Pro-elastogenic effects of bone marrow mesenchymal stem cell-derived smooth muscle cells on cultured aneurysmal smooth muscle cells.
Abdominal aortic aneurysms (AAAs) involve slow proteolysis and loss of structural matrix components (collagen and elastin), which lead to wall thinning, weakening and ultimate rupture. At this time, no established non-surgical therapy is available to slow or arrest AAA growth. Inhibiting matrix metalloproteases (MMPs; e.g. MMP2 and -9) overexpressed within AAAs is insufficient to arrest AAA growth, since resident smooth muscle cells (SMCs) are poorly elastogenic and cannot overcome elastolysis to reinstate a healthy elastic matrix. Towards overcoming this limitation, this first study sought to determine the utility of rat bone marrow mesenchymal stem cell (BM-MSC)-derived SMCs to stimulate elastin and elastic matrix synthesis and assembly by aneurysmal SMCs (EaRASMCs). BM-MSCs were successfully differentiated into cells of an SMC lineage (SMLCs). Our study indicates that BM-MSC-derived SMLCs secrete trophic factors, contained in conditioned medium (CM) from their cultures, that, when exposed to EaRASMC cultures in real time, stimulate elastin precursor and matrix deposition and crosslinking by these elastogenically deficient cells, with added benefits in terms of attenuating MMPs, specifically MMP9. The results thus lend support to a proposed cell therapy for AAAs, based on the use of BM-MSC-derived SMLCs. Although we observed no particular improvement in elastic fibre formation, no attenuation of MMP2 activity and increase in amounts of active MMP2 enzyme, we believe that this study justifies follow-up studies to improve upon these outcomes. Future studies will explore the effects of concentrated CM collected from long-term SMLC cultures on EaRASMCs and also investigate the elastogenic output of SMLCs themselves. Copyright © 2014 John Wiley & Sons, Ltd.
Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA.|Department of Biology, University of Akron, Akron, OH, USA.
Ganesh
G
Swaminathan
Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, USA.
Venkat S
VS
Gadepalli
Department of Cell Biology and Physiology, Washington University, St. Louis, MO, USA.
Ivan
I
Stoilov
Department of Cell Biology and Physiology, Washington University, St. Louis, MO, USA.
Robert P
RP
Mecham
Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, USA.
Raj R
RR
Rao
Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA.|Department of Biology, University of Akron, Akron, OH, USA.
Anand
A
Ramamurthi
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000473:pathology*; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004549:Elastin / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D019899:Paracrine Communication / Q000187:drug effects; D017207:Rats, Sprague-Dawley
D017077:Culture Media, Conditioned; D003094:Collagen; D004549:Elastin; D020778:Matrix Metalloproteinase 2
SMC differentiation; abdominal aortic aneurysm; cell therapy; elastin regeneration; elastogenesis; smooth muscle cell