Document Detail


Toward a mouse model of hind limb ischemia to test therapeutic angiogenesis.
MedLine Citation:
PMID:  22836102     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
INTRODUCTION: Several clinical trials are currently evaluating stem cell therapy for patients with critical limb ischemia that have no other surgical or endovascular options for revascularization. However, these trials are conducted with different protocols, including use of different stem cell populations and different injection protocols, providing little means to compare trials and guide therapy. Accordingly, we developed a murine model of severe ischemia to allow methodic testing of relevant clinical parameters.
METHODS: High femoral artery ligation and total excision of the superficial femoral artery was performed on C57BL/6 mice. Mononuclear cells (MNCs) were isolated from the bone marrow of donor mice, characterized using fluorescence-activated cell sorting, and injected (5×10(5) to 2×10(6)) into the semimembranosus (proximal) or gastrocnemius (distal) muscle. Vascular and functional outcomes were measured using invasive Doppler imaging, laser Doppler perfusion imaging, and the Tarlov and ischemia scores. Histologic analysis included quantification of muscle fiber area and number as well as capillary density.
RESULTS: Blood flow and functional outcomes were improved in MNC-treated mice compared with controls over 28 days (flow: P<.0001; Tarlov: P=.0004; ischemia score: P=.0002). MNC-treated mice also showed greater gastrocnemius fiber area (P=.0053) and increased capillary density (P=.0004). Dose-response analysis showed increased angiogenesis and gastrocnemius fiber area but no changes in macroscopic vascular flow or functional scores. Overall functional outcomes in mice injected proximally to the ischemic area were similar to mice injected more distally, but muscle flow, capillary density, and gastrocnemius fiber area were increased (P<.05).
CONCLUSIONS: High femoral ligation with complete excision of the superficial femoral artery is a reliable model of severe hind limb ischemia in C57BL/6 mice that shows a response to MNC treatment for functional and vascular outcomes. A dose response to the injection of MNCs appears to be present, at least microscopically, suggesting that an optimal cell number for stem cell therapy exists and that preclinical testing needs to be performed to optimally guide human trials. Injection of MNCs proximal to the site of ischemia may provide different outcomes compared with distal injection and warrants additional study.
Authors:
Robert A Brenes; Caroline C Jadlowiec; Mackenzie Bear; Peter Hashim; Clinton D Protack; Xin Li; Wei Lv; Michael J Collins; Alan Dardik
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-24
Journal Detail:
Title:  Journal of vascular surgery     Volume:  56     ISSN:  1097-6809     ISO Abbreviation:  J. Vasc. Surg.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-27     Completed Date:  2013-03-11     Revised Date:  2014-05-01    
Medline Journal Info:
Nlm Unique ID:  8407742     Medline TA:  J Vasc Surg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1669-79; discussion 1679     Citation Subset:  IM    
Copyright Information:
Published by Mosby, Inc.
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MeSH Terms
Descriptor/Qualifier:
Animals
Disease Models, Animal*
Femoral Artery / surgery
Hindlimb / blood supply*
Ischemia / etiology*,  pathology,  therapy*
Male
Mice
Mice, Inbred C57BL
Muscle, Skeletal / blood supply,  pathology
Neovascularization, Physiologic / physiology*
Stem Cell Transplantation*
Grant Support
ID/Acronym/Agency:
R01 HL095498/HL/NHLBI NIH HHS; R01-HL095498-01/HL/NHLBI NIH HHS
Comments/Corrections

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