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Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo.
Circulation. 2009 Jan 20; 119(2):281-9.Circ

Abstract

BACKGROUND

The importance and therapeutic value of stem cells in lymphangiogenesis are poorly understood. We evaluated the potential of human and murine mesenchymal stem cells (MSCs) to acquire a lymphatic phenotype in vitro and to enhance lymphatic regeneration in vivo.

METHODS AND RESULTS

We assessed the lymphendothelial differentiation of human and murine MSCs after induction with supernatant derived from human dermal microvascular endothelial cells, isolated lymphatic endothelial cells, and purified vascular endothelial growth factor (VEGF)-C in vitro. We used human or murine progenitor MSC lines and then characterized the lymphatic phenotype by morphology, migratory capacity, and the expression of lymphatic markers such as Prox-1, podoplanin, Lyve-1, VEGF receptor-2, and VEGF receptor-3. Using a murine lymphatic edema model, we assessed the potential of these cells to form a functional lymphatic vasculature in vivo after injection of syngeneic MSCs. Incubation with supernatant from lymphatic endothelial cells induced an endothelium-like morphology and the expression of lymphendothelial markers in both human and murine MSCs in vitro. MSCs showed migratory activity along a VEGF-C gradient, which was enhanced by VEGF-C conditioning. In vivo, the local application of MSCs resulted in a significant decrease in edema formation (-20.1%; P<0.01 versus untreated tails) after 3 weekly cell injections and restored the drainage of intradermally injected methylene blue after 7 weekly injections.

CONCLUSIONS

MSCs were capable of expressing a lymphatic phenotype when exposed to lymph-inductive media and purified VEGF-C. Migratory activity toward VEGF-C in vitro suggests homing capability in vivo. Restoration of lymphatic drainage after injection of MSCs in a lymphedema model indicates that MSCs play a role in lymphatic regeneration. The potential clinical application of MSC in wound healing and reduction of lymphatic edema warrants further research.

Authors+Show Affiliations

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. CConrad1@partners.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19118255

Citation

Conrad, Claudius, et al. "Multipotent Mesenchymal Stem Cells Acquire a Lymphendothelial Phenotype and Enhance Lymphatic Regeneration in Vivo." Circulation, vol. 119, no. 2, 2009, pp. 281-9.
Conrad C, Niess H, Huss R, et al. Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. Circulation. 2009;119(2):281-9.
Conrad, C., Niess, H., Huss, R., Huber, S., von Luettichau, I., Nelson, P. J., Ott, H. C., Jauch, K. W., & Bruns, C. J. (2009). Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. Circulation, 119(2), 281-9. https://doi.org/10.1161/CIRCULATIONAHA.108.793208
Conrad C, et al. Multipotent Mesenchymal Stem Cells Acquire a Lymphendothelial Phenotype and Enhance Lymphatic Regeneration in Vivo. Circulation. 2009 Jan 20;119(2):281-9. PubMed PMID: 19118255.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. AU - Conrad,Claudius, AU - Niess,Hanno, AU - Huss,Ralf, AU - Huber,Stephan, AU - von Luettichau,Irene, AU - Nelson,Peter J, AU - Ott,Harald C, AU - Jauch,Karl-Walter, AU - Bruns,Christiane J, Y1 - 2008/12/31/ PY - 2009/1/2/entrez PY - 2009/1/2/pubmed PY - 2009/2/14/medline SP - 281 EP - 9 JF - Circulation JO - Circulation VL - 119 IS - 2 N2 - BACKGROUND: The importance and therapeutic value of stem cells in lymphangiogenesis are poorly understood. We evaluated the potential of human and murine mesenchymal stem cells (MSCs) to acquire a lymphatic phenotype in vitro and to enhance lymphatic regeneration in vivo. METHODS AND RESULTS: We assessed the lymphendothelial differentiation of human and murine MSCs after induction with supernatant derived from human dermal microvascular endothelial cells, isolated lymphatic endothelial cells, and purified vascular endothelial growth factor (VEGF)-C in vitro. We used human or murine progenitor MSC lines and then characterized the lymphatic phenotype by morphology, migratory capacity, and the expression of lymphatic markers such as Prox-1, podoplanin, Lyve-1, VEGF receptor-2, and VEGF receptor-3. Using a murine lymphatic edema model, we assessed the potential of these cells to form a functional lymphatic vasculature in vivo after injection of syngeneic MSCs. Incubation with supernatant from lymphatic endothelial cells induced an endothelium-like morphology and the expression of lymphendothelial markers in both human and murine MSCs in vitro. MSCs showed migratory activity along a VEGF-C gradient, which was enhanced by VEGF-C conditioning. In vivo, the local application of MSCs resulted in a significant decrease in edema formation (-20.1%; P<0.01 versus untreated tails) after 3 weekly cell injections and restored the drainage of intradermally injected methylene blue after 7 weekly injections. CONCLUSIONS: MSCs were capable of expressing a lymphatic phenotype when exposed to lymph-inductive media and purified VEGF-C. Migratory activity toward VEGF-C in vitro suggests homing capability in vivo. Restoration of lymphatic drainage after injection of MSCs in a lymphedema model indicates that MSCs play a role in lymphatic regeneration. The potential clinical application of MSC in wound healing and reduction of lymphatic edema warrants further research. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/19118255/Multipotent_mesenchymal_stem_cells_acquire_a_lymphendothelial_phenotype_and_enhance_lymphatic_regeneration_in_vivo_ L2 - http://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.108.793208?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -