ITIH5 inhibits proliferation, adipogenic differentiation, and secretion of inflammatory cytokines of human adipose stem cells-A new key in treating obesity?

Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is widely expressed in the human body, and it is detected to be particularly abundant in adipose tissue. ITIH5 expression is increased in people with obesity compared to lean persons and is decreased by diet-induced weight loss. This suggests that ITIH5 may be involved in the development of adiposity and clinical metabolic variables, although its exact function remains unknown. We measured the protein concentration of ITIH5 in adipose samples from patients undergoing abdominoplasty and tested for correlation with the subjects' BMI as well as inflammatory mediators. We stimulated human adipose stem cells (ASCs) with recombinant (r)ITIH5 protein and tested for an effect on proliferation, differentiation, and immunosuppressive properties when the cells were exposed to an artificial inflammatory environment. We found positive correlations between ITIH5 levels and the BMI (p < .001) as well as concentrations of inflammatory cytokines (TNF-α, IL-6, and MCP-1) in adipose tissue (p < .01). Application of the rITIH5 protein inhibited both proliferation (p < .001) and differentiation of ASCs. Especially, the development of mature adipocytes was reduced by over 50%. Moreover, rITIH5 decreased the release of IL-6 and MCP-1 when the cells were exposed to TNF-α and IL-1ß (p < .001). Our data suggest that ITIH5 is an adipokine that is increasingly released during human adipose tissue development, acting as a regulator that inhibits proliferation and adipogenic differentiation of ASCs. ITIH5 thus presents itself as a positive regulator of adipose tissue homeostasis, possibly protecting against both hyperplasia and hypertrophy of adipose tissue and the associated chronic inflammation.

GPR55 inhibits the pro-adipogenic activity of anandamide in human adipose stromal cells.

The endocannabinoid anandamide (AEA) stimulates adipogenesis via the cannabinoid receptor CB1 in adipose stromal cells (ASCs). However, AEA interacts also with nonclassical cannabinoid receptors, including transient receptor potential cation channel (TRPV)1 and G protein-coupled receptor (GPR)55. Their roles in AEA mediated adipogenesis of human ASCs have not been investigated. We examined the receptor-expressions by immunostaining on human ASCs and tested their functionality by measuring the expression of immediate early genes (IEGs) related to the transcription factor-complex AP-1 upon exposition to receptor agonists. Cells were stimulated with increasing concentrations of specific ligands to investigate the effects on ASC viability (proliferation and metabolic activity), secretory activity, and AEA mediated differentiation. ASCs expressed both receptors, and their activation suppressed IEG expression. TRPV1 did not affect viability or cytokine secretion. GPR55 decreased proliferation, and it inhibited the release of hepatocyte growth factor. Blocking GPR55 increased the pro-adipogenic activity of AEA. These data suggest that GPR55 functions as negative regulator of cannabinoid mediated pro-adipogenic capacity in ASCs.

Association between Donor Age and Osteogenic Potential of Human Adipose Stem Cells in Bone Tissue Engineering.

Adipose stem cells (ASCs) have multilineage differentiation capacity and hold great potential for regenerative medicine. Compared to bone marrow-derived mesenchymal stem cells (bmMSCs), ASCs are easier to isolate from abundant sources with significantly higher yields. It is generally accepted that bmMSCs show age-related changes in their proliferation and differentiation potentials, whereas this aspect is still controversial in the case of ASCs. In this review, we evaluated the existing data on the effect of donor age on the osteogenic potential of human ASCs. Overall, a poor agreement has been achieved because of inconsistent findings in the previous studies. Finally, we attempted to delineate the possible reasons behind the lack of agreements reported in the literature. ASCs represent a heterogeneous cell population, and the osteogenic potential of ASCs can be influenced by donor-related factors such as age, but also gender, lifestyle, and the underlying health and metabolic state of donors. Furthermore, future studies should consider experimental factors in in vitro conditions, including passaging, cryopreservation, culture conditions, variations in differentiation protocols, and readout methods.

HER3 (ERBB3) amplification in liposarcoma - a putative new therapeutic target?

BACKGROUND: Liposarcomas are among the most common mesenchymal malignancies. However, the therapeutic options are still very limited and so far, targeted therapies had not yet been established. Immunotherapy, which has been a breakthrough in other oncological entities, seems to have no efficacy in liposarcoma. Complicating matters further, classification remains difficult due to the diversity of morphologies and nonspecific or absent markers in immunohistochemistry, leaving molecular pathology using FISH or sequencing as best options. Many liposarcomas harbor MDM2 gene amplifications. In close relation to the gene locus of MDM2, HER3 (ERBB3) gene is present and co-amplification could occur. Since the group of HER/EGFR receptor tyrosine kinases and its inhibitors/antibodies play a role in a broad spectrum of oncological diseases and treatments, and some HER3 inhibitors/antibodies are already under clinical investigation, we hypothesized that in case of HER3 co-amplifications a tumor might bear a further potential therapeutic target. METHODS: We performed FISH analysis (MDM2, DDIT3, HER3) in 56 archived cases and subsequently performed reclassification to confirm the diagnosis of liposarcoma. RESULTS: Next to 16 out of 56 cases needed to be re-classified, in 20 out of 54 cases, a cluster-amplification of HER3 could be detected, significantly correlating with MDM2 amplification. Our study shows that the entity of liposarcomas show specific molecular characteristics leading to reclassify archived cases by modern, established methodologies. Additionally, in 57.1% of these cases, HER3 was cluster-amplified profusely, presenting a putative therapeutic target for targeted therapy. CONCLUSION: Our study serves as the initial basis for further investigation of the HER3 gene as a putative therapeutic target in liposarcoma.

Adipose and lipoma stem cells: A donor-matched comparison.

Lipomas are slow growing benign fat tumors that develop in soft tissues of the mesoderm. Thus, the specific (dys-)function of mesenchymal stem cells (MSCs) has been suggested in the development of lipomas, but details of the tumor pathogenesis remain unclear. Existing studies comparing stem cells from native adipose (adipose stem cells [ASCs]) and lipomatous tissues (LSCs) have reported contradicting findings. However, harvesting ASCs and LSCs from different individuals might have influenced proper comparison. Therefore, we aimed to characterize donor-matched ASCs and LSCs to investigate metabolic activity, proliferation, capability for tri-linear differentiation (chondrogenesis, adipogenesis, osteogenesis), and the secretome of mature adipocytes and lipomacytes. Both stem cell types did not differ in metabolic activity, but ASCs demonstrated stronger proliferation than LSCs. While there was no difference in proteoglycan accumulation during chondrogenic differentiation, adipogenesis was higher in ASCs, with more lipid vacuole formation. Conversely, LSCs showed increased osteogenesis by higher calcium deposition. Lipomacytes showed stronger secretory activity and released higher levels of certain adipokines. Our findings indicated that LSCs possessed important characteristics of MSCs, including ASCs. However, LSCs' low proliferation and adipogenic differentiation behavior did not appear to account for enhanced tissue proliferation, but the secretome of lipomacytes could contribute to lipomatous neoplasm.

Prospective analysis of grip strength and load distribution after surgical treatment of common diseases of the hand with novel's manugraphy® system.

BACKGROUND: Carpal tunnel syndrome, A1 annular pulley stenosis and Dupuytren's contracture are among the most common conditions of the hand. In this study, we investigated the impact of surgical procedure on hand grip strength and high-resolution spatial load distribution in individuals suffering from those diseases over a follow-up period of one year. MATERIALS AND METHODS: In this prospective study, data of 9 patients with carpal tunnel syndrome, 12 patients with A1 annular pulley stenosis and 7 patients with Dupuytren's contracture were evaluated. Only patients with unilateral disease were included providing the contralateral hand as an intra-individual control. Grip strength was measured with cylindrical instruments in two different sizes with respect to the hand size of the patients. Maximum and average values of grip strength as well as spatial load distribution in each finger, thenar, hypothenar and palm were analyzed. Data of the affected patients were collected preoperatively and 6 weeks, 6 months and 1 year postoperatively. Grip strength and spatial load distribution were compared preoperatively to postoperatively. In addition, DASH score, Levine score, 2-point discrimination and degree of flexion contracture were assessed. RESULTS: The patients with A1 annular pulley stenosis showed a significant increase in grip strength 6 months and one year postoperatively. Patients with carpal tunnel syndrome and Dupuytren's contracture showed no significant difference in grip strength over the course of time. An increase in the percentual grip strength of the thenar in patients with carpal tunnel disease and within the affected finger in A1 annular pulley stenosis was observed over the course of time. The DASH score was significantly lower in all patient cohorts one year postoperatively. CONCLUSION: Surgical procedure in carpal tunnel syndrome, A1 annular ligament stenosis and Dupuytren's contracture improves the functionality of the hand in everyday life. Some areas of the hand seem to compensate other weaker areas in grip strength.

Measures for Preventing Infection in Burn Surgery.

The skin is the largest human organ and an important barrier to protect against the environment. Burns damage the skin and thus destroy this anatomical barrier. This makes initially sterile wounds susceptible to colonization by pathogenic germs. In severely burned patients, immune competence decreases as part of the burn disease. Sepsis and multiple organ failure as a result of infection are the main causes of death in this cohort. Therefore, prevention and recognition of infections as well as surgical treatment and targeted anti-infective therapy are of great importance. In this article, we present up-to-date solutions for the treatment of burn wounds by means of plastic and reconstructive surgery to minimize the risk of infection. We demonstrate the principles of infection defense by the skin barrier. We outline the principles of burns and how to perform an appropriate diagnosis and therapy, from outpatient therapy to intensive care therapy, depending on the severity. We address the typical bacteria responsible for wound infections in severely burned patients and how to prevent and treat them. We also describe the hygiene measures that must be used in a severe burn unit to reduce the risk of complications such as infection and improve patient survival.

Effects of Silicone Breast Implants on Human Cell Types In Vitro: A Closer Look on Host and Implant.

BACKGROUND: Silicone (gel) breast implants (SBI) are used world-wide for breast augmentation, and reconstruction or to correct breast deformities. They consist of two compounds: an elastomer silicone shell (envelope) and a silicone gel filler (core). Breast Implant Illness (BII) is a term used for women with SBI, who suffer from various of symptoms including myalgia, arthralgia, fatigue, fever, dry eyes and/or dry mouth (sicca), as well as cognitive disturbances, which are rated by these woman as response to SBI. The pathogenesis of these adverse effects as well as the histocompatibility and the SBI-cell interaction of silicone and its surrounding tissue (implant-host tissue interface) is a subject of current research. The main purpose of this review is to provide an overview of the current knowledge regarding the effects of silicone (gel and elastomer surfaces) of a SBI on different human cell types from experimental - in vitro - models. METHODS: A comprehensive research was conducted by two independent reviewers in March and July of 2020 in the PubMed, MEDLINE, and Cochrane databases. RESULTS: A number of 1328 articles on this topic were initially identified, of which 62 could be finally included an analysed in this review. CONCLUSION: SBI may lead to a physiologic pro-inflammatory and foreign body host response with fibrous encapsulation accompanied by a disturbed Th17/Treg balance and IL-17 production. No causal relationship is known for systemic symptoms and/or autoimmune outcomes in the context of BII. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The endocannabinoid receptors CB1 and CB2 affect the regenerative potential of adipose tissue MSCs.

Human adipose tissue includes large quantities of mesenchymal stromal cells (atMSCs), which represent an abundant cell source for therapeutic applications in the field of regenerative medicine. Adipose tissue secrets various soluble factors including endocannabinoids, and atMSCs express the cannabinoid receptors CB1 and CB2. This indicates that adipose tissue possesses an endocannabinoid system (ECS). The ECS is also ascribed great significance for wound repair, e.g. by modulating inflammation. However, the exact effects of CB1/CB2 activation in human atMSCs have not been investigated, yet. In the present study, we stimulated human atMSCs with increasing concentrations (1-30 µM) of the unspecific cannabinoid receptor ligand WIN55,212-2 and the specific CB2 agonist JWH-133, either alone or co-applied with the receptor antagonist Rimonabant (CB1) or AM 630 (CB2). We investigated the effects on metabolic activity, cell number, differentiation and cytokine release, which are important processes during tissue regeneration. WIN decreased metabolic activity and cell number, which was reversed by Rimonabant. This suggests a CB1 dependent mechanism, whereas the number of atMSCs was increased after CB2 ligation. WIN and JWH increased the release of VEGF, TGF-ß1 and HGF. Adipogenesis was enhanced by WIN, which could be reversed by blocking CB1. There was no effect on osteogenesis, and only WIN increased chondrogenic differentiation. Our results indicate that definite activation of the cannabinoid receptors exerted different effects in atMSCs, which could be of specific value in cell-based therapy for wound regeneration.

Human adipose-derived stem cells support lymphangiogenesis in vitro by secretion of lymphangiogenic factors.

Lymphedema is a chronic progressive disease ultimately resulting in severe, disfiguring swelling and permanent changes of the affected tissues. Presently, there is no causal treatment approach of lymphedema. Therefore, most therapies are purely symptomatic. However, the recent use of stem cell-based therapies has offered new prospects for alternative treatment options. The present study was performed to investigate the effects of human adipose-derived stem cells (ADSCs) on human dermal lymphatic endothelial cells (HDLECs) in terms of basic in vitro lymphangiogenic assays (WST-8 assay, scratch assay, transmigration assay, sprouting assay, tube formation assay). The influence of ADSC-conditioned medium (ADSC-CM) on HDLECs was compared to recombinant VEGF-C, bFGF and HGF. Further ADSC-CM was characterized by protein microarray and enzyme-linked immunosorbent assay (ELISA). Although key-lymphangiogenic growth factors - like VEGF-C - could only be detected in low concentrations within the conditioned medium (CM), HDLECs were potently stimulated to proliferate, migrate and to form tube like structures by ADSC-CM. Despite concentrations more than hundredfold higher than those found in the conditioned medium, stimulation with recombinant VEGF-C, bFGF and HGF was still weaker compared to ADSC-CM. These results highlight the effectiveness of growth factors secreted by ADSC to stimulate HDLEC, potentially providing a promising new therapeutic approach for the treatment of lymphedema.

The History of Carbon Monoxide Intoxication.

Intoxication with carbon monoxide in organisms needing oxygen has probably existed on Earth as long as fire and its smoke. What was observed in antiquity and the Middle Ages, and usually ended fatally, was first successfully treated in the last century. Since then, diagnostics and treatments have undergone exciting developments, in particular specific treatments such as hyperbaric oxygen therapy. In this review, different historic aspects of the etiology, diagnosis and treatment of carbon monoxide intoxication are described and discussed.

Mesenchymal Stem Cells and the Generation of Neomuscle Tissue.

Skeletal muscle represents the largest mass of tissue in the body and is essential for motion and posture. Traumatic injury, tumor ablation, prolonged denervation or genetic defects lead to skeletal myopathies. The loss of muscle function or its regenerative properties often results in pain, deformity, and joint malfunction. The regenerative capacity of skeletal muscles depends on adult muscle stem cells, the so-called satellite cells; however, the population of these myogenic precursors, and thus their potential to restore large muscle tissue defects, is strongly limited. On the other hand, surgical treatment of skeletal muscle loss is hampered by the scarcity of functional replacement tissue. Only a few options currently exist to provide functional and aesthetic restoration of lost muscle tissues, other than free muscle flap transfer. While this reconstructive technique is a common practice, it involves the risk of significant donor-site morbidity. Therefore, alternative cells with the potential to regenerate muscle tissue need to be examined. Recently, many surgeons have studied the potential clinical application of mesenchymal stem cells (MSCs), which are an adult stem cell population that can undergo differentiation along the mesodermal lineage and secrete growth factors that can enhance tissue regeneration processes by promoting neovascularization. The regenerative potential of MSCs has been widely studied in vitro and in vivo in animal models. MSCs from adipose tissue as well as bone marrow have been shown to bear myogenic potential, which makes them ideal candidate stem cells for skeletal muscle tissue engineering applications. When compared to reconstructive procedures using autograft tissues, MSC therapy offers the potential of reducing or even eliminating donor-site morbidity. This review gives a comprehensive overview of the use of MSCs in in vitro muscle generation and in vivo muscle regeneration.

Plastic Surgery Reconstruction of Chronic/Non-Healing Wounds.

In western countries, approximately 1 % of individuals are affected by chronic wounds during their lifetime. Due to changing demographics, this incidence will likely increase in the future. Additionally, the high prevalence is accompanied by substantial treatment expenditures. Therefore, it is of global interest to find effective treatment algorithms. In this article, we present up-to-date solutions for treating chronic / difficult to heal and complex wounds by means of plastic and reconstructive surgery. We outline the principles of chronic wounds and how to perform an appropriate diagnosis. Close cooperation and interdisciplinary exchange are important for optimizing treatment. We report the principles of wound debridement and the role of negative pressure wound therapy. Moreover, we discuss the state of the art of defect reconstruction by means of skin grafting, with or without acellular dermal matrices, local tissue transfers and free tissue transfers. In very complex cases, the local macrovascular blood flow is greatly reduced and there are few, if any, recipient vessels for free flap reconstruction. We discuss the role of arteriovenous loops to overcome this problem.

Quantification of chondrogenic differentiation in monolayer cultures of mesenchymal stromal cells.

Determining inhibitory or supportive effects of biological, chemical or physical factors on cell fates, including chondrogenic differentiation of mesenchymal stromal cells (MSCs), requires quantification techniques that are rapid, reproducible, and able to monitor these effects over time. Methods currently used to analyze chondrogenic differentiation are either qualitative staining procedures or indirect DNA quantifications. Because of these limitations, further methods are needed to improve determination of chondrogenic differentiation. In the present study, we applied a histological staining method, which is established for investigation of articular cartilage degeneration by use of Safranin O dye, on chondrogenic differentiated cells in monolayer cultures. MSCs were differentiated on 12-well formats, at increasing concentrations of TGF-ß3, cell numbers, and incubation times. Quantification was performed by solubilizing the adsorbed dye into isopropanol followed by determining the optical density (O.D.) through spectrophotometry. Our results show that the O.D. is directly related to cell numbers and incubation periods, and that the technique is applicable to study agents which affect chondrogenic differentiation.

Patient's quality of life after surgery and radiotherapy for extremity soft tissue sarcoma - a retrospective single-center study over ten years.

BACKGROUND AND OBJECTIVES: The purpose of this study is to analyze major complication rates and different aspects of health-related quality of life (HRQoL) in extremity soft tissue sarcoma (STS) patients treated with or without radio (chemo) therapy and surgery. METHODS: We performed a retrospective analysis of all patients who underwent Extremity STS excision from 2004 to 2014 (182 patients included). Patients' data were collected from patients' records. HRQoL was assessed by using EORTC QLQ-C30. RESULTS: A total of 182 patients underwent sarcoma resection. After neoadjuvant radiochemotherapy (RCT), the major-complication rate amounted to 28% (vs. 7%, no radiotherapy, p <  0.001). Major-complication rates after adjuvant radiotherapy (RT) occurred in 8% (vs. 7%, no radiotherapy, p = 0.265). Comparison QoL scores between treating with neoadjuvant RCT or without RT revealed significant worse scores with neoadjuvant RCT. Further stratification of disease control of these patients showed significant reduced scores in the group of disease-free patients with neoadjuvant RCT compared to irradiated disease-free patients. DISCUSSION: To date, there have only been a few investigations of QoL in STS. Retrospective study on quality of life have limitations, like a lack of baseline evaluation of QoL. Patient candidated to radiation therapy could have had worse QoL baseline due to more advanced disease. Disease status of the patients who answered the questionnaires could have been an influence of QoL and we could show reduced scores in the group of disease-free patients with neoadjuvant RCT, but not for the patients with recurrence or metastasis, so it is very hard to discriminate whether radiation therapy could really have an impact or not. CONCLUSION: This study might assist in further improving the understanding of QoL in STS patients and may animate for prospective studies examining the oncological therapies impact on HRQoL.

Cannabidiol restores differentiation capacity of LPS exposed adipose tissue mesenchymal stromal cells.

Multipotent mesenchymal stromal cells (MSCs) support wound healing processes. These cells express toll-like receptors (TLRs). TLRs perform important key functions when the immune system is confronted with danger signals. TLR ligation by lipopolysaccharides (LPS) activates MSCs and induces intracellular signaling cascades, which affect their differentiation profile, increase the release of inflammatory cytokines and the production of reactive oxygen species. Continuing exposure to LPS triggers prolonged inflammatory reactions, which may lead to deleterious conditions, e.g. non-healing wounds. Cannabidiol (CBD) exerts anti-inflammatory processes through cannabinoid receptor dependent and independent mechanisms. In the present study, we examined whether CBD could influence the inflammatory MSC phenotype. Exposure to LPS increased the release of IL-6, as well as other soluble factors, and elevated levels of oxidized macromolecules found in cell homogenisates. While the amount of IL-6 was unaffected, co-treatment with CBD reduced the oxidative stress acting on the cells. LPS inhibited adipogenic as well as chondrogenic differentiation, which was attenuated by CBD treatment. In the case of adipogenesis, the disinhibitory effect probably depended on CBD interaction with the peroxisome proliferator-activated receptor-γ. CBD could exert mild immunosuppressive properties on MSCs, while it most effectively acted anti-oxidatively and by restoring the differentiation capacity upon LPS treatment.

Autologous Breast Reconstruction with Transverse Rectus Abdominis Musculocutaneous (TRAM) or Deep Inferior Epigastric Perforator (DIEP) Flaps: An Analysis of the 100 Most Cited Articles.

Post-mastectomy autologous reconstruction with abdominal tissue has evolved over the past 4 decades and is a common reconstructive modality today. To gain more insight into this evolution, we performed an analysis of the 100 most commonly cited articles focusing on autologous breast reconstruction with transverse rectus abdominis musculocutaneous (TRAM) or deep inferior epigastric perforator (DIEP) flaps. A review of the ISI Web of Knowledge database was performed. Only peer-reviewed articles in English were included for analysis. Articles were ranked by their total citations as well as citation density (citations divided by years since publication). The 100 most cited articles were analyzed by their bibliographic parameters. The 100 most cited articles were published in 12 journals. The highest ranked plastic surgery journal published almost 2/3 of the articles. All articles were published within 23 years and marked the "rising age" of autologous breast reconstruction with TRAM and DIEP flaps. The focus of clinical research changed over this time period and ranged from innovations in surgical technique to analysis of clinical outcomes, comparative analyses with other reconstructive modalities, timing of reconstruction, and preoperative diagnostic workup, as well as cost-effectiveness analyses. This literature review illustrates the dramatic change that has occurred subsequent to introduction of abdominal flaps for breast reconstruction. While the use of abdominal flaps has become widely accepted for breast reconstruction, many questions remain unanswered, thus highlighting the need for ongoing clinical investigation.

Free Latissimus Dorsi Myocutaneous Flap in a 6-Month-Old Child for Reconstruction of a Temporal Fossa Defect After Teratoma Resection.

Although free flap reconstruction has already gained widespread acceptance in pediatric patients, little is known about the outcome of free tissue transfer in head and neck reconstruction in pediatric patients. We present a case of a 6-month-old boy with a large volume deficit in the right temporal fossa after resection of a teratoma. This led to a large volume deficit with widely undermined skin margins. Therefore, we provided volume augmentation by microsurgical free latissimus dorsi myocutaneous flap transplantation. Intraoperative use of laser-assisted indocyanine green angiography indicated excellent flap perfusion. Postoperative magnetic resonance imaging showed adequate flap perfusion with no signs of flap necrosis. To our best knowledge, this case presents the youngest patient who underwent free flap transplantation in the head and neck region. Our case demonstrates that microvascular surgery can play an important role in particular cases in pediatric oncology, even in very young patients.

The potential role of telocytes in Tissue Engineering and Regenerative Medicine.

Research and ideas for potential applications in the field of Tissue Engineering (TE) and Regenerative Medicine (RM) have been constantly increasing over recent years, basically driven by the fundamental human dream of repairing and regenerating lost tissue and organ functions. The basic idea of TE is to combine cells with putative stem cell properties with extracellular matrix components, growth factors and supporting matrices to achieve independently growing tissue. As a side effect, in the past years, more insights have been gained into cell-cell interaction and how to manipulate cell behavior. However, to date the ideal cell source has still to be found. Apart from commonly known various stem cell sources, telocytes (TC) have recently attracted increasing attention because they might play a potential role for TE and RM. It becomes increasingly evident that TC provide a regenerative potential and act in cellular communication through their network-forming telopodes. While TE in vitro experiments can be the first step, the key for elucidating their regenerative role will be the investigation of the interaction of TC with the surrounding tissue. For later clinical applications further steps have to include an upscaling process of vascularization of engineered tissue. Arteriovenous loop models to vascularize such constructs provide an ideal platform for preclinical testing of future therapeutic concepts in RM. The following review article should give an overview of what is known so far about the potential role of TC in TE and RM.

Mesenchymal stem cells promote lymphangiogenic properties of lymphatic endothelial cells.

Lymphatic metastasis is one of the main prognostic factors concerning long-term survival of cancer patients. In this regard, the molecular mechanisms of lymphangiogenesis are still rarely explored. Also, the interactions between stem cells and lymphatic endothelial cells (LEC) in humans have not been well examined. Therefore, the main objective of this study was to assess the interactions between mesenchymal stem cells (MSC) and LEC using in vitro angiogenesis assays. Juvenile LEC were stimulated with VEGF-C, bFGF, MSC-conditioned medium (MSC-CM) or by co-culture with MSC. LEC proliferation was assessed using a MTT assay. Migration of the cells was determined with a wound healing assay and a transmigration assay. To measure the formation of lymphatic sprouts, LEC spheroids were embedded in collagen or fibrin gels. The LEC's capacity to form capillary-like structures was assessed by a tube formation assay on Matrigel® . The proliferation, migration and tube formation of LEC could be significantly enhanced by MSC-CM and by co-culture with MSC. The effect of stimulation with MSC-CM was stronger compared to stimulation with the growth factors VEGF-C and bFGF in proliferation and transmigration assays. Sprouting was stimulated by VEGF-C, bFGF and by MSC-CM. With this study, we demonstrate the potent stimulating effect of the MSC secretome on proliferation, migration and tube formation of LEC. This indicates an important role of MSC in lymphangiogenesis in pathological as well as physiological processes.