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Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) represents a cluster of metabolic abnormalities. The prevalence of MetS has surged, transforming it into a pressing public health concern that could potentially affect around 20%–25% of the global population. As MetS continues its ascent, diverse interventions, pharmacological, nonpharmacological and combined have been deployed. Yet, a comprehensive remedy that fully eradicates MetS symptoms remains elusive, compounded by the risks of polypharmacy's emergence. Acknowledging the imperative to grasp MetS's intricate pathologies, deeper insights for future research and therapy optimisation become paramount. Conventional treatments often target specific syndrome elements. However, a novel approach emerges in mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) therapy, promising a holistic shift. MSC‐EVs, tiny membranous vesicles secreted by mesenchymal stem cells, have garnered immense attention for their multifaceted bioactivity and regenerative potential. Their ability to modulate inflammation, enhance tissue repair and regulate metabolic pathways has prompted researchers to explore their therapeutic application in MetS. This review primarily aims to provide an overview of how MSC‐EVs therapy can improve metabolic parameters in subjects with MetS disease and also introduce the usefulness of NMR spectroscopy in assessing the efficacy of MSC‐EVs therapy for treating MetS. Significance statement: Given the significant public health implications of MetS, continuous research aiming to empower individuals in managing this condition is crucial. Rigorous investigation into MSC‐EVs therapy as a promising alternative to whole‐cell therapy is underway. Notably, MSC‐EVs treatment has been observed to induce various metabolic alterations in subjects with MetS, such as restoration of significant metabolic pathways and metabolite levels that are affected by MetS. NMR spectroscopy has played a pivotal role in identifying different biomarkers related to MetS and examining the physical characteristics of mesenchymal stem cells (MSCs). This review focuses on presenting the potential of MSC‐EVs in normalising metabolic parameters in MetS and emphasizes the value of NMR spectroscopy in studying intricate pharmacometabolomic aspects related to MSC‐EVs therapy. [ABSTRACT FROM AUTHOR]

Articular cartilage is an avascular tissue with a limited capacity for self-regeneration, leading the tissue to osteoarthritis (OA). Mesenchymal stem cells (MSCs) are promising for cartilage tissue engineering, as they are capable of differentiating into chondrocyte-like cells and secreting a number of active molecules that are important for cartilage extracellular matrix (ECM) synthesis. The aim of this study was to evaluate the potential of easily accessible menstrual blood-derived MSC (MenSC) paracrine factors in stimulating bone marrow MSC (BMMSCs) chondrogenic differentiation and to investigate their role in protecting cartilage from degradation in vitro. MenSCs and BMMSCs chondrogenic differentiation was induced using four different growth factors: TGF-β3, activin A, BMP-2, and IGF-1. The chondrogenic differentiation of BMMSCs was stimulated in co-cultures with MenSCs and cartilage explants co-cultured with MenSCs for 21 days. The chondrogenic capacity of BMMSCs was analyzed by the secretion of four growth factors and cartilage oligomeric matrix protein, as well as the release and synthesis of cartilage ECM proteins, and chondrogenic gene expression in cartilage explants. Our results suggest that MenSCs stimulate chondrogenic response in BMMSCs by secreting activin A and TGF-β3 and may have protective effects on cartilage tissue ECM by decreasing the release of GAGs, most likely through the modulation of activin A related molecular pathway. In conclusion, paracrine factors secreted by MenSCs may turn out to be a promising therapeutical approach for cartilage tissue protection and repair. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells: they have received great attention in the field of regenerative medicine due to their ability to differentiate into different cell types and their ability to secrete a wide range of biologically active molecules that repair and regenerate tissues. Stem cells are usually isolated from bone marrow, adipose tissue, or other adult tissues and can be grown in culture media to generate large numbers of cells. Stem cells are widely used in veterinary medicine: for the treatment of bone diseases, diseases of the respiratory and digestive systems, immune diseases. The therapeutic effect of stem cells is due to the anti-inflammatory and immunomodulatory effects of the cells themselves and their excretory products. In general, the continuous investigation and development of Veterinary key therapies is essential to improve animal health and well-being, promote Translational Medicine, and thereby benefit human health. Mesenchymal stem cells have been studied as a potential treatment for various gastrointestinal diseases in cattle, including inflammatory bowel disease and Colitis. Stem cells can be used to replace damaged or diseased tissue by differentiating between specific cell types required for repair and regeneration. Stem cells can also secrete factors that promote tissue regeneration, which can enhance their therapeutic potential. Diverse alternatives provide an attractive option for the possibility of developing clinical applications of stem cells in veterinary medicine. [ABSTRACT FROM AUTHOR]

Senescence of activated hepatic stellate cells (aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression. Senescent cells often accompanied by a multi‐faceted senescence‐associated secretory phenotype (SASP). Induction of aHSCs senescence by inhibiting SASP may be a potential therapeutic model against hepatic fibrosis. To evaluate the role of atractylenolide III (ATR III) in the development of chemotherapeutic drug‐induced SASPs in hepatic stellate cells. Etoposide‐induced senescent HSC‐LX2 model was established and treated with ATR III at different concentrations (20, 30 and 40 μM). We found that ATR III dose‐dependently enhanced senescence in etoposide‐induced LX2 cells. ATR III dose‐dependently decreased the release and expression of SASP factors (interleukin [IL]‐1α, IL‐1β, IL6 and IL‐8) in senescent cells. ATR III regulated cyclic GMP‐AMP synthase (cGAS)/nuclear factor κ (NF‐κB) signalling to affect SASP expression in senescent cells. The addition of 2'3′ cGAMP counteracted the effect of ATR III. The release of SASP factors in the conditioned medium from senescent cells could affect cell migration, proliferation and contraction through paracrine manner. Our results indicated ATR III could still enter senescence and prevent the production of SASP and its paracrine effects in senescent cells, an effect that may be related to the possible inhibition of cGAS/NF‐κB signalling by ATR III. Our study proves that ATR III may be an effective potential drug against liver fibrosis by promoting aHSC senescence, which can provide a new choice for the future clinical treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

Keratinocytes regulate melanogenesis in a paracrine manner. Previous studies have shown that melatonin can directly inhibit melanin production in the melanocytes. However, it is unclear whether melatonin can also indirectly regulate melanogenesis through the keratinocytes. In this study, we explored the role of melatonin in regulating keratinocyte‐mediated melanogenesis using reconstructed human epidermis (RHE). Melatonin showed an inhibitory effect on melanin synthesis in this model. Furthermore, the conditioned media from melatonin‐treated HaCaT cells downregulated melanogenesis‐related genes, including MITF, TYR, TYRP1, DCT and RAB27A in the pigment MNT1 cells, and decreased levels of phosphorylated ERK, JNK and p38. RNA sequencing further showed that mitochondrial functions and oxidative stress pathway in the MNT1 cells were inhibited by the conditioned medium from melatonin‐treated HaCaT cells. Furthermore, melatonin reduced the secretion of ET‐1 and PTGS2 from HaCaT cells by inhibiting the JAK2/STAT3 signalling pathway. In conclusion, melatonin downregulates the paracrine factors ET‐1 and PTGS2 in the keratinocytes by inhibiting the JAK2/STAT3 pathway, which reduces melanin production in pigment cells. Thus, melatonin has a potential therapeutic effect on skin pigmentation disorders. [ABSTRACT FROM AUTHOR]

Accumulated experimental and clinical evidence supports the development of human allogeneic liver-derived progenitor cells (HALPCs) to treat fibro-inflammatory liver diseases. The aim of the present study was to evaluate their therapeutic effect in a non-alcoholic steatohepatitis (NASH)-STAM mouse model. The immune signaling characteristics of HALPCs were first assessed in vitro. Upon inflammation treatment, HALPCs secreted large amounts of potent bioactive prostaglandin E2 and indoleamine 2,3-dioxygenase, which significantly reduced CD4+ T-lymphocyte proliferation and secretion of proinflammatory cytokines. In vivo, HALPCs were intravenously administered as single or triple shots (of a dose of 12.5 × 106 cells/kg BW) in STAM mice. Transplantation of HALPCs was associated with a significant decrease in the NAFLD activity score at an early stage and in both inflammation and hepatocyte ballooning scores in late-stage NASH. Sirius red staining analyses revealed decreased collagen deposition in the pericentral region at both stages of NASH. Altogether, these findings showed the anti-inflammatory and anti-fibrotic features of HALPCs in an in vivo NASH model, which suggests their potential to reverse the progression of this chronic fibro-inflammatory disease. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a wound-healing process that occurs in response to severe injuries and is hallmarked by the excessive accumulation of extracellular matrix or scar tissues within the liver. Liver fibrosis can be either acute or chronic and is induced by a variety of hepatotoxic causes, including lipid deposition, drugs, viruses, and autoimmune reactions. In advanced fibrosis, liver cirrhosis develops, a condition for which there is no successful therapy other than liver transplantation. Although liver transplantation is still a viable option, numerous limitations limit its application, including a lack of donor organs, immune rejection, and postoperative complications. As a result, there is an immediate need for a different kind of therapeutic approach. Recent research has shown that the administration of mesenchymal stromal cells (MSCs) is an attractive treatment modality for repairing liver injury and enhancing liver regeneration. This is accomplished through the cell migration into liver sites, immunoregulation, hepatogenic differentiation, as well as paracrine mechanisms. MSCs can also release a huge variety of molecules into the extracellular environment. These molecules, which include extracellular vesicles, lipids, free nucleic acids, and soluble proteins, exert crucial roles in repairing damaged tissue. In this review, we summarize the characteristics of MSCs, representative clinical study data, and the potential mechanisms of MSCs-based strategies for attenuating liver cirrhosis. Additionally, we examine the processes that are involved in the MSCs-dependent modulation of the immune milieu in liver cirrhosis. As a result, our findings lend credence to the concept of developing a cell therapy treatment for liver cirrhosis that is premised on MSCs. MSCs can be used as a candidate therapeutic agent to lengthen the survival duration of patients with liver cirrhosis or possibly reverse the condition in the near future. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is among the major triggers of cardiovascular disease, also promoting thrombosis, restenosis, and neoatherosclerosis within the conduit and coronary artery upon the coronary artery bypass graft surgery. To recapitulate the paracrine interactions between arterial and venous endothelial cells (ECs) by cross-addition of the conditioned medium to the respective cell cultures. Conditioned (24 hours) serum-free medium from confluent primary human coronary artery ECs (HCAEC), primary human internal thoracic artery ECs (HITAEC) and primary human saphenous vein ECs (HSaVEC) was added to a confluent monolayer of intact HCAEC, HITAEC, and HSaVEC for another 24 hours. Cellular response has been assessed by reverse transcription-quantitative polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay. Gene expression analysis showed that HITAEC-conditioned medium ameliorated inflammatory response in HCAEC, in contrast to HSaVEC-conditioned medium. In turn, HCAEC-conditioned medium maintained the endothelial phenotype of HITAEC. Further, HCAEC- and HITAEC-conditioned medium stimulated release of pro-angiogenic molecules by intact HCAEC and HSaVEC cultures. HSaVEC-conditioned medium notably reduced the secretion of pro-inflammatory cytokine interleukin-6 in all cell cultures. Conclusions: Paracrine interactions between HITAEC and HCAEC govern their anti-inflammatory status and enhance HCAEC angiogenic potential, partially explaining the higher primary patency of arterial conduits and resistance of coronary artery to thrombosis, restenosis and neoatherosclerosis in the long-term period after total arterial revascularisation. [ABSTRACT FROM AUTHOR]

Although human Cardiac Progenitor Cells (hCPCs) are not retained by host myocardium they still improve cardiac function when injected into ischemic heart. Emerging evidence supports the hypothesis that hCPC beneficial effects are induced by paracrine action on resident cells. Extracellular vesicles (EVs) are an intriguing mechanism of cell communication based on the transport and transfer of peptides, lipids, and nucleic acids that have the potential to modulate signaling pathways, cell growth, migration, and proliferation of recipient cells. We hypothesize that EVs are involved in the paracrine effects elicited by hCPCs and held accountable for the response of the infarcted myocardium to hCPC-based cell therapy. To test this theory, we collected EVs released by hCPCs isolated from healthy myocardium and evaluated the effects they elicited when administered to resident hCPC and cardiac fibroblasts (CFs) isolated from patients with post-ischemic end-stage heart failure. Evidence emerging from our study indicated that hCPC-derived EVs impacted upon proliferation and survival of hCPCs residing in the ischemic heart and regulated the synthesis and deposition of extracellular-matrix by CFs. These findings suggest that beneficial effects exerted by hCPC injection are, at least to some extent, ascribable to the delivery of signals conveyed by EVs. [ABSTRACT FROM AUTHOR]

Organ transplantation is essential and crucial for saving and enhancing the lives of individuals suffering from end-stage organ failure. Major challenges in the medical field include the shortage of organ donors, high rates of organ rejection, and long wait times. To address the current limitations and shortcomings, cellular therapy approaches have been developed using mesenchymal stem/stromal cells (MSC). MSC have been isolated from various sources, have the ability to differentiate to important cell lineages, have anti-inflammatory and immunomodulatory properties, allow immunosuppressive drug minimization, and induce immune tolerance towards the transplanted organ. Additionally, rapid advances in the fields of tissue engineering and regenerative medicine have emerged that focus on either generating new organs and organ sources or maximizing the availability of existing organs. This review gives an overview of the various properties of MSC that have enabled its use as a cellular therapy for organ preservation and transplant. We also highlight emerging fields of tissue engineering and regenerative medicine along with their multiple sub-disciplines, underlining recent advances, widespread clinical applications, and potential impact on the future of tissue and organ transplantation. [ABSTRACT FROM AUTHOR]

The lung is the first and most frequent organ to fail among sepsis patients. The mortality rate of sepsis‐related acute lung injury (ALI) is high. Despite appropriate antimicrobial therapy, no treatment strategies are available for sepsis‐induced ALI. Stem cell‐mediated paracrine signaling is a potential treatment method for various diseases. This study aimed to examine the effects of induced pluripotent stem cell‐derived conditioned medium (iPSC‐CM) combined with antibiotics on ALI in a rat model of Escherichia coli‐induced sepsis. Rats were administered either iPSC‐CM or the vehicle (saline) with antibiotics (ceftriaxone). After 72 h, liquid biopsy, bronchoalveolar lavage fluid (BALF), and tissues were harvested for analysis. Survival rates were observed for up to 3 days. Furthermore, we examined the effects of iPSC‐CM on cytokine production, metalloproteinase 9 (MMP‐9) expression, and NLRP3–ASC interaction in RAW264.7 cells stimulated with lipopolysaccharide/interferon‐γ (LPS/IFN‐γ). Combined treatment of iPSC‐CM with antibiotics significantly improved survival in E. coli‐infected rats (p = 0.0006). iPSC‐CM ameliorated E. coli‐induced infiltration of macrophages, reducing the number of cells in BALF, and suppressing interleukin (IL)‐1β, MIP‐2, IL‐6, and MMP‐9 messenger RNA in lung sections. iPSC‐CM treatment attenuated NLRP3 expression and inhibited NLRP3 inflammasome activation by disrupting NLRP3‐mediated ASC complex formation in LPS/IFN‐γ‐primed RAW264.7 cells. This study reveals the mechanisms underlying iPSC‐CM‐conferred anti‐inflammatory activity in ALI through the attenuation of macrophage recruitment to the lung, thus inactivating NLRP3 inflammasomes in macrophages. iPSC‐CM therapy may be a useful adjuvant treatment to reduce sepsis‐related mortality by ameliorating ALI. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a serious health concern, yet there is a lack of standardized treatment to combat its long-lasting effects. The objective of the present study was to provide an overview of the limitation of conventional stem-cell therapy in the treatment of TBI and to discuss the application of novel acellular therapies and their advanced strategies to enhance the efficacy of stem cells derived therapies in the light of published study data. Moreover, we also discussed the factor to optimize the therapeutic efficiency of stem cell-derived acellular therapy by overcoming the challenges for its clinical translation. Hence, we concluded that acellular therapy possesses the potential to bring a breakthrough in the field of regenerative medicine to treat TBI. Traumatic brain injury (TBI) is a devastating disorder that can lead to lifelong disability. Due to the complexity of TBI, to date, there is no effective and specific treatment available, other than preventive measures or intensive care to minimize the rate of mortality. Though increasingly evident studies have reported the effective role of stem cells therapy to treat TBI. However, direct exposure to stem cells has its limitation. Therefore, this study aimed to present an overview of the challenges associated with commonly used stem-cell therapy and to discuss and establish the ground for novel cell-free therapy in light of previously reported research. We hope this review will help to understand the role of cell-free therapy stem cells in the treatment of head injury and pave the way for the development of future treatments. [ABSTRACT FROM AUTHOR]

Antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as or ciRS-7) is an important member of the circular RNA family and is involved in the regulation of numerous biological functions. Keratinocytes and fibroblasts (FBs) affect melanogenesis through paracrine effects. However, whether ciRS-7 is involved in melanogenesis by regulating paracrine effects remains unclear. This study demonstrates for the first time that ciRS-7 is highly expressed in keratinocytes, FBs, and melanocytes (MCs). Ultraviolet B (UVB) irradiation promotes ciRS-7 expression in keratinocytes and FBs. Following inhibition of ciRS-7 expression in keratinocytes and FBs, the culture supernatant from these cells inhibited melanogenesis of MCs. Further analyses revealed that the expression and secretion of fibroblast growth factor 2 (FGF2) and phosphorylation of STAT3 and AKT in keratinocytes and FBs were significantly downregulated following inhibition of ciRS-7 expression, whereas the level of miR-7 was increased. Overexpression of miR-7 in keratinocytes and FBs significantly inhibited the expression of FGF2. In conclusion, our findings demonstrate that UVB-induced ciRS-7 triggers melanogenesis in MCs through regulation of the miR-7/STAT3 and AKT/FGF2 paracrine axis in both keratinocytes and FBs. ciRS-7 may serve as a regulator in the development of pigmented skin diseases. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) are a subset of heterogeneous non-hematopoietic fibroblast-like cells that can differentiate into cells of multiple lineages, such as chondrocytes, osteoblasts, adipocytes, myoblasts, and others. These multipotent MSCs can be found in nearly all tissues but mostly located in perivascular niches, playing a significant role in tissue repair and regeneration. Additionally, MSCs interact with immune cells both in innate and adaptive immune systems, modulating immune responses and enabling immunosuppression and tolerance induction. Understanding the biology of MSCs and their roles in clinical treatment is crucial for developing MSC-based cellular therapy for a variety of pathological conditions. Here, we review the progress in the study on the mechanisms underlying the immunomodulatory and regenerative effects of MSCs; update the medical translation of MSCs, focusing on the registration trials leading to regulatory approvals; and discuss how to improve therapeutic efficacy and safety of MSC applications for future. [ABSTRACT FROM AUTHOR]

The acute respiratory distress syndrome (ARDS) is a multifaceted lung disorder in which no specific therapeutic intervention is able to effectively improve clinical outcomes. Despite an improved understanding of molecular mechanisms and advances in supportive care strategies, ARDS remains associated with high mortality, and survivors usually face long-term morbidity. In recent years, preclinical studies have provided mounting evidence of the potential of mesenchymal stem cell (MSC)-based therapies in lung diseases and critical illnesses. In several models of ARDS, MSCs have been demonstrated to induce anti-inflammatory and anti-apoptotic effects, improve epithelial and endothelial cell recovery, and enhance microbial and alveolar fluid clearance, thus resulting in improved lung and distal organ function and survival. Early-stage clinical trials have also demonstrated the safety of MSC administration in patients with ARDS, but further, large-scale investigations are required to assess the safety and efficacy profile of these therapies. In this review, we summarize the main mechanisms whereby MSCs have been shown to exert therapeutic effects in experimental ARDS. We also highlight questions that need to be further elucidated and barriers that must be overcome in order to efficiently translate MSC research into clinical practice. [ABSTRACT FROM AUTHOR]

Recent advances in wound healing have made cell therapy a potential approach for the treatment of various types of skin defects such as trauma, burns, scars and diabetic leg ulcers. Cultured keratinocytes have been applied to burn patients since 1981. Patients with acute and chronic wounds can be treated with autologous/allograft cultured keratinocytes. There are various methods for cultivation of epidermal keratinocytes used in cell therapy. One of the important properties of an efficient cell therapy is the preservation of epidermal stem cells. Mesenchymal Stem Cells (MSCs) are major regulatory cells involved in the acceleration of wound healing via induction of cell proliferation, angiogenesis and stimulating the release of paracrine signaling molecules. Considering the beneficial effects of MSCs on wound healing, the main aim of the present study is investigating paracrine effects of Adipose-derived Mesenchymal Stem Cell (Ad-MSCs) on cultivation of keratinocytes with focusing on preservation of stem cells and their differentiation process. We further introduced a new approach for culturing isolated keratinocytes in vitro in order to generate epidermal keratinocyte sheets without using a feeder layer. To do so, Ad-MSC conditioned medium was applied as an alternative to commercial media for keratinocyte cultivation. In this study, the expression of several stem/progenitor cell (P63, K19 and K14) and differentition (K10, IVL and FLG) markers was examined using real time PCR on days 7, 14 and 21 of culture in keratinocytes in Ad-MSC conditioned medium. P63 and α6 integrin expression was also evaluated via flow cytometry. The results were compared with control group including keratinocytes cultured in EpiLife medium and our data indicated that this Ad-MSC conditioned medium is a good alternative for keratinocyte cultivation and producing epidermal sheets for therapeutic and clinical purposes. The reasons are the expression of stem cell and differentiation markers and overcoming the requirement for feeder layer which leads to a xenograft-free transplantation. Besides, this approach has low cost and is easier to perform. However, more in vitro and in vivo experiments as well as safety evaluation required before clinical applications. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a disease that causes high morbidity and has become a major health problem. Liver fibrosis can lead to the end stage of liver diseases (livercirrhosisand hep- atocellularcarcinoma). Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, the shortage of organ donors, high cost of medical surgery, immunological rejection and transplantation complications severely hamper liver transplantation therapy. Mesenchymal stem cells (MSCs) have been regarded as promising cells for clinical applications in stem cell therapy in the treatment of liver diseases due to their unique multipotent differentiation capacity, immunoregulation and paracrine effects. Although liver fibrosis improvements by MSC transplantation in preclinical experiments as well as clinical trials have been reported, the in vivo fate of MSCs after transportation and their therapeutic mechanisms remain unclear. In this present study, we isolated MSCs from the bone marrow of rhesus macaques. The cells exhibited typical MSC markers and could differentiate into chondrocytes, osteocytes, and adipocytes, which were not affected by labeling with enhanced green fluorescent protein (EGFP). The harvested MSCs respond to interferon- stimulation and have the ability to inhibit lymphocyte proliferation in vitro. EGFP-labeled MSCs (1x106 cells) were transplanted into mice with carbon tetrachloride-induced liver fibrosis via tail vein injection. The ability of the heterogenic MSC infusion to ameliorate liver fibrosis in mice was evaluated by a blood plasma chemistry index, pathological examination and liver fibrosis-associated gene expression. Additionally, a small number of MSCs that homed and engrafted in the mouse liver tissues were evaluated by immunofluorescence analysis. Our results showed that the transplantation of heterogenic MSCs derived from monkey bone marrow can be used to treat liver fibrosis in the mouse model and that the paracrine effects of MSCs may play an important role in the improvement of liver fibrosis. [ABSTRACT FROM AUTHOR]

Endothelial-to-mesenchymal transition (EndMT) is a process in which endothelial cells lose polarity and cell-to cell contacts, and undergo a dramatic remodeling of the cytoskeleton. It has been implicated in initiation and progression of pulmonary arterial hypertension (PAH). However, the characteristics of cells which have undergone EndMT cells in vivo have not been reported and so remain unclear. To study this, sugen5416 and hypoxia (SuHx)-induced PAH was established in Cdh5-Cre/Gt(ROSA)26Sortm4(ACTB-tdTomato,EGFP)Luo/J double transgenic mice, in which GFP was stably expressed in pan-endothelial cells. After 3 wk of SuHx, flow cytometry and immunohistochemistry demonstrated CD144-negative and GFP-positive cells (complete EndMT cells) possessed higher proliferative and migratory activity compared with other mesenchymal cells. While CD144-positive and α-smooth muscle actin (α-SMA)-positive cells (partial EndMT cells) continued to express endothelial progenitor cell markers, complete EndMT cells were Sca-1-rich mesenchymal cells with high proliferative and migratory ability. When transferred in fibronectin-coated chamber slides containing smooth muscle media, α-SMA robustly expressed in these cells compared with cEndMT cells that were grown in maintenance media. Demonstrating additional paracrine effects, conditioned medium from isolated complete EndMT cells induced enhanced mesenchymal proliferation and migration and increased angiogenesis compared with conditioned medium from resident mesenchymal cells. Overall, these findings show that EndMT cells could contribute to the pathogenesis of PAH both directly, by transformation into smooth muscle-like cells with higher proliferative and migratory potency, and indirectly, through paracrine effects on vascular intimal and medial proliferation. [ABSTRACT FROM AUTHOR]

For decades, mesenchymal stem (MSCs) cells have been used for cardiovascular diseases as regenerative therapy. This review is an attempt to summarize the types of MSCs involved in myocardial infarction (MI) therapy, as well as its possible mechanisms effects, especially the paracrine one in MI focusing on the studies (human and animal) conducted within the last 10 years. Recently, reports showed that MSC therapy could have infarct-limiting effects after MI in both experimental and clinical trials. In this context, various types of MSCs can help cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Furthermore, MSCs could produce paracrine growth factors that increase the survival of nearby cardiomyocytes, as well as increase angiogenesis through recruitment of stem cell from bone marrow or inducing vessel growth from existing capillaries. Recent research suggests that the paracrine effects of MSCs could be mediated by extracellular vesicles including exosomes. Exosomal microRNAs (miRNAs) released by MSCs are promising therapeutic hotspot target for MI. This could be attributed to the role of miRNA in cardiac biology, including cardiac regeneration, stem cell differentiation, apoptosis, neovascularization, cardiac contractility and cardiac remodeling. Furthermore, gene-modified MSCs could be a recent promising therapy for MI to enhance the paracrine effects of MSCs, including better homing and effective cell targeted tissue regeneration. Although MSC therapy has achieved considerable attention and progress, there are critical challenges that remains to be overcome to achieve the most effective successful cell-based therapy in MI. [ABSTRACT FROM AUTHOR]

Over the past decade, cell therapies have provided promising strategies for the treatment of ischaemic cardiomyopathy. Particularly, the beneficial effects of stem cells, including bone marrow stem cells ( BMSCs), endothelial progenitor cells ( EPCs), mesenchymal stem cells ( MSCs), embryonic stem cells ( ESCs), and induced pluripotent stem cells ( iPSCs), have been demonstrated by substantial preclinical and clinical studies. Nevertheless stem cell therapy is not always safe and effective. Hence, there is an urgent need for alternative sources of cells to promote cardiac regeneration. Human villous trophoblasts ( HVTs) play key roles in embryonic implantation and placentation. In this study, we show that HVTs can promote tube formation of human umbilical vein endothelial cells ( HUVECs) on Matrigel and enhance the resistance of neonatal rat cardiomyocytes ( NRCMs) to oxidative stress in vitro. Delivery of HVTs to ischaemic area of heart preserved cardiac function and reduced fibrosis in a mouse model of acute myocardial infarction ( AMI). Histological analysis revealed that transplantation of HVTs promoted angiogenesis in AMI mouse hearts. In addition, our data indicate that HVTs exert their therapeutic benefit through paracrine mechanisms. Meanwhile, injection of HVTs to mouse hearts did not elicit severe immune response. Taken together, our study demonstrates HVT may be used as a source for cell therapy or a tool to study cell-derived soluble factors for AMI treatment. [ABSTRACT FROM AUTHOR]

Objectives: The receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors are novel clinically effective agents that inhibit osteoclast differentiation, function, and survival by binding to RANKL. Medication-related osteonecrosis of the jaw (MRONJ), caused as a result of treatment using denosumab, is a newly emerging type of bone necrosis, the exact pathogenesis of which is unknown. Several studies recently showed that the intravenous administration of mesenchymal stem cells (MSCs) improved the osteonecrosis of the jaw, and it was hypothesized that paracrine effects by secretomes from MSCs are the main constituent. Our aim was to investigate the effects of serum-free conditioned media from human MSCs (MSC-CM) and RANKL inhibitors on osteoclast differentiation. Materials and methods: Cytokines included in MSC-CM were identified using the cytokine array analysis. MSC-CM was added to the culture medium of rat osteoclast precursors containing RANKL inhibitor. Osteoclast differentiation assays, immunohistochemistry, real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis, and pit formation assays were performed. Results: MSC-CM included various cytokines such as the recruitment of cell osteogenesis angiogenesis and cell proliferation. MSC-CM promoted osteoclast differentiation and expression of master regulatory transcriptional factors for osteoclastogenesis. In addition, MSC-CM showed function maintenance in osteoclasts despite the presence of RANKL inhibitors. Conclusions: Our findings suggest that secretomes in MSC-CM were related to the regulation of osteoclast differentiation, which may reduce the effect of RANKL inhibitors. Clinical relevance: New combinations of drugs using factors included in MSC-CM have effective therapeutic modality for treating patients with MRONJ. [ABSTRACT FROM AUTHOR]

Leydig cell nodular hyperplasia (LCNH) is a lesion that is less characterized than the familiar Leydig cell tumors. The paracrine effects of these lesions on adjacent gonadal stroma have not been widely documented. We present two cases of precocious puberty in pre-pubertal boys found to have a single LCNH with adjacent focal maturation of the seminiferous tubules. Blood tests showed elevated serum testosterone and dehydroepiandrosterone (DHEAS). Ultrasound revealed unilateral testicular enlargement with irregular echogenicity. Radical orchiectomy was performed. Histologically Leydig cell nodular proliferation without destruction of surrounding tubules was seen. Mature seminiferous tubules undergoing spermatogenesis were noted adjacent to the lesion, while away from the lesion seminiferous tubules were as expected in pre-pubescent boys. These cases emphasize the potential presence of both paracrine and endocrine effects in Leydig cell nodular hyperplasia. However, instances of the endocrine effects of hyperplastic Leydig cell lesions are more widely reported than the paracrine effects. [ABSTRACT FROM PUBLISHER]

Possible association between anaplastic large cell lymphoma (ALCL) and breast implants has been suggested. In this context, formation of the periprosthetic capsule has been reported as a cause of inflammation, which plays a key role in tumor onset. Tumors take advantage of inflammation to influence and interfere with the host immune response by secreting multiple factors, and their onset and survival is in turn affected by the paracrine effects from mesenchymal stem cells (MSCs). In this study, we tried to clarify how inflammation can modify the immunobiology and the exerted paracrine effect of MSCs. MSCs derived from both inflamed (I-MSCs) and control (C-MSCs) tissues were isolated and co-cultured with an ALCL cell line. Proliferation rate and the expression of selected cytokines were tested. I-MSCs secrete higher levels of cytokine related to chronic inflammation than C-MSCs. After co-cultures with KI-JK cells, C- and I-MSCs show the same variation in the cytokine expression, with an increase of IL2, IL4, IL5, IL10, IL13, TNF-α, TGF-β, and G-CSF. Proliferation of ALCL cells was not influenced by co-cultures. Our results state that (i) inflamed microenvironment affects the immunobiology of MSCs modifying the profile of the expressed cytokines, and (ii) the paracrine effects exerted by MSCs on ALCL cells are not influenced by inflammation. Moreover, it seems that ALCL cells are able to manipulate MSCs' immunoregulatory properties to evade the host immune control. Nevertheless, this ability is not associated with inflammation and the question about BIA-ALCL is not proved by our experiments. [ABSTRACT FROM AUTHOR]

The regulation of vascular resistance in fishes has largely been studied using isolated large conductance vessels, yet changes in tissue perfusion/vascular resistance are primarily mediated by the dilation/constriction of small arterioles. Thus, we adapted mammalian isolated microvessel techniques for use in fish, and examined how several agents affected the tone/resistance of isolated coronary arterioles (< 150 µm) from steelhead trout (O. mykiss) acclimated to 10, 5 and 1°C. At 10°C, the vessels showed a concentration-dependent dilation to adenosine (ADE; 61 ± 8%), sodium nitroprusside (SNP; 35 ± 10%) and serotonin (SER; 27 ± 2%) (all values maximum responses). A biphasic response (mild contraction then dilation) was observed in vessels exposed to increasing concentrations of epinephrine (EPI; 34 ± 9% dilation) and norepinephrine (NE; 32 ± 7% dilation), whereas the effect was less pronounced with bradykinin (BK; 12.5 ± 3.5% constriction vs. 6 ± 6% dilation). Finally, a mild constriction was observed after exposure to acetylcholine (ACh; 6.5 ± 1.4%), while endothelin (ET)-1 caused a strong dose-dependent increase in tone (79 ± 5% constriction). Acclimation temperature had varying effects on the responsiveness of vessels. The dilations induced by EPI, ADE, SER and SNP were reduced/eliminated at 5°C and/or 1°C as compared to 10°C. In contrast, acclimation to 5 and 1°C increased the maximum constriction induced by ACh and the sensitivity of vessels to ET-1 (but not the maximum response) at 1°C was greater. Acclimation temperature had no effect on the response to NE, and responsiveness to BK was variable. [ABSTRACT FROM AUTHOR]

Adipose-derived stem cells (ADSCs) are known to secrete various cytokines, which affect fibroblast function through paracrine effects. In the present study, the paracrine effects of ADSCs on the function and senescence of young and aged human dermal fibroblasts (HDFs) were investigated in vitro. ADSCs and HDFs were isolated from healthy donors and flow cytometry was used for immunophenotype identification. ADSCs were co-cultured with young or aged human dermal fibroblasts in Transwell plates, and control groups were established accordingly. Cellular proliferation was measured by an MTT assay. Type I collagen, matrix metalloproteinase-1 (MMP-1) and senescence-associated β-galactosidase (SA-β-GAL) mRNA expression were measured by quantitative polymerase chain reaction. It was identified that ADSCs promoted proliferation of co-cultured HDFs and induced increased expression of type I collagen and decreased expression of MMP-1. The co-cultured HDFs exhibited increased expression of SA-β-GAL. These results demonstrated that ADSCs improve fibroblast function through paracrine effects. The increased expression of SA-β-GAL indicated an accelerated aging process. It is proposed that ADSCs may improve fibroblast function, but not reverse the age status in vitro. [ABSTRACT FROM AUTHOR]

Several investigators have cultivated marrow stromal cells and have identified a population of mesenchymal stem cells (MSCs). These cells expand extensively in vitro and exhibit multilineage differentiation potential. The lack of MSC-specific markers impedes identification of MSC functions. Further in vivo studies of these cells may elucidate the nature of MSCs. Although the nature of MSCs remains unclear, nonclonal stromal cultures are used as a source of putative MSCs for therapeutic purposes. Preclinical studies and clinical trials assumed that transplanted MSCs exert their effects through their differentiation properties or through the release of molecules that restore tissue functions and modulate immune cells. These studies reported contradictory results and failed to meet expectations. Thus, it is important to note that current protocols for MSC therapy are primarily based on the use of in vitro expanded nonclonal MSCs. Clearly defining the physiological features of in situ MSCs and the in vitro and in vivo properties of nonclonal cultures of stromal cells, which are often misidentified as pure stem cell cultures, may explain the reported failures of MSC therapy. This review will address these issues. [ABSTRACT FROM AUTHOR]

Many studies in different biological systems have revealed that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) modulates signaling pathways triggered at the plasma membrane by agents such as Wnt, transforming growth factor (TGF)-β, epidermal growth factor (EGF), and others. In addition, 1α,25(OH)2D3 may affect gene expression by paracrine mechanisms that involve the regulation of cytokine or growth factor secretion by neighboring cells. Moreover, post-transcriptional and post-translational effects of 1α,25(OH)2D3 add to or overlap with its classical modulation of gene transcription rate. Together, these findings show that vitamin D receptor (VDR) cannot be considered only as a nuclear-acting, ligand-modulated transcription factor that binds to and controls the transcription of target genes. Instead, available data support the view that much of the complex biological activity of 1α,25(OH)2D3 resides in its capacity to interact with membrane-based signaling pathways and to modulate the expression and secretion of paracrine factors. Therefore, we propose that future research in the vitamin D field should focus on the interplay between 1α,25(OH)2D3 and agents that act at the plasma membrane, and on the analysis of intercellular communication. Global analyses such as RNA-Seq, transcriptomic arrays, and genome-wide ChIP are expected to dissect the interactions at the gene and molecular levels. [ABSTRACT FROM AUTHOR]

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In recent years, a constant growth of knowledge and clinical applications of stem cells have been observed. Mesenchymal stromal cells, also described as mesenchymal stem cells (MSCs) represent a particular cell type for research and therapy because of their ability to differentiate into mesodermal lineage cells. The most investigated source of MSCs is bone marrow (BM). Yet, collection of BM is an invasive procedure associated with significant discomfort to the patient. The procedure results in a relatively low number of these cells, which can decrease with donor´s age. Therefore, it seems to be very important to find other sources of mesenchymal stem cells nowadays. A human placenta, which is routinely discarded postpartum, in spite of its natural aging process, is still a rich source of stem cells capable to proliferate and in vitro differentiate in many directions. Besides homing and differentiation in the area of injury, MSCs there elicit strong paracrine effects stimulating the processes of repair. In this review, we focus on the biology, characteristics and potential clinical applications of cells derived from human fetal membranes: amnion and chorion. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma multiforme (GBM) is a highly invasive brain tumour, characterized by its ability to secrete factors promoting its virulence. Brain endothelial cells (BECs) in the GBM environment are physiologically modulated. The present study investigated the modulatory effects of normoxically and hypoxically induced glioblastoma U-87 cell secretions on BECs. Methods: Conditioned media (CM) were derived by cultivating U-87 cells under hypoxic incubation (5% O2) and normoxic incubation (21% O2). Treated bEnd.3 cells were evaluated for mitochondrial dehydrogenase activity, mitochondrial membrane potential (ΔΨm), ATP production, transendothelial electrical resistance (TEER), and endothelial tight-junction (ETJ) gene expression over 96 h. Results: The coculture of bEnd.3 cells with U-87 cells, or exposure to either hypoxic or normoxic U-87CM, was associated with low cellular viability. The ΔΨm in bEnd.3 cells was hyperpolarized after hypoxic U-87CM treatment (p < 0.0001). However, normoxic U-87CM did not affect the state of ΔΨm. BEC ATP levels were reduced after being cocultured with U-87 cells, or with hypoxic and normoxic CM (p < 0.05). Suppressed mitochondrial activity in bEnd.3 cells was associated with increased transendothelial permeability, while bEnd.3 cells significantly increased the gene expression levels of ETJs (p < 0.05) when treated with U-87CM. Conclusions: Hypoxic and normoxic glioblastoma paracrine factors differentially suppressed mitochondrial activity in BECs, increasing the BECs' barrier permeability. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) can play an active role in the reconstruction of the ocular surface; however, the mechanisms by which the implanted MSCs exert their effects remain elusive. In the present study, we investigated the influences of MSCs on cell proliferation and growth factor expression of corneal limbal epithelial cells (LECs) in vitro. Rat LECs were either cocultured with rat MSCs or cultured in rat MSC-conditioned medium. The harvested LECs were subjected to light microscopy, MTT assay, bromodeoxyuridine (BrdU) staining, flow cytometry and real-time quantitative RT-PCR analysis, respectively. Light microscopy showed that coculturing of LECs with MSCs significantly increased the proliferation of LECs. The MTT assay showed that MSC-conditioned medium significantly increased the cell viability of LECs compared to those incubated with plain medium. BrdU immunostaining and flow-cytometric analysis of the cell cycle showed that the cell proliferation rate of LECs cocultured with MSCs was significantly higher than that of LECs cultured alone. Real-time quantitative RT-PCR analysis showed that expression of epidermal growth factor in LECs cocultured with MSCs was significantly higher than that in LECs cultured alone. However, expression of basic fibroblast growth factor showed no difference under the two culture conditions. These results indicate that MSCs promote the survival and proliferation of LECs, and these effects may be mediated in a paracrine manner. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: Stem cells present a variety of clinical implications in the lungs. According to their origin, these cells can be divided into embryonic and adult stem cells; however, due to the important ethical and safety limitations that are involved in the embryonic stem cell use, most studies have chosen to focus on adult stem cell therapy. This article aims to present and clarify the recent advances in the field of stem cell biology, as well as to highlight the effects of mesenchymal stem cell (MSC) therapy in the context of acute lung injury/acute respiratory distress syndrome and chronic disorders such as lung fibrosis and chronic obstructive pulmonary disease. Methods: For this purpose, we performed a critical review of adult stem cell therapies, covering the main clinical and experimental studies published in Pubmed databases in the past 11 years. Different characteristics were extracted from these articles, such as: the experimental model, strain, cellular type and administration route used as well as the positive or negative effects obtained. Results: There is evidence for beneficial effects of MSC on lung development, repair, and remodeling. The engraftment in the injured lung does not occur easily, but several studies report that paracrine factors can be effective in reducing inflammation and promoting tissue repair. MSC releases several growth factors and anti-inflammatory cytokines that regulate endothelial and epithelial permeability and reduce the severity of inflammation. Conclusion: A better understanding of the mechanisms that control cell division and differentiation, as well as of their paracrine effects, is required to enable the optimal use of bone marrow-derived stem cell therapy to treat human respiratory diseases. [ABSTRACT FROM AUTHOR]

Ischemic heart diseases are the leading cause of death in the Western world. With increasing numbers of patients surviving their acute myocardial infarction owing to effective heart catheter techniques and intensive care treatment, congestive heart failure has become an increasing health concern. With therapeutic options for the prevention and treatment of ischemic heart disease being limited at present, huge efforts have been made in the field of stem cell research to try to establish new approaches for myocardial tissue regeneration. Owing to their pronounced differentiation potential, pluripotent stem cells seem to represent the most promising cell source for future engineering of myocardial replacement tissue. However, several crucial hurdles regarding cell yield and purity of the cultured cardiovascular progenitor cells have still not been overcome to facilitate a clinical application today. By contrast, plenty of adult stem and progenitor cells have already been well characterized and investigated in human disease. However, all of these heterogeneous cell lines primarily seem to work in a paracrine manner on ischemic myocardial tissue, rather than transdifferentiating into contractile cardiomyocytes. This article will focus on the production, application and present limitations of stem cells potentially applicable for myocardial repair. INSET: Key issues. [ABSTRACT FROM AUTHOR]

Background aims. The aim of this study was to evaluate the paracrine effects of canine umbilical cord blood (cUCB) mesenchymal stromal cells (MSC) mixed with β-tricalcium phosphate (β-TCP) on bone regeneration in ectopic implantation. Methods. β-TCP mixed with cUCB MSC (UCB-MSC group), cell lysates (cell lysate group) or a control (control group) were respectively implanted in a subcutaneous pouches in the back of beagle dogs . The implants were harvested 1, 4, 7, 14, 28, 56, 84 days after implantation. Histological findings and stain analyzes of tartrate-resistant acid phosphatase (TRACP) and assays of alkaline phosphatase (ALP) and TRACP were evaluated. The mRNA expression levels of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) were analyzed using semi-quantitative reverse transcription - polymerase chain reactions (RT-PCR). An enzyme-linked immunosorbent assay (ELISA) was used to confirm the protein expression levels of IL-6, COX-2, VEGF and TGF-β. Results. TRACP-positive cells were observed in all groups 7 days after implantation. ALP and TRACP activities in the UCB-MSC group 84 days after implantation were significantly higher than those of the control (P>0.05). Histologic findings after 84 days showed that the osteoid matrix area in the UCB-MSC group was significantly larger than that of the control ( P<0.05). The mRNAs levels of IL-1, IL-6 and VEGF in UCB-MSC and cell lysate groups on day 1 were up-regulated compared with the control. The protein levels of IL-6 and VEGF in the UCB-MSC group at day 1 were significantly higher than that of the other groups ( P<0.05). Conclusions. It is suggested that a significant release of cytokines by cUCB MSC, 1 day following implantation, could enhance bone regeneration. [ABSTRACT FROM AUTHOR]

Weil BR, Abarbanell AM, Herrmann JL, Wang Y, Meidrum DR. High glucose concentration in cell culture medium does not acutely affect human mesenchymal stem cell growth factor production or proliferation. Am J Physiol Regul integr Comp Physiol 296: Rl735-Rl743, 2009. First published April 22, 2009; doi: 10.1152/ajpregu.90876.2008.-Optimizing the function and proliferative capacity of stem cells is essential to maximize their therapeutic benefits. High glucose concentrations are known to have detrimental effects on many cell types. We hypothesized that human mesenchymal stem cells (hMSCs) cultured in high glucose-containing media would exhibit diminished proliferation and attenuated production of VEOF, hepatocyte growth factor (HGF), and FGF2 in response to treatment with TNF-α, LPS, or hypoxia. hMSCs were plated in medium containing low (5.5 mM) and high (20 mM or 30 mM) glucose concentrations and treated with TNF-α, LPS, or hypoxia. Supernatants were collected at 24 and 48 h and assayed via ELISA for VEGF, HGF, and FGF2. In addition, hMSCs were cultured on 96-well plates at the above glucose concentrations, and proliferation at 48 h was determined via bromo-2'-deoxy-uridine (BrdU) incorporation. At 24 and 48 h, TNF-α, LPS, and hypoxia-treated hMSCs produced significantly higher VEOF, HOF, and FGF2 compared with control. Hypoxia-induced VEGF production by hMSCs was the most pronounced change over baseline. At both 24 and 48 h, glucose concentration did not affect production of VEOF, HGF, or FGF2 by untreated hMSCs and those treated with TNF-α, LPS, or hypoxia. Proliferation of hMSCs as determined via BrdU incorporation was unaffected by glucose concentration of the media. Contrary to what has been observed with other cells, hMSCs may be resistant to the short-term effects of high glucose. Ongoing efforts to characterize and optimize ex vivo and in vivo conditions are critical if the therapeutic benefits of MSCs are to be maximized. [ABSTRACT FROM AUTHOR]

Circulating progenitor cells home to and engraft to sites of ischemia, mediated in part by the adhesion molecule L-selectin; however, accumulation in tissues such as the heart is low. In this study, an acellular collagen-based matrix containing sialyl LewisX (sLeX), which binds L-selectin, was developed in order to enhance the endogenous progenitor cell therapeutic response. Its effect on progenitor cells and angiogenesis were assessed in vitro and using a hindlimb ischemia model with rats. In culture, the sLeX collagen matrix recruited more CD133+CD34+L-selectin+ cells than collagen-only matrix, with adhesion mediated by L-selectin binding. Increased angiogenic/chemotactic cytokine production and improved resistance to apoptosis appeared in cells cultured on sLeX-collagen matrix. In vivo, mobilization of endogenous circulating progenitor cells was increased, and greater recruitment of these and systemically injected human peripheral blood CXCR4+L-selectin+ cells to sLeX-collagen treated limbs was observed compared to collagen-only. This condition was associated with differences in angiogenic/chemotactic cytokine levels, with greater arteriole density and increased perfusion in sLeX-collagen treated hindlimbs. With these factors taken together, we demonstrated that an acellular matrix-bound ligand approach can enhance the mobilization, recruitment, and therapeutic effects of endogenous and/or transplanted progenitor cells, possibly through paracrine and antiapoptotic mechanisms, and could be used to improve cell-based regenerative therapies. [ABSTRACT FROM AUTHOR]

Paracrine factors of human mesenchymal stem cells (hMSCs) have the potential of preventing adverse cardiac remodeling after myocardial infarction (MI). S100A8 and S100A9 are calcium-binding proteins playing essential roles in the regulation of inflammation and fibrous tissue formation, and they might modulate the paracrine effect of hMSCs. We isolated human amniotic mesenchymal stem cells (hAMSCs) and examined the changes in the expression level of regulatory genes of inflammation and fibrosis after hAMSCs were treated with S100A8/A9. The anti-inflammatory and anti-fibrotic effects of hAMSCs pretreated with S100A8/A9 were shown to be superior to those of hAMSCs without S100A8/A9 pretreatment in the cardiomyocyte hypoxia/reoxygenation experiment. We established a murine myocardial ischemia/reperfusion model to compare the therapeutic effects of the conditioned medium of hAMSCs with or without S100A8/A9 pretreatment. We found the hearts administered with a conditioned medium of hAMSCs with S100A8/A9 pretreatment had better left ventricular systolic function on day 7, 14, and 28 after MI. These results suggest S100A8/A9 enhances the paracrine therapeutic effects of hAMSCs in aspects of anti-inflammation, anti-fibrosis, and cardiac function preservation after MI. [ABSTRACT FROM AUTHOR]

Bone marrow stromal cells (BMSCs) contain progenitors capable of participating in postnatal angiogenesis. Hypoxiainducible factors (HIFs) mediate endothelial activation by driving the expression of multiple angiogenic factors. We explored the potential of HIF-1α and HIF-2α modification in BMSCs, as a tool to improve cell-based angiogenic therapy. BMSCs were retrovirally transduced to express stable forms of HIF-1α and HIF-2α. HIF-1α and, to a greater extent, HIF-2α overexpression promoted differentiation of BMSCs to the endothelial lineage, evident by CD31 and Tie-2 expression and improved adhesive properties. Whereas chemotaxis toward stromal-derived factor 1 was higher in both HIF-α-expressing BMSCs, enhanced migration toward vascular endothelial growth factor was found only following overexpression of HIF- 2α, supported by a robust expression of its receptor, Flk-1. HIF-α expression was associated with upregulation of angiogenic proteins and improved tube formation. Cytokine arrays of endothelial cells stimulated by medium collected from HIF-α-expressing BMSCs revealed further angiogenic activation and improved adhesive capacity. Eventually, delivery of HIF-2α-transduced BMSCs induced a more robust angiogenic response, compared with shamtransduced or HIF-1α-transduced BMSCs in the corneal micropocket angiogenesis model. Our results support the use of HIF-α genes, particularly HIF-2α, to augment the efficacy of future cell-based therapy. [ABSTRACT FROM AUTHOR]

Neurons, glia, and endothelial cells of the cerebral microvasculature co-exist in intimate proximity in nervous tissues, and their homeostatic interactions in health, as well as coordinated response to injury, have led to the concept that they form the basic elements of a functional neurovascular unit. During the course of normal cellular metabolism, growth, and development, each of these brain cell types secrete various species of potentially neurotoxic peptides and factors, events that increase in magnitude as brain cells age. This article reviews contemporary research on the secretory products of the three primary cell types that constitute the neurovascular unit in deep brain regions. We provide some novel in vitro data that illustrate potentially pathogenic paracrine effects within primary cells of the neurovascular unit. For example, the pro-inflammatory cytokine interleukin (IL)-1β was found to stimulate amyloid-β (Aβ) peptide release from human neural cells, and human brain microvessel endothelial cells exposed to transient hypoxia were found to secrete IL-1β at concentrations known to induce Aβ42 peptide release from human neural cells. Hypoxia and excessive IL-1β and Aβ42 abundance are typical pathogenic stress factors implicated in the initiation and development of common, chronic neurological disorders such as Alzheimer's disease. These data support the hypothesis that paracrine effects of stressed constituent cells of the neurovascular unit may contribute to “spreading effects” characteristic of progressive neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Background: Cholecystokinin inhibits the secretion of gastrin from antral G cells, an effect that is speculated to be mediated by D cells secreting somatostatin. The aim of the study was to test directly whether cholecystokinin inhibition of antral gastrin secretion is mediated by somatostatin. Methods: The effects of CCK on gastrin and somatostatin secretion were studied in isolated vascularly perfused preparations of pig antrum before and after immunoneutralization brought about by infusion of large amounts of a high affinity monoclonal antibody against somatostatin. Results: CCK infusion at 10 -9 M and 10 -8 M decreased gastrin output to 70.5% ± 7.6% ( n = 8) and 76.3% ± 3.6% ( n = 7) of basal output, respectively. CCK at 10 -10 M had no effect ( n = 6). Somatostatin secretion was dose-dependently increased by CCK infusion and increased to 268 ± 38.2% ( n = 7) of basal secretion during infusion of CCK at 10 -8 M. Immunoneutralization of somatostatin caused a doubling of the basal secretion of gastrin, but did not affect the CCK-induced decrease in gastrin secretion. Conclusion: CCK inhibits gastrin secretion independently of paracrine somatostatin secretion. [ABSTRACT FROM AUTHOR]

A 32 kDa estrogen-induced, sialic acid-specific agglutinin (P-SAS) was isolated from rat endometrium in its proestrus stage [1]. To investigate the functional importance of P-SAS in the uterine milieu, specific binding assays were carried out with 125I-labeled P-SAS and different cellular components of the uterus (epithelial, stromal and myometrial cells), that were isolated from different stages of the estrus cycle. The results indicate that although the protein is secreted from the epithelial cells in the estrogenic phase, it binds specifically to the stromal cells, especially to those isolated from the diestrus stage of the estrus cycle. The specific binding, however, is seen to decrease with the progression of pregnancy. Scatchard analysis performed with varying amounts of 125I-P-SAS in the presence of excess cold P-SAS revealed that the binding occurs with a Ka = 1.69 × 108 M-1. As P-SAS binds specifically to sialic acids on the stromal cell surface, further characterization of the sialic acid molecule to which P-SAS binds was carried out by gas liquid chromatography (GLC). The studies revealed that P-SAS preferentially binds to N-glycolylneuraminic acid, which is attached to the penultimate sugar of the stromal cell surface glycoprotein chain via α2,6 linkage. As P-SAS is further known to be mitogenic [2], the effect of P-SAS on cultured stromal cells was studied in vitro. The growth regulatory assays revealed that P-SAS induced 3H-thymidine uptake by stromal cells in culture. Thus, from the above observations, paracrine effects of P-SAS on the stromal cells and on the subsequent growth and development of the uterus can be assumed. [ABSTRACT FROM AUTHOR]

We previously reported that c-KIT+ human amniotic-fluid derived stem cells obtained from leftover samples of routine II trimester prenatal diagnosis (fetal hAFS) are endowed with regenerative paracrine potential driving pro-survival, anti-fibrotic and proliferative effects. hAFS may also be isolated from III trimester clinical waste samples during scheduled C-sections (perinatal hAFS), thus offering a more easily accessible alternative when compared to fetal hAFS. Nonetheless, little is known about the paracrine profile of perinatal hAFS. Here we provide a detailed characterization of the hAFS total secretome (i.e., the entirety of soluble paracrine factors released by cells in the conditioned medium, hAFS-CM) and the extracellular vesicles (hAFS-EVs) within it, from II trimester fetal- versus III trimester perinatal cells. Fetal- and perinatal hAFS were characterized and subject to hypoxic preconditioning to enhance their paracrine potential. hAFS-CM and hAFS-EV formulations were analyzed for protein and chemokine/cytokine content, and the EV cargo was further investigated by RNA sequencing. The phenotype of fetal- and perinatal hAFS, along with their corresponding secretome formulations, overlapped; yet, fetal hAFS showed immature oxidative phosphorylation activity when compared to perinatal ones. The profiling of their paracrine cargo revealed some differences according to gestational stage and hypoxic preconditioning. Both cell sources provided formulations enriched with neurotrophic, immunomodulatory, anti-fibrotic and endothelial stimulating factors, and the immature fetal hAFS secretome was defined by a more pronounced pro-vasculogenic, regenerative, pro-resolving and anti-aging profile. Small RNA profiling showed microRNA enrichment in both fetal- and perinatal hAFS-EV cargo, with a stably- expressed pro-resolving core as a reference molecular signature. Here we confirm that hAFS represents an appealing source of regenerative paracrine factors; the selection of either fetal or perinatal hAFS secretome formulations for future paracrine therapy should be evaluated considering the specific clinical scenario. [ABSTRACT FROM AUTHOR]

Background/Aims: A trophic role of gastrin has been convincingly demonstrated in the oxyntic mucosa of the stomach, but is still a matter of debate in the lower gastrointestinal tract. Methods: In order to examine the role of circulating gastrin in colorectal adenoma and carcinoma fasting serum gastrin concentrations were determined in 351 patients undergoing complete colonoscopy. Results: In comparison to controls (n = 145) more patients with either polyps (n = 125) or colorectal carcinoma (n = 81) have slightly increased serum gastrin concentrations, leading to an increased mean, but no change in median serum gastrin levels. In 3 patients preoperatively increased serum gastrin concentrations were normalized after surgical removal of the polyp and/or tumor, suggesting a local release of gastrin from the polyp/tumor. Gastrin concentrations do not correlate with the histopathological classification or malignant potential of adenomatous polyps. Conclusion: In view of these findings a significant role of circulating endogenous gastrin in human colorectal carcinogenesis seems to be unlikely. [ABSTRACT FROM AUTHOR]

Pulmonary neuroendocrine cells produce bioactive peptides such as gastrin-releasing peptide (GRP) at high levels in developing fetal lung. The role of GRP and other peptides in promoting branching morphogenesis, cell proliferation, and cell differentiation during lung organogenesis is reviewed. Possible roles for bioactive peptides derived from these cells in the pathophysiology of perinatal lung disorders are discussed. [ABSTRACT FROM AUTHOR]

Cell density effects were investigated on tumorous hormonal secretion from 10 pituitary adenomas: 3 somatotrophinomas secreting GH and PRL; 7 gonadotrophinomas, 3 co-secreted both FSH and LH, all 7 secreted LH. Enzymatically dispersed tissue was plated out in 24-well plates at 5 ×10[sup 5] , 10[sup 5] , 5 ×10[sup 4] and 10[sup 4] cells/well in serum-free media. Media were collected weekly for 2 weeks. Results: In 3 of 3 somatotrophinomas, GH and PRL secretion was higher (p < 0.05) at both week 1 and 2 from 10[sup 4] cells/well, but similar at other cell densities. In all 3 gonadotrophinomas, the FSH secretory rate was highest at 5 ×10[sup 5] cells/well which fell as cell density decreased. Conversely, in 7 of 7 gonadotrophinomas the LH secretory rate was highest at 10[sup 4] cells/well (p < 0.01) which fell as cell density increased. Conclusion: These data suggest that paracrine factors may modulate tumorous GH, PRL, FSH and LH secretion, and show that FSH and LH secretion vary inversely as cell density increases. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is still the leading cause of death worldwide. Coronary artery occlusion, or myocardial infarction (MI) causes massive loss of cardiomyocytes. The ischemia area is eventually replaced by a fibrotic scar. From the mechanical dysfunctions of the scar in electronic transduction, contraction and compliance, pathological cardiac dilation and heart failure develops. Once end-stage heart failure occurs, the only option is to perform heart transplantation. The sequential changes are termed cardiac remodeling, and are due to the lack of endogenous regenerative actions in the adult human heart. Regenerative medicine and biomedical engineering strategies have been pursued to repair the damaged heart and to restore normal cardiac function. Such strategies include both cellular and acellular products, in combination with biomaterials. In addition, substantial progress has been made to elucidate the molecular and cellular mechanisms underlying heart repair and regeneration. In this review, we summarize and discuss current therapeutic approaches for cardiac repair and provide a perspective on novel strategies that holding potential opportunities for future research and clinical translation. [ABSTRACT FROM AUTHOR]

Although saphenous veins (SVs) are commonly used as conduits for coronary artery bypass grafting (CABG), internal thoracic artery (ITA) grafts have significantly higher long-term patency. As SVs and ITA endothelial cells (ECs) have a considerable level of heterogeneity, we suggested that synergistic paracrine interactions between CA and ITA ECs (HCAECs and HITAECs, respectively) may explain the increased resistance of ITA grafts and adjacent CAs to atherosclerosis and restenosis. In this study, we measured the gene and protein expression of the molecules responsible for endothelial homeostasis, pro-inflammatory response, and endothelial-to-mesenchymal transition in HCAECs co-cultured with either HITAECs or SV ECs (HSaVECs) for an ascending duration. Upon the co-culture, HCAECs and HITAECs showed augmented expression of endothelial nitric oxide synthase (eNOS) and reduced expression of endothelial-to-mesenchymal transition transcription factors Snail and Slug when compared to the HCAEC–HSaVEC model. HCAECs co-cultured with HITAECs demonstrated an upregulation of HES1, a master regulator of arterial specification, of which the expression was also exclusively induced in HSaVECs co-cultured with HCAECs, suggestive of their arterialisation. In addition, co-culture of HCAECs and HITAECs promoted the release of pro-angiogenic molecules. To conclude, co-culture of HCAECs and HITAECs results in reciprocal and beneficial paracrine interactions that might contribute to the better performance of ITA grafts upon CABG. [ABSTRACT FROM AUTHOR]

Adipose-derived stem cells (ASCs) are promising therapeutic cells for ischemic heart diseases, due to the ease and efficiency of acquisition, the potential of myocardial lineage differentiation, and the paracrine effects. Recently, many researchers have claimed that the ASC-based myocardial repair is mainly attributed to its paracrine effects, including the anti-apoptosis, pro-angiogenesis, anti-inflammation effects, and the inhibition of fibrosis, rather than the direct differentiation into cardiovascular lineage cells. However, the usage of ASCs comes with the problems of low cardiac retention and survival after transplantation, like other stem cells, which compromises the effectiveness of the therapy. To overcome these drawbacks, researchers have proposed various strategies for improving survival rate and ensuring sustained paracrine secretion. They also investigated the safety and efficacy of phase I and II clinical trials of ASC-based therapy for cardiovascular diseases. In this review, we will discuss the characterization and paracrine effects of ASCs on myocardial repair, followed by the strategies for stimulating the paracrine secretion of ASCs, and finally their clinical usage. [ABSTRACT FROM AUTHOR]