Bone Marrow-Derived Mesenchymal Stem Cells Drive Lymphangiogenesis

Maertens, Ludovic; Erpicum, Charlotte; Detry, Bruno; Blacher, Silvia; Lenoir, Bénédicte; Carnet, Oriane; Péqueux, Christel; Cataldo, Didier; Lecomte, J; Paupert, Jenny; Noël, Agnès

doi:10.1371/journal.pone.0106976

Cited by 33 publications

(23 citation statements)

References 55 publications

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“…S5), however, suggesting either a very early requirement for Cx43 in LECs or their precursors, before the Lyve-1 promoter is active, or that the Cx43 −/− -specific defects were due to the absence of Cx43 from a non-LEC cell-type. Cx43 is known to be expressed by mesenchymal stem cells, which can affect lymphangiogenesis (Valiunas et al, 2004; Buttler et al, 2013; Maertens et al, 2014), as well as macrophages and lymphocytes (Glass et al, 2015), which have been implicated in pathological lymphangiogenesis (Betterman and Harvey, 2016). In addition, Cx43 expression in thymic regulatory T cell precursors enhances the production of Foxp3 + regulatory T cells (Kuczma et al 2011), a population of cells which were recently shown to modulate lymphedema and promote lymphatic vessel function (Gousopoulos et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Munger

Davis

Simon

2017

Developmental Biology

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Lymphatic valves (LVs) are cusped luminal structures that permit the movement of lymph in only one direction and are therefore critical for proper lymphatic vessel function. Congenital valve aplasia or agenesis can, in some cases, be a direct cause of lymphatic disease. Knowledge about the molecular mechanisms operating during the development and maintenance of LVs may thus aid in the establishment of novel therapeutic approaches to treat lymphatic disorders. In this study, we examined the role of Connexin43 (Cx43), a gap junction protein expressed in lymphatic endothelial cells (LECs), during valve development. Mouse embryos with a null mutation in Cx43 (Gja1) were previously shown to completely lack mesenteric LVs at embryonic day 18. However, interpreting the phenotype of Cx43−/− mice was complicated by the fact that global deletion of Cx43 causes perinatal death due to heart defects during embryogenesis. We have now generated a mouse model (Cx43ΔLEC) with a lymphatic-specific ablation of Cx43 and show that the absence of Cx43 in LECs causes a delay (rather than a complete block) in LV initiation, an increase in immature valves with incomplete leaflet elongation, a reduction in the total number of valves, and altered lymphatic capillary patterning. The physiological consequences of these lymphatic changes were leaky valves, insufficient lymph transport and reflux, and a high incidence of lethal chylothorax. These results demonstrate that the expression of Cx43 is specifically required in LECs for normal development of LVs.

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Section: Discussionmentioning

confidence: 99%

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Munger

Davis

Simon

2017

Developmental Biology

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“…Mesenchymal stem cells (MSCs) are a population of pluripotent progenitor cells that originate from bone marrow or other tissues, such as adipose tissue and cord blood, and play a crucial role in lung cancer cell growth, metastasis 14 . Over the past decade, MSCs are increasingly being used in tissue engineering and cell-based therapies in all fields, including novel therapeutic strategy for a variety of lung diseases, in which BMMSCs are the most studied cell therapy 24 , 25 .…”

Section: Discussionmentioning

confidence: 99%

“…Human BMMSCs from a physiologic bone environment can home to orthotopically implanted primary human breast tumors 12 , and promote breast cancer metastasis when mixed with human breast carcinoma cells 13 . Thus, BMMSCs stimulate lymphangiogenesis in physiological and pathological (malignant tumor) conditions 14 .…”

Section: Introductionmentioning

confidence: 99%

Bone Marrow Derived Mesenchymal Stem Cells Involve in the Lymphangiogenesis of Lung Cancer and Jinfukang Inhibits the Involvement In Vivo

Zhou

Wang

et al. 2017

J. Cancer

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Lymphangiogenesis plays an important role in cancer metastasis. Bone marrow-derived mesenchymal stem cells (BMMSCs) migrate to the site of tumorigenesis and in turn promote the metastasis. However, whether BMMSCs involve in the lymphangiogenesis of lung cancer is unclear. Jinfukang has clinically been used for the treatment of non small cell lung cancer (NSCLC) in China. In this study, to investigate the involvement of BMMSCs in lymphangiogenesis in lung cancer, and evaluate the inhibitory effect of Jinfukang on the lymphangiogenesis, chimeric mice were prepared by transplanting bone marrow from green fluorescent protein (GFP) transgenic mice (C57BL/6-EGFP) into irradiated C57BL/6 mice. Then, the chimeric mice were injected subcutaneously with freshly prepared Lewis lung carcinoma cell suspension to make lung tumor model, and the model mice were further orally administrated with Jinfukang once per day for 3 weeks. Four weeks after the bone marrow transplantation, GFP-positive cells primarily existed in bone marrow of acceptor mice, and three more weeks after, Lewis lung carcinoma cells formed a tumor mass in chimeric mice. Observation of GFP-positive cells revealed that BMMSCs transferred into the lung tumor. Immunofluorescent analyses of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), a lymphatic endothelium marker, demonstrated a part of lymphatic endothelial cells in lung cancer were derived from BMMSCs, and those lymphatic endothelial cells contributed to the lung tumor lymphangiogenesis. Furthermore, Jinfukang treatment resulted in a significant reduction of the average weight of the tumor mass in chimeric mice, and displayed a significant lower number of LYVE-1 positive cells. The present results suggest that BMMSCs transfer to tumor, differentiate into lymphatic endothelial cells, and involve in the lymphangiogenesis in lung cancer of mice. Jinfukang inhibits the lung tumor mass via suppression of the BMMSCs transformation and lung tumor lymphangiogenesis. Our findings might provide the potential for the cancer therapies.

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“…In order to make further advances in the fields of tissue engineering and regenerative medicine as well as to address questions related to the lymphatic spread of tumour cells, a better understanding of the underlying mechanisms of lymphangiogenesis and the interactions between LEC, other cells, and in particular stem cells is needed. In contrast to the well‐characterized interactions between MSC and BEC, to the best of our knowledge, the paracrine interactions between MSC and LEC have not been studied in detail using primary human cells until now . Therefore, the aim of this study was to evaluate the in vitro interactions of LEC and MSC as a basis for further lymphangiogenesis and metastasis research.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cells promote lymphangiogenic properties of lymphatic endothelial cells

Robering

Weigand

Pfuhlmann

et al. 2018

J Cellular Molecular Medi

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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.

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Bone Marrow-Derived Mesenchymal Stem Cells Drive Lymphangiogenesis

Cited by 33 publications

References 55 publications

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Bone Marrow Derived Mesenchymal Stem Cells Involve in the Lymphangiogenesis of Lung Cancer and Jinfukang Inhibits the Involvement In Vivo

Mesenchymal stem cells promote lymphangiogenic properties of lymphatic endothelial cells

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