title: Bone marrow-derived mesenchymal stromal cells improve vascular regeneration and reduce leukocyte-endothelium activation in critical ischemic murine skin in a dose-dependent manner.
abstract: OBJECTIVE
  Stem cells participate in vascular regeneration following critical ischemia. However, their angiogenic and remodeling properties, as well as their role in ischemia-related endothelial leukocyte activation, need to be further elucidated. Herein, we investigated the effect of bone marrow-derived mesenchymal stromal cells (BM-MSCs) in a critically ischemic murine skin flap model.
  
  
  METHODS
  Groups received either 1 × 10(5), 5 × 10(5), or 1 × 10(6) BM-MSCs or cell-free conditioned medium (CM). Controls received sodium chloride. Intravital fluorescence microscopy was performed for morphological and quantitative assessment of micro-hemodynamic parameters over 12 days.
  
  
  RESULTS
  Tortuosity and diameter of conduit-arterioles were pronounced in the MSC groups (P < 0.01), whereas vasodilation was shifted to the end arteriolar level in the CM group (P < 0.01). These effects were accompanied by angiopoietin-2 expression. Functional capillary density and red blood cell velocity were enhanced in all treatment groups (P < 0.01). Although a significant reduction of rolling and sticking leukocytes was observed in the MSC groups with a reduction of diameter in postcapillary venules (P < 0.01), animals receiving CM exhibited a leukocyte-endothelium interaction similar to controls. This correlated with leukocyte common antigen expression in tissue sections (P < 0.01) and p38 mitogen-activated protein kinase expression from tissue samples. Cytokine analysis from BM-MSC culture medium revealed a 50% reduction of pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-12, tumor necrosis factor-α, interferon-γ) and chemokines (keratinocyte chemoattractant, granulocyte colony-stimulating factor) under hypoxic conditions.
  
  
  CONCLUSIONS
  We demonstrated positive effects of BM-MSCs on vascular regeneration and modulation of endothelial leukocyte adhesion in critical ischemic skin. The improvements after MSC application were dose-dependent and superior to the use of CM alone.
authors: Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland.
authors: Riccardo
authors: R
authors: Schweizer
authors: Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland.
authors: Pranitha
authors: P
authors: Kamat
authors: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors: Dennis
authors: D
authors: Schweizer
authors: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors: Cyrill
authors: C
authors: Dennler
authors: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors: Shengye
authors: S
authors: Zhang
authors: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors: Jonas T
authors: JT
authors: Schnider
authors: Center for Clinical Research, University of Zurich, Zurich, Switzerland.
authors: Souzan
authors: S
authors: Salemi
authors: Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland.
authors: Pietro
authors: P
authors: Giovanoli
authors: Center for Clinical Research, University of Zurich, Zurich, Switzerland.
authors: Daniel
authors: D
authors: Eberli
authors: Department of Clinical Research, University of Bern, Bern, Switzerland; Department of Ophthalmology, University of Bern, Inselspital, Bern, Switzerland.
authors: Volker
authors: V
authors: Enzmann
authors: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors: Dominique
authors: D
authors: Erni
authors: Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland; Center for Clinical Research, University of Zurich, Zurich, Switzerland. Electronic address: jan.plock@usz.ch.
authors: Jan A
authors: JA
authors: Plock
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D002196:Capillaries / Q000473:pathology / Q000502:physiology*; D002450:Cell Communication; D002478:Cells, Cultured; D004727:Endothelium / Q000378:metabolism / Q000502:physiology*; D005260:Female; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology; D007962:Leukocytes / Q000378:metabolism / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration / Q000502:physiology*; D012867:Skin / Q000098:blood supply* / Q000276:immunology
keywords: angiogenesis; arteriogenesis; conditioned medium; immunomodulation; mesenchymal stromal cells; paracrine function; vascular regeneration