Mesenchymal stem cell modification of endothelial matrix regulates their vascular differentiation.
Mesenchymal stem cells (MSCs) respond to a variety of differentiation signal provided by their local environments. A large portion of these signals originate from the extracellular matrix (ECM). At the same time, MSCs secrete various matrix-altering agents, including proteases, that alter ECM-encoded differentiation signals. Here we investigated the interactions between MSC and ECM produced by endothelial cells (EC-matrix), focusing not only on the differentiation signals provided by EC-matrix, but also on MSC-alteration of these signals and the resultant affects on MSC differentiation. MSCs were cultured on EC-matrix modified in one of three distinct ways. First, MSCs cultured on native EC-matrix underwent endothelial cell (EC) differentiation early during the culture period and smooth muscle cell (SMC) differentiation at later time points. Second, MSCs cultured on crosslinked EC-matrix, which is resistant to MSC modification, differentiated towards an EC lineage only. Third, MSCs cultured on EC-matrix pre-modified by MSCs underwent SMC-differentiation only. These MSC-induced matrix alterations were found to deplete the factors responsible for EC-differentiation, yet activate the SMC-differentiation factors. In conclusion, our results demonstrate that the EC-matrix contains factors that support MSC differentiation into both ECs and SMCs, and that these factors are modified by MSC-secreted agents. By analyzing the framework by which EC-matrix regulates differentiation in MSCs, we have uncovered evidence of a feedback system in which MSCs are able to alter the very matrix signals acting upon them.
Lozito
Thomas P
TP
Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
Taboas
Juan M
JM
Kuo
Catherine K
CK
Tuan
Rocky S
RS
D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology* / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000166:cytology*; D005109:Extracellular Matrix / Q000502:physiology*; D025461:Feedback, Physiological; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology