. Many stem cell effects are believed mediated by paracrine factors (PFs) secreted by the stem cells which potentiate tissue repair via activation and enhancement of intrinsic host repair mechanisms We therefore sought to create an “intravascular paracrine factor factory” by harnessing stem cells on a stent using a nanofiber (NF) stent sleeve, and thus providing a sheltered milieu for cells to continuously produce PFs on-stent. The NF sleeve acts as a substrate on which stem cells grow, and as a semi-permeable barrier that protects cells from washout and host immune response while allowing free outward passage of PFs. NF stent sleeves were created by covering stents with electrospun poly-lactic-co-glycolic acid nanofibers and were then uniformly coated with mesenchymal stem cells (MSCs). NF sleeves blocked cell passage but did not hamper MSC attachment or proliferation, and did not alter MSC morphology or surface markers. NF sleeve MSCs continued to secrete PFs that were biologically active and successfully induced tubulogenesis in human endothelial cells. NF stent sleeves seeded with allogeneic MSCs implanted in pigs remained patent at 7 days without thrombotic occlusion or immune rejection. Our results demonstrate the feasibility of creating an intravascular PF factory using a stem cell impregnated NF stent sleeve, and pave the way for animal studies to assess the efficacy of local PF production to treat ischemic artery disease. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) in tumors have emerged as progenitors involved in stroma formation and metastasis of cancers, partially owing to their abilities to differentially express paracrine factors related to the proliferation and invasion of cancer cells. In this regard, increasing evidence has shown that MSCs have impacts on the malignancy of colon cancer, however, the underpinning mechanisms by which MSCs promote cancer metastasis remain elusive. Methods: To investigate the crosstalk between adipose-derived MSCs (AMSCs) isolated from adipose tissues and colon cancer cells, a co-culture transwell model of AMSCs and colon cancer cells was employed, and the activation of Wnt signaling and paracrine factors in colon cancer cells and AMSCs were measured. Results: The results showed that AMSCs could enhance the metastatic capacity of colon cancer cells with an elevated expression of mesenchymal-epithelial transition (EMT)-associated genes in a contact-dependent manner. Reciprocally, colon cancer cells were able to induce AMSCs to produce metastasis-related factors and cytokines, such as FGF10, VEGFC and matrix metalloproteinases (MMPs) in part through a mechanism of an activation of Wnt signaling, by which these factors in turn activate Wnt signaling of colon cancer cells. Intriguingly, an inhibition of Wnt signaling leads a reduced capacity of invasion and colony formation of colon cancer cells in vitro, and the tumorigenicity of cancer cells in a murine model. Conclusions: These findings thus suggest that the crosstalk between the Wnt signaling of cancer cells and paracrine factors of AMSCs has an implication in colon cancer malignancy. This study thus uncovers a novel Wnt-paracrine factors mediated-crosstalk between colon cancer cells and AMSCs in cancer malignancy. [ABSTRACT FROM AUTHOR]

Melasma is a pigmentation disorder characterized by common clinical findings. However, the pathogenic mechanisms involved are heterogeneous in different individuals and ethnic groups. We have reviewed the pathophysiological mechanisms involved in melasma. Although the pathogenesis has not entirely been elucidated thus far, new findings are being identified by research groups. Epidemiologic studies may provide clues on the involvement of genetic factor(s), UV irradiation, or hormones in melasma. Some of the mechanisms of altered skin pigmentation, such as UV-induced pigmentation, may also be applicable to the pathogenesis of melasma. In fact, an increase in similar keratinocyte-derived melanogenic factors and their receptors occur in both UV-induced melanogenesis and melasma. Increased expression of female sex hormone receptors and the identification of the PDZ domain containing 1 (PDZK1) signaling mechanism provide insights to further our understanding of melasma. In addition to keratinocyte-derived paracrine factors, the role of paracrine factors from dermal fibroblasts, such as stem cell factor (SCF) and Wnt inhibitory factor-1 (WIF-1), is elucidated in melasma. Furthermore, the involvement of ion exchangers and microRNAs (miRNAs), such as H19 miRNA (miR-675), are also suggested. [ABSTRACT FROM AUTHOR]

The therapeutic effects of stem cell transplantation in ischemic disease are mediated by the production of paracrine bioactive factors. However, the bioactive factors secreted by human mesenchymal stem cells (hMSCs) and their angiogenic activity are not clearly identified or determined. We here found that hMSC-derived conditioned media (hMSC-CdM) stimulated in vitro angiogenic activity of endothelial cells and contained significant levels of various growth factors and cytokines, such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and transforming growth factor-beta1 (TGF-β1). The angiogenic activity of hMSC-CdM was significantly inhibited by pretreatment with neutralizing antibodies against VEGF, MCP-1, and IL-6, but not against TGF-β1 and HGF. A mixture of those inhibitory antibodies blocked CdM-mediated activation of angiogenic signals, as well as inhibited CdM-mediated in vivo angiogenesis. Moreover, local injection of CdM increased angiogenesis and promoted blood flow in mice with hindlimb ischemia, and these effects were inhibited by co-treatment with these inhibitory antibodies. These results indicate that hMSC-CdM represents a promising cell-free therapeutic strategy for neovascularization in ischemic diseases. These results suggest the combination of VEGF, MCP-1, and IL-6 as a commercial application for therapeutic angiogenesis. [ABSTRACT FROM AUTHOR]

Adenosine, endogenous purine nucleoside, is an ATP metabolite that also acts as an extracellular signaling molecule. The concentration of extracellular adenosine rises during hypoxia and cell damage leading to numerous pleiotropic effects. Although it has been shown that local adenosine concentrations are significantly increased during burn injury their effects at the site of the damage remain poorly investigated. Circulating myeloid cells express surface specific adenosine receptors and during burn injury they migrate to the damaged site. We have shown that during stimulation of the myeloid cells adenosine receptors for 72 h an alternative antigenic phenotype developed, which differed from that of (adenosine) unstimulated cells: the expression of the monocyte marker CD14 was preserved with already expressed dendritic cell markers (CD209, CD1a). These cells had also higher levels of mRNA expression of proinflammatory cytokines and chemoattractants (IL-6, IL-8, IL-1β). Being injected into the site of the burn injury the adenosine modified myeloid cells increased the bulk density of the mixed cellular infiltrate (granulocytes, monocytes, fibroblasts) by day 7. Thus, we have found that one of the effects of adenosine at the site of burn injury consists in increased migration of granulocytes and monocytes in response to the increased production of paracrine factors by myeloid cells. [ABSTRACT FROM AUTHOR]

Des-γ-carboxy prothrombin (DCP) is a prothrombin precursor produced in hepatocellular carcinoma (HCC). Because of deficiency of vitamin K or γ-glutamyl carboxylase in HCC cells, the 10 glutamic acid (Glu) residues in prothrombin precursor did not completely carboxylate to γ-carboxylated glutamic acid (Gla) residues, leaving some Glu residues remained in N-terminal domain. These prothrombin precursors with Glu residues are called DCPs. DCP displays insufficient coagulation activity. Since Liebman reported an elevated plasma DCP in patients with HCC, DCP has been used in the diagnosis of HCC. Recently, its biological malignant potential has been specified to describe DCP as an autologous growth factor to stimulate HCC growth and a paracrine factor to integrate HCC with vascular endothelial cells. DCP was found to stimulate HCC growth through activation of the DCP-Met-JAK1-STAT3 signaling pathway. DCP might increase HCC invasion and metastasis through activation of matrix metalloproteinase (MMPs) and the ERK1/2 MAPK signaling pathway. DCP has also been found to play a crucial role in the formation of angiogenesis. DCP could increase the angiogenic factors released from HCC and vascular endothelial cells. These effects of DCP in angiogenesis might be related to activation of the DCP-KDR-PLC-γ-MAPK signaling pathway. In this article, we summarized recent studies on DCP in biological roles related to cancer progression and angiogenesis in HCC. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Aim: Intra-myocardial injection of adult bone marrow-derived stem cells (MSC) has recently been proposed as a therapy to repair damaged cardiomyocytes after acute myocardial infarction (AMI). PGI2 has vasodilatation effects; however, the effects of combining both MSC and PGI2 therapy on AMI have never been evaluated. Main methods: We genetically enhanced prostaglandin I synthase (PGIS) gene expression in mouse mesenchymal stem cells (MSC) using lentiviral vector transduction (MSCPGIS). Mice were subjected to an AMI model and injected (intra-myocardially) with either 5×104 MSCs or MSCPGIS before surgery. Fourteen days post AMI, mice were analyzed with echocardiography, immunohistochemistry, and apoptotic, and traditional tissue assays. Key findings: Lenti-PGIS transduction did not change any characteristic of the MSCs. PGIS over-expressed MSCs secreted 6-keto-PGF1α in the culture medium and decreased free radical damage during hypoxia/re-oxygenation and H2O2 treatment. Furthermore, splenocyte proliferation was significantly suppressed with MSCPGIS as compared with MSCs alone. Fourteen days post AMI, echocardiography showed more improvement in cardiac function of the MSCPGIS group than the MSC alone group, sham-operated group, or artery ligation only group. The histology of MSCPGIS treated hearts revealed MSCs in the infarcted region and decreased myocardial fibrosis/apoptosis with limited cardiac remodeling. Furthermore, the level of the vascular endothelial growth factor was elevated in the MSCPGIS group as compared to the other three groups. Significance: In summary, our results provide both in vitro and in vivo evidence for the beneficial role of MSCPGIS in limiting the process of detrimental cardiac remodeling in a mouse AMI model during early stages of the disease. [Copyright &y& Elsevier]

Exposure to solar ultraviolet radiation (UV) is the main etiological factor for skin cancer, including melanoma. Cutaneous pigmentation, particularly eumelanin, afforded by melanocytes is the main photoprotective mechanism, as it prevents UV-induced DNA damage in the epidermis. Therefore, maintaining genomic stability of melanocytes is crucial for prevention of melanoma, as well as keratinocyte-derived basal and squamous cell carcinoma. A critical independent factor for preventing melanoma is DNA repair capacity. The response of melanocytes to UV is mediated mainly by a network of paracrine factors that not only activate melanogenesis, but also DNA repair, anti-oxidant, and survival pathways that are pivotal for maintenance of genomic stability and prevention of malignant transformation or apoptosis. However, little is known about the stress response of melanocytes to UV and the regulation of DNA repair pathways in melanocytes. Unraveling these mechanisms might lead to strategies to prevent melanoma, as well as non-melanoma skin cancer. [ABSTRACT FROM AUTHOR]

Abstract: Stem cell-based therapy is emerging as a novel approach for myocardial repair over conventional cardiovascular therapies. In addition to embryonic stem cells and adult stem cells from noncardiac sources, there is a small population of resident stem cells in the heart from which new cardiac cells (myocytes, vascular endothelial cells and smooth muscle cells) can be derived and used for cardiac repair in case of heart injury. It has been proposed that the clinical benefit of stem cells may arise from secreted proteins that mediate regeneration in a paracrine/autocrine manner. To be able to track the regulatory pathway on a molecular basis, utilization of proteomics in stem cell research is essential. Proteomics offers a tool that can address questions regarding stem cell response to disease/injury. [Copyright &y& Elsevier]

Abstract: For myocardial regeneration therapy, the low differentiation capability of functional cardiomyocytes sufficient to replace the damaged myocardial tissue is one of the major difficulties. Using Nkx2.5-GFP knock-in ES cells, we show a new efficient method to obtain cardiomyocytes from embryonic stem (ES) cells. The proportion of GFP-positive cells was significantly increased when ES cells were cultured with a conditioned medium from aortic endothelial cells (ECs), accompanied by upregulation of cardiac-specific genes as well as other mesodermal genes. The promotion was more prominent when EC-conditioned medium was added at an early stage of ES cell differentiation culture (Day 0–3). Inhibitors of bone morphogenic protein (BMP), cyclooxygenase (COX), and nitric oxide synthetase (NO) prevented the promotion of cardiomyogenesis by EC-conditioned medium. These results suggest that supplementation of EC-conditioned medium enables cardiomyocytes to be obtained efficiently through promotion of mesoderm induction, which is regulated by BMP, COX, and NOS. [Copyright &y& Elsevier]

Abstract Background Bone morphogenetic proteins (BMPs) were first described for their roles in bone formation, but they now also are known to possess additional activities, including those relating to embryogenesis. The objectives of this work were to 1) determine if peri-attachment bovine conceptuses and bovine trophoblast cells (CT1) contain transcripts for BMP2 and 4, an innate inhibitor noggin (NOG), and BMP2/4 receptors (BMPRII, ACVR1, BMPR1A, BMPR1B), and 2) determine if BMP2 or 4 supplementation to CT1 cells affects cell proliferation, differentiation or trophoblast-specific gene expression. Methods RNA was isolated from day 17 bovine conceptuses and CT1 cells. After RT-PCR, amplified products were cloned and sequenced. In other studies CT1 cells were treated with BMP2 or 4 at various concentrations and effects on cell viability, cell differentiation and abundance of IFNT and CSH1 mRNA were evaluated. Results Transcripts for BMP2 and 4 were detected in bovine conceptuses and CT1 cells. Also, transcripts for each BMP receptor were detected in conceptuses and CT1 cells. Transcripts for NOG were detected in conceptuses but not CT1 cells. Cell proliferation was reduced by BMP4 but not BMP2 supplementation. Both factors reduced IFNT mRNA abundance but had no effect on CSH1 mRNA abundance in CT1 cells. Conclusions The BMP2/4 ligand and receptor system presides within bovine trophectoderm prior to uterine attachment. BMP4 negatively impacts CT1 cell growth and both BMPs affect IFNT mRNA abundance.

We have developed a co-culture system to study paracrine effects of fetal mesenchyme cells on the growth of primary mammary epithelial cells of the mouse. The method should be adaptable for study of interaction of a variety of cell populations. The procedure is simple and inexpensive. The culture consists of four layers: a monolayer of mesenchyme cells on a plastic culture dish, a soft agarose layer overlaying the cell monolayer, epithelial cells suspended in collagen gel placed atop the agarose, and culture medium above the collagen gel. The agarose layer prevents direct contact of two different cell populations but allows soluble molecules produced by either cell population to diffuse through the system, so as to contact and interact with the other cell population. [ABSTRACT FROM AUTHOR]

Cell-based regenerative therapies involving stem or progenitor cells are considered as possible therapeutic modalities to treat non-communicable and degenerative diseases. Recently, regenerative outcomes of cell-based therapies have been linked to paracrine factors and extracellular vesicles [EVs] released by the transplanted cells rather than the transplanted cells themselves. EVs contain a cargo that includes microRNAs [miRNAs], mRNAs, as well as proteins. Their role in mediating intercellular communication has been acknowledged in several studies. However, the regenerative potential of the miRNAs, mRNAs, and proteins that are present in EVs is a matter of ongoing scientific debate. In this review, we discuss EVs as an alternative to stem cell-based therapy to treat some of the non-communicable and degenerative diseases. Moreover, we also propose that pre-treatment of the cells could help to produce EVs enriched with particular miRNAs, mRNAs, and/or proteins that could support the successful regeneration of a targeted organ., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The heart contains a wide range of cell types, which are not isolated but interact with one another via multifarious paracrine, autocrine and endocrine factors. In terms of cardiac angiogenesis, previous studies have proved that regulating the communication between cardiomyocytes and endothelial cells is efficacious to promote capillary formation. Firstly, this study investigated the effect and underlying mechanism of bioactive glass (BG) acted on vascular endothelial growth factor (VEGF) paracrine signaling in cardiomyocytes. We found that bioactive ions released from BG significantly promoted the VEGF production and secretion of cardiomyocytes. Subsequently, we proved that cardiomyocyte-derived VEGF played an important role in mediating the behavior of endothelial cells. Further research showed that the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/hypoxia-inducible factor 1α (HIF-1α) signaling pathway was upregulated by BG, which was involved in VEGF expression of cardiomyocytes. This study revealed that by means of modulating cellular crosstalk via paracrine signaling of host cells in heart is a new direction for the application of BGs in cardiac angiogenesis. • Bioactive glass (BG) activated VEGF paracrine signaling in cardiomyocytes. • BG regulated cardiomyocyte-endothelial cell communication. • BG enhanced PI3K/Akt/HIF-1α signaling pathway in cardiomyocytes. • Silicon in BG presented stimulatory effect on cardiac angiogenesis. [ABSTRACT FROM AUTHOR]

Extracellular matrix (ECM) components play an important role in maintaining skeletal muscle function, but excessive accumulation of ECM components interferes with skeletal muscle regeneration after injury, eventually inducing fibrosis. Increased oxidative stress level caused by dystrophin deficiency is a key factor in fibrosis in Duchenne muscular dystrophy (DMD) patients. Mesenchymal stem cells (MSCs) are considered a promising therapeutic agent for various diseases involving fibrosis. In particular, the paracrine factors secreted by MSCs play an important role in the therapeutic effects of MSCs. In this study, we investigated the effects of MSCs on skeletal muscle fibrosis. In 2–5-month-old mdx mice intravenously injected with 1 × 105 Wharton's jelly (WJ)-derived MSCs (WJ-MSCs), fibrosis intensity and accumulation of calcium/necrotic fibers were significantly decreased. To elucidate the mechanism of this effect, we verified the effect of WJ-MSCs in a hydrogen peroxide-induced fibrosis myotubes model. In addition, we demonstrated that matrix metalloproteinase-1 (MMP-1), a paracrine factor, is critical for this anti-fibrotic effect of WJ-MSCs. These findings demonstrate that WJ-MSCs exert anti-fibrotic effects against skeletal muscle fibrosis, primarily via MMP-1, indicating a novel target for the treatment of muscle diseases, such as DMD. [ABSTRACT FROM AUTHOR]

Background: Whether combined transplantation of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) is more effective than transplantation of a single cell type in the restoration of erectile function is unknown., Aim: To investigate the effect of combined transplantation of MSCs and EPCs on restoration of erectile function in rats with cavernous nerve injury (CNI)., Methods: MSCs were isolated from human bone marrow and EPCs were isolated from human umbilical cord blood. MSCs and EPCs were identified by flow cytometry and in vitro differentiation or immunofluorescence staining. 25 8-week-old male Sprague-Dawley rats were allocated to 1 of 5 groups: sham operation group, bilateral CNI group receiving periprostatic implantation of MSCs plus EPCs, MSCs, EPCs, or phosphate buffered saline (control group). 2 weeks after CNI and treatment, erectile function of rats was measured by electrically stimulating the CN. The penis and major pelvic ganglia were harvested for histologic examinations. RNA and protein levels of neurotrophin factors (vascular endothelial growth factor, nerve growth factor, and brain-derived neurotrophic factor) in mono- or coculture MSCs and EPCs were assessed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively., Outcomes: Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. Histologic examinations of the penis and major pelvic ganglia and RNA and protein levels of neurotrophin factors in MSCs and EPCs were performed., Results: MSCs and EPCs expressed the specified cell markers and exhibited the typical appearance and characteristics. Treatments using MSCs and/or EPCs could increase endothelial and smooth muscle contents of the corpus cavernosum, decrease caspase-3 expression and increase penile neuronal nitric oxide synthase expression, and restore the neural component of the major pelvic ganglia in rats with CNI. Combined transplantation of MSCs and EPCs had a better effect on improving erectile function than single transplantation of MSCs or EPCs. Expression levels of vascular endothelial growth factor and nerve growth factor in coculture MSCs and EPCs were significantly higher than those of primary MSCs or EPCs., Clinical Translation: Combined transplantation of MSCs and EPCs was more effective in restoring erectile function in CNI-related erectile dysfunction models., Strengths and Limitations: The study, for the 1st time, proved that combined transplantation of MSCs and EPCs was more effective in restoring erectile function in rats with CNI. The rat model might not represent the human condition., Conclusion: Combined periprostatic transplantation of MSCs and EPCs could restore erectile function in rats with CNI more effectively. MSCs might restore CN fibers by secreting neurotrophin factors such as vascular endothelial growth factor and nerve growth factor, and EPCs could enhance the paracrine activity of MSCs. Fang J-f, Huang X-n, Han X-y, et al. Combined Transplantation of Mesenchymal Stem Cells and Endothelial Progenitor Cells Restores Cavernous Nerve Injury-Related Erectile Dysfunction. J Sex Med 2018;15:284-295., (Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Stem cell factor (SCF), a ligand of the c-kit receptor, is a critical cytokine, which contributes to cell migration, proliferation, and survival. It has been shown that SCF expression increases after myocardial infarction (MI) and may be involved in cardiac repair. The aim of this study was to determine whether gene transfer of membrane-bound human SCF improves cardiac function in a large animal model of MI., Methods and Results: A transmural MI was created by implanting an embolic coil in the left anterior descending artery in Yorkshire pigs. One week after the MI, the pigs received direct intramyocardial injections of either a recombinant adenovirus encoding for SCF (Ad.SCF, n=9) or β-gal (Ad.β-gal, n=6) into the infarct border area. At 3 months post-MI, ejection fraction increased by 12% relative to baseline after Ad.SCF therapy, whereas it decreased by 4.2% (P=0.004) in pigs treated with Ad.β-gal. Preload-recruitable stroke work was significantly higher in pigs after SCF treatment (Ad.SCF, 55.5±11.6 mm Hg versus Ad.β-gal, 31.6±12.6 mm Hg, P=0.005), indicating enhanced cardiac function. Histological analyses confirmed the recruitment of c-kit(+) cells as well as a reduced degree of apoptosis 1 week after Ad.SCF injection. In addition, increased capillary density compared with pigs treated with Ad.β-gal was found at 3 months and suggests an angiogenic role of SCF., Conclusions: Local overexpression of SCF post-MI induces the recruitment of c-kit(+) cells at the infarct border area acutely. In the chronic stages, SCF gene transfer was associated with improved cardiac function in a preclinical model of ischemic cardiomyopathy., (© 2014 American Heart Association, Inc.)

Adenosine, endogenous purine nucleoside, is an ATP metabolite that also acts as an extracellular signaling molecule. The concentration of extracellular adenosine rises during hypoxia and cell damage leading to numerous pleiotropic effects. Although a high concentration of adenosine was found at burn injury, the effect has not been well elucidated. We have studied human peripheral blood myeloid cell, due to their expression of specific adenosine receptors and capacity to migrate to the site of burn injury. We have shown that myeloid cells after 72 hours of stimulation of adenosine receptors develop altered expression of surface antigens: preserved monocyte's marker CD14 with already expressed dendritic cell markers (CD209, CD1a). Whereas untreated cells have already lost monocyte marker in 72 hours, and express CD1a more abundantly. Adenosine modified myeloid cells express also higher levels of mRNA of proinflammatory cytokines and chemoattractants (IL-6, IL-8, IL-1 b). Using mouse model of the burn injury we have shown, that adenosine modified bone marrow derived myeloid cells injected in the site of the injury promote migration of granulocytes, monocytes, macrophages, and fibroblasts on the 7th day after burn. Thus, stimulation of adenosine receptors alters differentiation and function of myeloid cells. In the site of burn injury adenosine modified myeloid cells augment cell migration due to paracrine factors.