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.
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.
Thomas P
TP
Lozito
Juan M
JM
Taboas
Catherine K
CK
Kuo
Rocky S
RS
Tuan
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