Paracrine effects of mesenchymal stem cells enhance vascular regeneration in ischemic murine skin

Schlosser, Stefan; Dennler, Cyrill; Schweizer, Riccardo; Eberli, Daniel; Stein, Jens V; Enzmann, Volker; Giovanoli, Pietro; Erni, Dominique; Plock, Jan A (2012). Paracrine effects of mesenchymal stem cells enhance vascular regeneration in ischemic murine skin. Microvascular research, 83(3), pp. 267-75. Oxford: Elsevier 10.1016/j.mvr.2012.02.011

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New theories on the regeneration of ischemic vasculature have emerged indicating a pivotal role of adult stem cells. The aim of this study was to investigate homing and hemodynamic effects of circulating bone marrow-derived mesenchymal stem cells (MSCs) in a critically ischemic murine skin flap model. Bone marrow-derived mesenchymal stem cells (Lin(-)CD105(+)) were harvested from GFP(+)-donor mice and transferred to wildtype C57BL/6 mice. Animals receiving GFP(+)-fibroblasts served as a control group. Laser scanning confocal microscopy and intravital fluorescence microscopy were used for morphological analysis, monitoring and quantitative assessment of the stem cell homing and microhemodynamics over two weeks. Immunohistochemical staining was performed for GFP, eNOS, iNOS, VEGF. Tissue viability was analyzed by TUNEL-assay. We were able to visualize perivascular homing of MSCs in vivo. After 4 days, MSCs aligned along the vascular wall without undergoing endothelial or smooth muscle cell differentiation during the observation period. The gradual increase in arterial vascular resistance observed in the control group was abolished after MSC administration (P<0.01). At capillary level, a strong angiogenic response was found from day 7 onwards. Functional capillary density was raised in the MSC group to 197% compared to 132% in the control group (P<0.01). Paracrine expression of VEGF and iNOS, but not eNOS could be shown in the MSC group but not in the controls. In conclusion, we demonstrated that circulating bone marrow-derived MSCs home to perivascular sites in critically ischemic tissue, exhibits paracrine function and augment microhemodynamics. These effects were mediated through arteriogenesis and angiogenesis, which contributed to vascular regeneration.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ophthalmology

UniBE Contributor:

Stein, Jens Volker and Enzmann, Volker

ISSN:

0026-2862

Publisher:

Elsevier

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:23

Last Modified:

17 Mar 2015 21:03

Publisher DOI:

10.1016/j.mvr.2012.02.011

PubMed ID:

22391452

Web of Science ID:

000303690800002

URI:

https://boris.unibe.ch/id/eprint/8129 (FactScience: 213614)

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